Joseph F. Goldberg, MD

This article has been adapted from an article originally published in Current Psychiatry (http://currentpsychiatry.com):Current Psychiatry. 2015;14(10):29-32,35-40,e6.

When a known depressed patient newly develops signs of mania or hypomania, a cascade of diagnostic and therapeutic questions ensues: Does the event “automatically” signify the presence of bipolar disorder (BD), or could manic symptoms be secondary to another underlying medical problem, a prescribed antidepressant or non-psychotropic medication, or illicit substances?

Even more questions confront the clinician: If mania symptoms are nothing more than an adverse drug reaction, will they go away by stopping the presumed offending agent? Or do symptoms always indicate the unmasking of a bipolar diathesis? Should anti-manic medication  be prescribed immediately? If so, which one(s) and for how long? How extensive a medical or neurologic workup is indicated?

And how do you differentiate ambiguous hypomania symptoms (irritability, insomnia, agitation) from other phenomena, such as akathisia, anxiety, and overstimulation?

In this article, we present an overview of how to approach and answer these key questions, so that you can identify, comprehend, and manage manic symptoms that arise in the course of your patient’s treatment for depression (Box).

Does Disease Exist on a Unipolar-Bipolar Continuum.

There has been a resurgence of interest in Kraepelin’s original notion of mania and depression as falling along a continuum, rather than being distinct categories of pathology. True bipolar mania has its own identifiable epidemiology, familiality, and treatment, but symptomatic shades of gray often pose a formidable diagnostic and therapeutic challenge.

For example, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) relaxed its definition of “mixed” episodes of BD to include subsyndromal mania features in unipolar depression. When a patient with unipolar depression develops a full, unequivocal manic episode, there usually isn’t much ambiguity or confusion about initial management: assure a safe environment, stop any antidepressants, rule out drug- or medically induced causes, and begin an acute anti-manic medication.

Next steps can, sometimes, be murkier:

• Formulate a definitive, overarching diagnosis
• Provide psycho-education
• Forecast return to work or school
• Discuss prognosis and likelihood of relapse
• Address necessary lifestyle modifications (eg, sleep hygiene, elimination of alcohol and illicit drug use)
• Determine whether indefinite maintenance pharmacotherapy is indicated—and, if so, with which medication(s).

A Diagnostic Formulation Isn’t Always Black and White

Ms. J, age 56, a medically healthy woman, has a 10-year history of depression and anxiety that has been treated effectively for most of that time with venlafaxine,
225 mg/d. The mother of 4 grown children, Ms. J has worked steadily for > 20 years as a flight attendant for an international airline.

Today, Ms. J is brought by ambulance from work to the emergency department in a paranoid and agitated state. The admission follows her having e-blasted airline corporate executives with a voluminous manifesto that she worked on around the clock the preceding week, in which she explained her bold ideas to revolutionize the airline industry, under her leadership.

Ms. J’s family history is unremarkable for psychiatric illness.

How Does One Approach A Case Such As Ms. J's?

Stark examples of classical mania, as depicted in this case vignette, are easy to recognize but not necessarily straightforward, nosologically. Consider the following not-so-straightforward elements of Ms. J’s case:

• A first-lifetime episode of mania or hypomania is rare after age 50
• Ms. J took a serotonin-norepinephrine reuptake inhibitor (SNRI) for many years without evidence of mood destabilization
• Years of repetitive chronobiological stress (including probable frequent time zone changes with likely sleep disruption) apparently did not trigger mood destabilization
• None of Ms. J’s 4 pregnancies led to postpartum mood episodes
• At least on the surface, there are no obvious features that point to likely causes of a secondary mania (eg, drug-induced, toxic, metabolic, or medical)
• Ms. J has no known family history of BD or any other mood disorder.

Approaching a case such as Ms. J’s must involve a systematic strategy that can best be broken into 2 segments: (1) a period of acute initial assessment and treatment and (2) later efforts focused on broader diagnostic evaluation and longer-term relapse prevention.

Initial Assessment and Treatment

Immediate assessment and management hinges on initial triage and forming a working diagnostic impression. Although full-blown mania usually is obvious (sometimes even without a formal interview), be alert to patients who might minimize or altogether disavow mania symptoms—often because of denial of illness, misidentification of symptoms, or impaired insight about changes in thinking, mood, or behavior.

Because florid mania, by definition, impairs psychosocial functioning, the context of an initial presentation often holds diagnostic relevance. Manic patients who display disruptive behaviors often are brought to treatment by a third party, whereas a less severely ill patient might be more inclined to seek treatment for herself (himself) when psychosis is absent and insight is less compromised or when the patient feels she (he) might be depressed.

It is not uncommon for a manic patient to report “depression” as the chief complaint or to omit elements related to psychomotor acceleration (such as racing thoughts or psychomotor agitation) in the description of symptoms. An accurate diagnosis often requires clinical probing and clarification of symptoms (eg, differentiating simple insomnia with consequent next-day fatigue from loss of the need for sleep with intact or even enhanced next-day energy) or discriminating racing thoughts from anxious ruminations that might be more intrusive than rapid.

Presentations of frank mania also can come to light as a consequence of symptoms, rather than as symptoms per se (eg, conflict in relationships, problems at work, financial reversals).

Particularly in patients who do not have a history of mania, avoid the temptation to begin or modify existing pharmacotherapy until you have performed a basic initial evaluation. Immediate considerations for initial assessment and management include the following:

Provide containment. Ensure a safe setting, level of care, and frequency of monitoring. Evaluate suicide risk (particularly when mixed features are present), and risk of withdrawal from any psychoactive substances.

Engage significant others. Close family members can provide essential history, particularly when a patient’s insight about her illness and need for treatment are impaired. Family members and significant others also often play important roles in helping to restrict access to finances, fostering medication adherence, preventing access to weapons in the home, and sharing information with providers about substance use or high-risk behavior.

Systematically assess for DSM-5 symptoms of mania and depression. DSM-5 modified criteria for mania/hypomania to necessitate increased energy, in addition to change in mood, to make a syndromal diagnosis. Useful during a clinical interview is the popular mnemonic DIGFAST to aid recognition of core mania symptoms:

• Distractibility
• Indiscretion/impulsivity
• Grandiosity
• Flight of ideas
• Activity increase
• Sleep deficit
• Talkativeness.

These symptoms should represent a departure from normal baseline characteristics; it often is helpful to ask a significant other or collateral historian how the
present symptoms differ from the patient’s usual state.

Assess for unstable medical conditions or toxicity states. When evaluating an acute change in mental status, toxicology screening is relatively standard and the absence of illicit substances should seldom, if ever, be taken for granted—especially because occult substance use can lead to identification of false-positive BD “cases.”¹

Stop any antidepressant. During a manic episode, continuing antidepressant medication serves no purpose other than to contribute to or exacerbate mania symptoms. Nonetheless, observational studies demonstrate that approximately 15% of syndromally manic patients continue to receive an antidepressant, often when a clinician perceives more severe depression during mania, multiple prior depressive episodes,current anxiety, or rapid cycling.²

Importantly, antidepressants have been shown to harm, rather than alleviate, presentations that involve a mixed state, and have no demonstrated value in preventing post-manic depression.³ Mere elimination of an antidepressant might ease symptoms during a manic or mixed episode.⁴

In some cases, it might be advisable to taper, not abruptly stop, a short halflife serotonergic antidepressant, even in the setting of mania, to minimize the potential for aggravating autonomic dysregulation that can result from antidepressant discontinuation effects.

Begin anti-manic pharmacotherapy. Initiation of an anti-manic mood stabilizer, such as lithium and divalproex, has been standard in the treatment of acute mania.

In the 1990s, protocols for oral loading of divalproex (20 to 30 mg/kg/d) gained popularity for achieving more rapid symptom improvement than might occur with lithium. In the current era, atypical antipsychotics have all but replaced mood stabilizers as an initial intervention to contain mania symptoms quickly (and with less risk than firstgeneration antipsychotics for acute adverse motor effects from so-called rapid neuroleptization).

Because atypical antipsychotics often rapidly subdue mania, psychosis, and agitation, regardless of the underlying process, many practitioners might feel more comfortable initiating them than a mood stabilizer when the diagnosis is ambiguous or provisional, although their longer-term efficacy and safety, relative to traditional mood stabilizers, remains contested. Considerations for choosing from among feasible anti-manic pharmacotherapies are summarized in Table 1.

Normalize the sleep-wake cycle. Chronobiological and circadian variables, such as irregular sleep patterns, are thought to contribute to the pathophysiology of affective switch in BD. Behavioral and pharmacotherapeutic efforts to impose a normal sleep-wake schedule are considered fundamental to stabilizing acute mania.

Facilitate next steps after acute stabilization. For inpatients, this might involve step-down to a partial hospitalization or intensive outpatient program, alongside taking steps to ensure continued treatment adherence and minimize relapse.

What Medical and Neurologic Workup is Appropriate?

Not every first lifetime presentation of mania requires extensive medical and neurologic workup, particularly among patients who have a history of depression and those whose presentation neatly fits the demographic and clinical profile of newly emergent BD. Basic assessment should determine whether any new medication has been started that could plausibly contribute to abnormal mental status (Table 2).

Nevertheless, evaluation of almost all first presentations of mania should include:

• Urine toxicology screen
• Complete blood count
• Comprehensive metabolic panel
• Thyroid-stimulating hormone assay
• Serum vitamin B12 level assay
• Serum folic acid level assay
• Rapid plasma reagin test.

Clinical features that usually lead a clinician to pursue a more detailed medical and neurologic evaluation of first-episode mania include:

• Onset age > 40
• Absence of a family history of mood disorder
• Symptoms arising during a major medical illness
• Multiple medications
• Suspicion of a degenerative or hereditary neurologic disorder
• Altered state of consciousness
• Signs of cortical or diffuse subcortical dysfunction (eg, cognitive deficits, motor deficits, tremor)
• Abnormal vital signs.

Depending on the presentation, additional testing might include:

• Tests of HIV antibody, immune autoantibodies, and Lyme disease antibody
• Heavy metal screening (when suggested by environmental exposure)
• Lumbar puncture (eg, in a setting of manic delirium or suspected central nervous system infection or paraneoplastic syndrome)
• Neuroimaging (note: MRI provides better visualization than CT of white matter pathology and small vessel cerebrovascular disease) electroencephalography.

Making An Overarching Diagnosis: Is Mania Always Bipolar Disorder?

Mania is considered a manifestation of BD when symptoms cannot be attributed to another psychiatric condition, another underlying medical or neurologic condition, or a toxic-metabolic state (Tables 3 and 4). Classification of mania that occurs soon after antidepressant exposure in patients without a known history of BD continues to be the subject of debate, varying in its conceptualization across editions of DSM.

The National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, observed a fairly low (approximately 10%) incidence of switch from depression to mania when an antidepressant is added to a mood stabilizer; the study authors concluded that much of what is presumed to be antidepressant-induced mania might simply be the natural course of illness.¹⁰

Notably, several reports suggest that antidepressants might pose a greater risk of mood destabilization in people with BD I than with either BD II or other suspected variants on the bipolar spectrum.

DSM-5 advises that a diagnosis of substance-induced mood disorder appropriately describes symptoms that spontaneously dissipate once an antidepressant has been discontinued, whereas a diagnosis of BD can be made when manic or hypomanic symptoms persist at a syndromal level after an antidepressant has been stopped and its physiological effects are no longer present. With respect to time course, the International Society of Bipolar Disorders proposes that, beyond 12 to 16 weeks after an antidepressant has been started or the dosage has been increased, it is unlikely that new-onset mania/hypomania can reasonably be attributed to “triggering” by an antidepressant (although antidepressants should be stopped when symptoms of mania emerge).¹¹ Several clinical features have been linked in the literature with an increased susceptibility to BD after an initial depressive episode, including:

• Early (pre-adolescent) age at onset of first mood disorder episode⁶
• Family history of BD, highly recurrent depression, or psychosis^12,13
• Psychosis when depressed.^7,14

A number of other characteristics of depressive illness—including seasonal depression, atypical depressive features, suicidality, irritability, anxiety or substance use comorbidity, postpartum mood episodes, and brief recurrent depressive episodes—have been described in the literature as potential correlates of a bipolar diathesis; none have proved to be robust or pathognomonic of a BD diagnosis, as opposed to a unipolar diagnosis.

Data from the NIMH Collaborative Depression Study suggest that recurrent mania/hypomania after an antidepressant-associated polarity switch is greater when a family history of BD is present; other clinical variables might hold less predictive value.¹⁵ In addition, although some practitioners consider a history of nonresponse to trials of multiple antidepressants suggestive of an underlying bipolar process, polarity is only one of many variables that must be considered in the differential diagnosis of antidepressantresistant depression. Likewise, molecular genetic studies do not support a link between antidepressant nonresponse and the likelihood of a diagnosis of BD.¹⁶

Indefinite Pharmacotherapy for Bipolar Disorder

An important but nagging issue when diagnosing BD after a first manic (or hypomanic) episode is the implied need for indefinite pharmacotherapy to sustain remission and prevent relapse and recurrence.

The likelihood of subsequent depression or mania/hypomania remains high after an index manic/hypomanic episode, particularly for 6 to 8 months after recovery.^8,17 Natural history data suggest that, during the year that follows a first lifetime mania, approximately 40% of patients experience a second manic episode.⁸ A second lifetime mania might be especially likely in patients whose index episode involved mood-congruent psychosis, low premorbid work functioning, and an initial manic episode, as opposed to a mixed episode or early age at onset.^8,17

In the absence of randomized, placebo-controlled studies of maintenance pharmacotherapy after a first lifetime manic episode, clinical judgment often drives decisions about the duration of continuing pharmacotherapy after initial symptoms resolve. The Texas Medication Algorithm Project for BD advises that:

General practice at this time is lifetime medication following 2 manic episodes, or 1 episode if it was a severe episode and/or significant family history of bipolar or major depressive disorder is present. For a first episode of bipolar mania with no family history of bipolar or major depressive disorders, medication tapering and discontinuation may be considered after the continuation period is completed (usually 6 months in remission), depending on the severity of the first episode, surrounding factors, and prodromal history.¹⁸

Similarly, in the most recent (2004) Expert Consensus Guideline Series for the Treatment of Bipolar Disorder, 84% of practitioner−respondents favored indefinite mood stabilizer therapy after a second lifetime manic episode.¹⁹ No recommendation was made about the duration of maintenance pharmacotherapy after a first lifetime manic/hypomanic episode.

Avoid or Reintroduce an Antidepressant if Depression Recurs After a First Mania?

Controversies surrounding antidepressant use in BD are extensive; detailed discussion is beyond the scope of this review (Goldberg and Ghaemi provided a broader discussion of risks and benefits of antidepressants in BD).²⁰ Although the main clinical concern regarding antidepressant use was, at one time, the potential to induce mania or accelerate the frequency of recurrent episodes, more recent, empirical studies suggest that the greater risk of using antidepressants for BD is lack of efficacy.^10,21

If a careful longitudinal history and clinical evaluation reveal that an initial manic episode heralds the onset of BD, decisions about whether to avoid an antidepressant (as opposed to using other, more evidence-based interventions for bipolar depression) depend on a number of variables, including establishing whether the index episode was manic or hypomanic; ruling out current subthreshold mixed features; and clarifying how recently mania developed. Decisions about future antidepressant use (or avoidance) might be less clear if an index manic/hypomanic episode was brief and self-limited once the antidepressant was stopped.

Although some experts eschew antidepressant monotherapy after such occurrences, there is no body of literature to inform decisions about the safety or efficacy of undertaking a future antidepressant trial in such patients. That said, reasonable judgment probably includes several considerations:

• Re-exposure to the same antidepressant that was associated with an induction of mania is likely riskier than choosing a different antidepressant; in general, purely serotonergic antidepressants or bupropion are considered to pose less risk of mood destabilization than is seen with an SNRI or tricyclic antidepressant.
• After a manic episode, a subsequent antidepressant trial generally shouldn’t be attempted without concurrent anti-manic medication.
• Introducing any antidepressant is probably ill-advised in the recent (~2 months) aftermath of acute manic/hypomanic symptoms.²²
• Patients and their significant other should be apprised of the risk of emerging symptoms of mania or hypomania, or mixed features, and should be familiar with key target symptoms to watch for. Prospective mood charting can be helpful.
• Patients should be monitored closely both for an exacerbation of depression and recurrence of mania/hypomania symptoms.
• Any antidepressant should be discontinued promptly at the first sign of psychomotor acceleration or the emergence of mixed features, as defined by DSM-5

Psychoeducation and Forecasting

Functional recovery from a manic episode can lag behind symptomatic recovery. Subsyndromal symptoms often persist after a full episode subsides.

Mania often is followed by a depressive episode, and questions inevitably arise about how to prevent and treat these episodes. Because the median duration of a manic episode is approximately 13 weeks, it is crucial for patients and their immediate family to recognize that recovery might be gradual, and that it will likely take time before she (he) can resume full-time responsibilities at work or school or in the home.²³

Today, a patient who is hospitalized for severe acute mania (as Ms. J was, in the case vignette) seldom remains an inpatient long enough to achieve remission of symptoms; sometimes, she (he) might continue to manifest significant symptoms, even though decisions about the “medical necessity” of ongoing inpatient care tend to be governed mainly by issues of safety and imminent danger. (See this article at CurrentPsychiatry.com for a Table of considerations when making the transition from the acute phase to the continuation phase of treatment.^20,24,25)

To minimize risk of relapse, psycho-education should include discussion of:

• Psychiatrically deleterious effects of alcohol and illicit drug use
• Suicide risk, including what to do in an emergency
• Protecting a regular sleep schedule and avoiding sleep deprivation
• The potential for poor medication adherence and management of side effects
• The role of adjunctive psychotherapy and effective stress management
• Familiarity with symptoms that serve as warning signs, and how to monitor their onset.

Click here to read the digital edition.

This article has been adapted from an article originally published in Current Psychiatry (http://currentpsychiatry.com):Current Psychiatry. 2015;14(10):29-32,35-40,e6.

When a known depressed patient newly develops signs of mania or hypomania, a cascade of diagnostic and therapeutic questions ensues: Does the event “automatically” signify the presence of bipolar disorder (BD), or could manic symptoms be secondary to another underlying medical problem, a prescribed antidepressant or non-psychotropic medication, or illicit substances?

Even more questions confront the clinician: If mania symptoms are nothing more than an adverse drug reaction, will they go away by stopping the presumed offending agent? Or do symptoms always indicate the unmasking of a bipolar diathesis? Should anti-manic medication  be prescribed immediately? If so, which one(s) and for how long? How extensive a medical or neurologic workup is indicated?

And how do you differentiate ambiguous hypomania symptoms (irritability, insomnia, agitation) from other phenomena, such as akathisia, anxiety, and overstimulation?

In this article, we present an overview of how to approach and answer these key questions, so that you can identify, comprehend, and manage manic symptoms that arise in the course of your patient’s treatment for depression (Box).

Does Disease Exist on a Unipolar-Bipolar Continuum.

There has been a resurgence of interest in Kraepelin’s original notion of mania and depression as falling along a continuum, rather than being distinct categories of pathology. True bipolar mania has its own identifiable epidemiology, familiality, and treatment, but symptomatic shades of gray often pose a formidable diagnostic and therapeutic challenge.

For example, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) relaxed its definition of “mixed” episodes of BD to include subsyndromal mania features in unipolar depression. When a patient with unipolar depression develops a full, unequivocal manic episode, there usually isn’t much ambiguity or confusion about initial management: assure a safe environment, stop any antidepressants, rule out drug- or medically induced causes, and begin an acute anti-manic medication.

Next steps can, sometimes, be murkier:

• Formulate a definitive, overarching diagnosis
• Provide psycho-education
• Forecast return to work or school
• Discuss prognosis and likelihood of relapse
• Address necessary lifestyle modifications (eg, sleep hygiene, elimination of alcohol and illicit drug use)
• Determine whether indefinite maintenance pharmacotherapy is indicated—and, if so, with which medication(s).

A Diagnostic Formulation Isn’t Always Black and White

Ms. J, age 56, a medically healthy woman, has a 10-year history of depression and anxiety that has been treated effectively for most of that time with venlafaxine,
225 mg/d. The mother of 4 grown children, Ms. J has worked steadily for > 20 years as a flight attendant for an international airline.

Today, Ms. J is brought by ambulance from work to the emergency department in a paranoid and agitated state. The admission follows her having e-blasted airline corporate executives with a voluminous manifesto that she worked on around the clock the preceding week, in which she explained her bold ideas to revolutionize the airline industry, under her leadership.

Ms. J’s family history is unremarkable for psychiatric illness.

How Does One Approach A Case Such As Ms. J's?

Stark examples of classical mania, as depicted in this case vignette, are easy to recognize but not necessarily straightforward, nosologically. Consider the following not-so-straightforward elements of Ms. J’s case:

• A first-lifetime episode of mania or hypomania is rare after age 50
• Ms. J took a serotonin-norepinephrine reuptake inhibitor (SNRI) for many years without evidence of mood destabilization
• Years of repetitive chronobiological stress (including probable frequent time zone changes with likely sleep disruption) apparently did not trigger mood destabilization
• None of Ms. J’s 4 pregnancies led to postpartum mood episodes
• At least on the surface, there are no obvious features that point to likely causes of a secondary mania (eg, drug-induced, toxic, metabolic, or medical)
• Ms. J has no known family history of BD or any other mood disorder.

Approaching a case such as Ms. J’s must involve a systematic strategy that can best be broken into 2 segments: (1) a period of acute initial assessment and treatment and (2) later efforts focused on broader diagnostic evaluation and longer-term relapse prevention.

Initial Assessment and Treatment

Immediate assessment and management hinges on initial triage and forming a working diagnostic impression. Although full-blown mania usually is obvious (sometimes even without a formal interview), be alert to patients who might minimize or altogether disavow mania symptoms—often because of denial of illness, misidentification of symptoms, or impaired insight about changes in thinking, mood, or behavior.

Because florid mania, by definition, impairs psychosocial functioning, the context of an initial presentation often holds diagnostic relevance. Manic patients who display disruptive behaviors often are brought to treatment by a third party, whereas a less severely ill patient might be more inclined to seek treatment for herself (himself) when psychosis is absent and insight is less compromised or when the patient feels she (he) might be depressed.

It is not uncommon for a manic patient to report “depression” as the chief complaint or to omit elements related to psychomotor acceleration (such as racing thoughts or psychomotor agitation) in the description of symptoms. An accurate diagnosis often requires clinical probing and clarification of symptoms (eg, differentiating simple insomnia with consequent next-day fatigue from loss of the need for sleep with intact or even enhanced next-day energy) or discriminating racing thoughts from anxious ruminations that might be more intrusive than rapid.

Presentations of frank mania also can come to light as a consequence of symptoms, rather than as symptoms per se (eg, conflict in relationships, problems at work, financial reversals).

Particularly in patients who do not have a history of mania, avoid the temptation to begin or modify existing pharmacotherapy until you have performed a basic initial evaluation. Immediate considerations for initial assessment and management include the following:

Provide containment. Ensure a safe setting, level of care, and frequency of monitoring. Evaluate suicide risk (particularly when mixed features are present), and risk of withdrawal from any psychoactive substances.

Engage significant others. Close family members can provide essential history, particularly when a patient’s insight about her illness and need for treatment are impaired. Family members and significant others also often play important roles in helping to restrict access to finances, fostering medication adherence, preventing access to weapons in the home, and sharing information with providers about substance use or high-risk behavior.

Systematically assess for DSM-5 symptoms of mania and depression. DSM-5 modified criteria for mania/hypomania to necessitate increased energy, in addition to change in mood, to make a syndromal diagnosis. Useful during a clinical interview is the popular mnemonic DIGFAST to aid recognition of core mania symptoms:

• Distractibility
• Indiscretion/impulsivity
• Grandiosity
• Flight of ideas
• Activity increase
• Sleep deficit
• Talkativeness.

These symptoms should represent a departure from normal baseline characteristics; it often is helpful to ask a significant other or collateral historian how the
present symptoms differ from the patient’s usual state.

Assess for unstable medical conditions or toxicity states. When evaluating an acute change in mental status, toxicology screening is relatively standard and the absence of illicit substances should seldom, if ever, be taken for granted—especially because occult substance use can lead to identification of false-positive BD “cases.”¹

Stop any antidepressant. During a manic episode, continuing antidepressant medication serves no purpose other than to contribute to or exacerbate mania symptoms. Nonetheless, observational studies demonstrate that approximately 15% of syndromally manic patients continue to receive an antidepressant, often when a clinician perceives more severe depression during mania, multiple prior depressive episodes,current anxiety, or rapid cycling.²

Importantly, antidepressants have been shown to harm, rather than alleviate, presentations that involve a mixed state, and have no demonstrated value in preventing post-manic depression.³ Mere elimination of an antidepressant might ease symptoms during a manic or mixed episode.⁴

In some cases, it might be advisable to taper, not abruptly stop, a short halflife serotonergic antidepressant, even in the setting of mania, to minimize the potential for aggravating autonomic dysregulation that can result from antidepressant discontinuation effects.

Begin anti-manic pharmacotherapy. Initiation of an anti-manic mood stabilizer, such as lithium and divalproex, has been standard in the treatment of acute mania.

In the 1990s, protocols for oral loading of divalproex (20 to 30 mg/kg/d) gained popularity for achieving more rapid symptom improvement than might occur with lithium. In the current era, atypical antipsychotics have all but replaced mood stabilizers as an initial intervention to contain mania symptoms quickly (and with less risk than firstgeneration antipsychotics for acute adverse motor effects from so-called rapid neuroleptization).

Because atypical antipsychotics often rapidly subdue mania, psychosis, and agitation, regardless of the underlying process, many practitioners might feel more comfortable initiating them than a mood stabilizer when the diagnosis is ambiguous or provisional, although their longer-term efficacy and safety, relative to traditional mood stabilizers, remains contested. Considerations for choosing from among feasible anti-manic pharmacotherapies are summarized in Table 1.

Normalize the sleep-wake cycle. Chronobiological and circadian variables, such as irregular sleep patterns, are thought to contribute to the pathophysiology of affective switch in BD. Behavioral and pharmacotherapeutic efforts to impose a normal sleep-wake schedule are considered fundamental to stabilizing acute mania.

Facilitate next steps after acute stabilization. For inpatients, this might involve step-down to a partial hospitalization or intensive outpatient program, alongside taking steps to ensure continued treatment adherence and minimize relapse.

What Medical and Neurologic Workup is Appropriate?

Not every first lifetime presentation of mania requires extensive medical and neurologic workup, particularly among patients who have a history of depression and those whose presentation neatly fits the demographic and clinical profile of newly emergent BD. Basic assessment should determine whether any new medication has been started that could plausibly contribute to abnormal mental status (Table 2).

Nevertheless, evaluation of almost all first presentations of mania should include:

• Urine toxicology screen
• Complete blood count
• Comprehensive metabolic panel
• Thyroid-stimulating hormone assay
• Serum vitamin B12 level assay
• Serum folic acid level assay
• Rapid plasma reagin test.

Clinical features that usually lead a clinician to pursue a more detailed medical and neurologic evaluation of first-episode mania include:

• Onset age > 40
• Absence of a family history of mood disorder
• Symptoms arising during a major medical illness
• Multiple medications
• Suspicion of a degenerative or hereditary neurologic disorder
• Altered state of consciousness
• Signs of cortical or diffuse subcortical dysfunction (eg, cognitive deficits, motor deficits, tremor)
• Abnormal vital signs.

Depending on the presentation, additional testing might include:

• Tests of HIV antibody, immune autoantibodies, and Lyme disease antibody
• Heavy metal screening (when suggested by environmental exposure)
• Lumbar puncture (eg, in a setting of manic delirium or suspected central nervous system infection or paraneoplastic syndrome)
• Neuroimaging (note: MRI provides better visualization than CT of white matter pathology and small vessel cerebrovascular disease) electroencephalography.

Making An Overarching Diagnosis: Is Mania Always Bipolar Disorder?

Mania is considered a manifestation of BD when symptoms cannot be attributed to another psychiatric condition, another underlying medical or neurologic condition, or a toxic-metabolic state (Tables 3 and 4). Classification of mania that occurs soon after antidepressant exposure in patients without a known history of BD continues to be the subject of debate, varying in its conceptualization across editions of DSM.

The National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, observed a fairly low (approximately 10%) incidence of switch from depression to mania when an antidepressant is added to a mood stabilizer; the study authors concluded that much of what is presumed to be antidepressant-induced mania might simply be the natural course of illness.¹⁰

Notably, several reports suggest that antidepressants might pose a greater risk of mood destabilization in people with BD I than with either BD II or other suspected variants on the bipolar spectrum.

DSM-5 advises that a diagnosis of substance-induced mood disorder appropriately describes symptoms that spontaneously dissipate once an antidepressant has been discontinued, whereas a diagnosis of BD can be made when manic or hypomanic symptoms persist at a syndromal level after an antidepressant has been stopped and its physiological effects are no longer present. With respect to time course, the International Society of Bipolar Disorders proposes that, beyond 12 to 16 weeks after an antidepressant has been started or the dosage has been increased, it is unlikely that new-onset mania/hypomania can reasonably be attributed to “triggering” by an antidepressant (although antidepressants should be stopped when symptoms of mania emerge).¹¹ Several clinical features have been linked in the literature with an increased susceptibility to BD after an initial depressive episode, including:

• Early (pre-adolescent) age at onset of first mood disorder episode⁶
• Family history of BD, highly recurrent depression, or psychosis^12,13
• Psychosis when depressed.^7,14

A number of other characteristics of depressive illness—including seasonal depression, atypical depressive features, suicidality, irritability, anxiety or substance use comorbidity, postpartum mood episodes, and brief recurrent depressive episodes—have been described in the literature as potential correlates of a bipolar diathesis; none have proved to be robust or pathognomonic of a BD diagnosis, as opposed to a unipolar diagnosis.

Data from the NIMH Collaborative Depression Study suggest that recurrent mania/hypomania after an antidepressant-associated polarity switch is greater when a family history of BD is present; other clinical variables might hold less predictive value.¹⁵ In addition, although some practitioners consider a history of nonresponse to trials of multiple antidepressants suggestive of an underlying bipolar process, polarity is only one of many variables that must be considered in the differential diagnosis of antidepressantresistant depression. Likewise, molecular genetic studies do not support a link between antidepressant nonresponse and the likelihood of a diagnosis of BD.¹⁶

Indefinite Pharmacotherapy for Bipolar Disorder

An important but nagging issue when diagnosing BD after a first manic (or hypomanic) episode is the implied need for indefinite pharmacotherapy to sustain remission and prevent relapse and recurrence.

The likelihood of subsequent depression or mania/hypomania remains high after an index manic/hypomanic episode, particularly for 6 to 8 months after recovery.^8,17 Natural history data suggest that, during the year that follows a first lifetime mania, approximately 40% of patients experience a second manic episode.⁸ A second lifetime mania might be especially likely in patients whose index episode involved mood-congruent psychosis, low premorbid work functioning, and an initial manic episode, as opposed to a mixed episode or early age at onset.^8,17

In the absence of randomized, placebo-controlled studies of maintenance pharmacotherapy after a first lifetime manic episode, clinical judgment often drives decisions about the duration of continuing pharmacotherapy after initial symptoms resolve. The Texas Medication Algorithm Project for BD advises that:

General practice at this time is lifetime medication following 2 manic episodes, or 1 episode if it was a severe episode and/or significant family history of bipolar or major depressive disorder is present. For a first episode of bipolar mania with no family history of bipolar or major depressive disorders, medication tapering and discontinuation may be considered after the continuation period is completed (usually 6 months in remission), depending on the severity of the first episode, surrounding factors, and prodromal history.¹⁸

Similarly, in the most recent (2004) Expert Consensus Guideline Series for the Treatment of Bipolar Disorder, 84% of practitioner−respondents favored indefinite mood stabilizer therapy after a second lifetime manic episode.¹⁹ No recommendation was made about the duration of maintenance pharmacotherapy after a first lifetime manic/hypomanic episode.

Avoid or Reintroduce an Antidepressant if Depression Recurs After a First Mania?

Controversies surrounding antidepressant use in BD are extensive; detailed discussion is beyond the scope of this review (Goldberg and Ghaemi provided a broader discussion of risks and benefits of antidepressants in BD).²⁰ Although the main clinical concern regarding antidepressant use was, at one time, the potential to induce mania or accelerate the frequency of recurrent episodes, more recent, empirical studies suggest that the greater risk of using antidepressants for BD is lack of efficacy.^10,21

If a careful longitudinal history and clinical evaluation reveal that an initial manic episode heralds the onset of BD, decisions about whether to avoid an antidepressant (as opposed to using other, more evidence-based interventions for bipolar depression) depend on a number of variables, including establishing whether the index episode was manic or hypomanic; ruling out current subthreshold mixed features; and clarifying how recently mania developed. Decisions about future antidepressant use (or avoidance) might be less clear if an index manic/hypomanic episode was brief and self-limited once the antidepressant was stopped.

Although some experts eschew antidepressant monotherapy after such occurrences, there is no body of literature to inform decisions about the safety or efficacy of undertaking a future antidepressant trial in such patients. That said, reasonable judgment probably includes several considerations:

• Re-exposure to the same antidepressant that was associated with an induction of mania is likely riskier than choosing a different antidepressant; in general, purely serotonergic antidepressants or bupropion are considered to pose less risk of mood destabilization than is seen with an SNRI or tricyclic antidepressant.
• After a manic episode, a subsequent antidepressant trial generally shouldn’t be attempted without concurrent anti-manic medication.
• Introducing any antidepressant is probably ill-advised in the recent (~2 months) aftermath of acute manic/hypomanic symptoms.²²
• Patients and their significant other should be apprised of the risk of emerging symptoms of mania or hypomania, or mixed features, and should be familiar with key target symptoms to watch for. Prospective mood charting can be helpful.
• Patients should be monitored closely both for an exacerbation of depression and recurrence of mania/hypomania symptoms.
• Any antidepressant should be discontinued promptly at the first sign of psychomotor acceleration or the emergence of mixed features, as defined by DSM-5

Psychoeducation and Forecasting

Functional recovery from a manic episode can lag behind symptomatic recovery. Subsyndromal symptoms often persist after a full episode subsides.

Mania often is followed by a depressive episode, and questions inevitably arise about how to prevent and treat these episodes. Because the median duration of a manic episode is approximately 13 weeks, it is crucial for patients and their immediate family to recognize that recovery might be gradual, and that it will likely take time before she (he) can resume full-time responsibilities at work or school or in the home.²³

Today, a patient who is hospitalized for severe acute mania (as Ms. J was, in the case vignette) seldom remains an inpatient long enough to achieve remission of symptoms; sometimes, she (he) might continue to manifest significant symptoms, even though decisions about the “medical necessity” of ongoing inpatient care tend to be governed mainly by issues of safety and imminent danger. (See this article at CurrentPsychiatry.com for a Table of considerations when making the transition from the acute phase to the continuation phase of treatment.^20,24,25)

To minimize risk of relapse, psycho-education should include discussion of:

• Psychiatrically deleterious effects of alcohol and illicit drug use
• Suicide risk, including what to do in an emergency
• Protecting a regular sleep schedule and avoiding sleep deprivation
• The potential for poor medication adherence and management of side effects
• The role of adjunctive psychotherapy and effective stress management
• Familiarity with symptoms that serve as warning signs, and how to monitor their onset.

Click here to read the digital edition.

This article has been adapted from an article originally published in Current Psychiatry (http://currentpsychiatry.com):Current Psychiatry. 2015;14(10):29-32,35-40,e6.

When a known depressed patient newly develops signs of mania or hypomania, a cascade of diagnostic and therapeutic questions ensues: Does the event “automatically” signify the presence of bipolar disorder (BD), or could manic symptoms be secondary to another underlying medical problem, a prescribed antidepressant or non-psychotropic medication, or illicit substances?

Even more questions confront the clinician: If mania symptoms are nothing more than an adverse drug reaction, will they go away by stopping the presumed offending agent? Or do symptoms always indicate the unmasking of a bipolar diathesis? Should anti-manic medication  be prescribed immediately? If so, which one(s) and for how long? How extensive a medical or neurologic workup is indicated?

And how do you differentiate ambiguous hypomania symptoms (irritability, insomnia, agitation) from other phenomena, such as akathisia, anxiety, and overstimulation?

In this article, we present an overview of how to approach and answer these key questions, so that you can identify, comprehend, and manage manic symptoms that arise in the course of your patient’s treatment for depression (Box).

Does Disease Exist on a Unipolar-Bipolar Continuum.

There has been a resurgence of interest in Kraepelin’s original notion of mania and depression as falling along a continuum, rather than being distinct categories of pathology. True bipolar mania has its own identifiable epidemiology, familiality, and treatment, but symptomatic shades of gray often pose a formidable diagnostic and therapeutic challenge.

For example, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) relaxed its definition of “mixed” episodes of BD to include subsyndromal mania features in unipolar depression. When a patient with unipolar depression develops a full, unequivocal manic episode, there usually isn’t much ambiguity or confusion about initial management: assure a safe environment, stop any antidepressants, rule out drug- or medically induced causes, and begin an acute anti-manic medication.

Next steps can, sometimes, be murkier:

• Formulate a definitive, overarching diagnosis
• Provide psycho-education
• Forecast return to work or school
• Discuss prognosis and likelihood of relapse
• Address necessary lifestyle modifications (eg, sleep hygiene, elimination of alcohol and illicit drug use)
• Determine whether indefinite maintenance pharmacotherapy is indicated—and, if so, with which medication(s).

A Diagnostic Formulation Isn’t Always Black and White

Ms. J, age 56, a medically healthy woman, has a 10-year history of depression and anxiety that has been treated effectively for most of that time with venlafaxine,
225 mg/d. The mother of 4 grown children, Ms. J has worked steadily for > 20 years as a flight attendant for an international airline.

Today, Ms. J is brought by ambulance from work to the emergency department in a paranoid and agitated state. The admission follows her having e-blasted airline corporate executives with a voluminous manifesto that she worked on around the clock the preceding week, in which she explained her bold ideas to revolutionize the airline industry, under her leadership.

Ms. J’s family history is unremarkable for psychiatric illness.

How Does One Approach A Case Such As Ms. J's?

Stark examples of classical mania, as depicted in this case vignette, are easy to recognize but not necessarily straightforward, nosologically. Consider the following not-so-straightforward elements of Ms. J’s case:

• A first-lifetime episode of mania or hypomania is rare after age 50
• Ms. J took a serotonin-norepinephrine reuptake inhibitor (SNRI) for many years without evidence of mood destabilization
• Years of repetitive chronobiological stress (including probable frequent time zone changes with likely sleep disruption) apparently did not trigger mood destabilization
• None of Ms. J’s 4 pregnancies led to postpartum mood episodes
• At least on the surface, there are no obvious features that point to likely causes of a secondary mania (eg, drug-induced, toxic, metabolic, or medical)
• Ms. J has no known family history of BD or any other mood disorder.

Approaching a case such as Ms. J’s must involve a systematic strategy that can best be broken into 2 segments: (1) a period of acute initial assessment and treatment and (2) later efforts focused on broader diagnostic evaluation and longer-term relapse prevention.

Initial Assessment and Treatment

Immediate assessment and management hinges on initial triage and forming a working diagnostic impression. Although full-blown mania usually is obvious (sometimes even without a formal interview), be alert to patients who might minimize or altogether disavow mania symptoms—often because of denial of illness, misidentification of symptoms, or impaired insight about changes in thinking, mood, or behavior.

Because florid mania, by definition, impairs psychosocial functioning, the context of an initial presentation often holds diagnostic relevance. Manic patients who display disruptive behaviors often are brought to treatment by a third party, whereas a less severely ill patient might be more inclined to seek treatment for herself (himself) when psychosis is absent and insight is less compromised or when the patient feels she (he) might be depressed.

It is not uncommon for a manic patient to report “depression” as the chief complaint or to omit elements related to psychomotor acceleration (such as racing thoughts or psychomotor agitation) in the description of symptoms. An accurate diagnosis often requires clinical probing and clarification of symptoms (eg, differentiating simple insomnia with consequent next-day fatigue from loss of the need for sleep with intact or even enhanced next-day energy) or discriminating racing thoughts from anxious ruminations that might be more intrusive than rapid.

Presentations of frank mania also can come to light as a consequence of symptoms, rather than as symptoms per se (eg, conflict in relationships, problems at work, financial reversals).

Particularly in patients who do not have a history of mania, avoid the temptation to begin or modify existing pharmacotherapy until you have performed a basic initial evaluation. Immediate considerations for initial assessment and management include the following:

Provide containment. Ensure a safe setting, level of care, and frequency of monitoring. Evaluate suicide risk (particularly when mixed features are present), and risk of withdrawal from any psychoactive substances.

Engage significant others. Close family members can provide essential history, particularly when a patient’s insight about her illness and need for treatment are impaired. Family members and significant others also often play important roles in helping to restrict access to finances, fostering medication adherence, preventing access to weapons in the home, and sharing information with providers about substance use or high-risk behavior.

Systematically assess for DSM-5 symptoms of mania and depression. DSM-5 modified criteria for mania/hypomania to necessitate increased energy, in addition to change in mood, to make a syndromal diagnosis. Useful during a clinical interview is the popular mnemonic DIGFAST to aid recognition of core mania symptoms:

• Distractibility
• Indiscretion/impulsivity
• Grandiosity
• Flight of ideas
• Activity increase
• Sleep deficit
• Talkativeness.

These symptoms should represent a departure from normal baseline characteristics; it often is helpful to ask a significant other or collateral historian how the
present symptoms differ from the patient’s usual state.

Assess for unstable medical conditions or toxicity states. When evaluating an acute change in mental status, toxicology screening is relatively standard and the absence of illicit substances should seldom, if ever, be taken for granted—especially because occult substance use can lead to identification of false-positive BD “cases.”¹

Stop any antidepressant. During a manic episode, continuing antidepressant medication serves no purpose other than to contribute to or exacerbate mania symptoms. Nonetheless, observational studies demonstrate that approximately 15% of syndromally manic patients continue to receive an antidepressant, often when a clinician perceives more severe depression during mania, multiple prior depressive episodes,current anxiety, or rapid cycling.²

Importantly, antidepressants have been shown to harm, rather than alleviate, presentations that involve a mixed state, and have no demonstrated value in preventing post-manic depression.³ Mere elimination of an antidepressant might ease symptoms during a manic or mixed episode.⁴

In some cases, it might be advisable to taper, not abruptly stop, a short halflife serotonergic antidepressant, even in the setting of mania, to minimize the potential for aggravating autonomic dysregulation that can result from antidepressant discontinuation effects.

Begin anti-manic pharmacotherapy. Initiation of an anti-manic mood stabilizer, such as lithium and divalproex, has been standard in the treatment of acute mania.

In the 1990s, protocols for oral loading of divalproex (20 to 30 mg/kg/d) gained popularity for achieving more rapid symptom improvement than might occur with lithium. In the current era, atypical antipsychotics have all but replaced mood stabilizers as an initial intervention to contain mania symptoms quickly (and with less risk than firstgeneration antipsychotics for acute adverse motor effects from so-called rapid neuroleptization).

Because atypical antipsychotics often rapidly subdue mania, psychosis, and agitation, regardless of the underlying process, many practitioners might feel more comfortable initiating them than a mood stabilizer when the diagnosis is ambiguous or provisional, although their longer-term efficacy and safety, relative to traditional mood stabilizers, remains contested. Considerations for choosing from among feasible anti-manic pharmacotherapies are summarized in Table 1.

Normalize the sleep-wake cycle. Chronobiological and circadian variables, such as irregular sleep patterns, are thought to contribute to the pathophysiology of affective switch in BD. Behavioral and pharmacotherapeutic efforts to impose a normal sleep-wake schedule are considered fundamental to stabilizing acute mania.

Facilitate next steps after acute stabilization. For inpatients, this might involve step-down to a partial hospitalization or intensive outpatient program, alongside taking steps to ensure continued treatment adherence and minimize relapse.

What Medical and Neurologic Workup is Appropriate?

Not every first lifetime presentation of mania requires extensive medical and neurologic workup, particularly among patients who have a history of depression and those whose presentation neatly fits the demographic and clinical profile of newly emergent BD. Basic assessment should determine whether any new medication has been started that could plausibly contribute to abnormal mental status (Table 2).

Nevertheless, evaluation of almost all first presentations of mania should include:

• Urine toxicology screen
• Complete blood count
• Comprehensive metabolic panel
• Thyroid-stimulating hormone assay
• Serum vitamin B12 level assay
• Serum folic acid level assay
• Rapid plasma reagin test.

Clinical features that usually lead a clinician to pursue a more detailed medical and neurologic evaluation of first-episode mania include:

• Onset age > 40
• Absence of a family history of mood disorder
• Symptoms arising during a major medical illness
• Multiple medications
• Suspicion of a degenerative or hereditary neurologic disorder
• Altered state of consciousness
• Signs of cortical or diffuse subcortical dysfunction (eg, cognitive deficits, motor deficits, tremor)
• Abnormal vital signs.

Depending on the presentation, additional testing might include:

• Tests of HIV antibody, immune autoantibodies, and Lyme disease antibody
• Heavy metal screening (when suggested by environmental exposure)
• Lumbar puncture (eg, in a setting of manic delirium or suspected central nervous system infection or paraneoplastic syndrome)
• Neuroimaging (note: MRI provides better visualization than CT of white matter pathology and small vessel cerebrovascular disease) electroencephalography.

Making An Overarching Diagnosis: Is Mania Always Bipolar Disorder?

Mania is considered a manifestation of BD when symptoms cannot be attributed to another psychiatric condition, another underlying medical or neurologic condition, or a toxic-metabolic state (Tables 3 and 4). Classification of mania that occurs soon after antidepressant exposure in patients without a known history of BD continues to be the subject of debate, varying in its conceptualization across editions of DSM.

The National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, or STEP-BD, observed a fairly low (approximately 10%) incidence of switch from depression to mania when an antidepressant is added to a mood stabilizer; the study authors concluded that much of what is presumed to be antidepressant-induced mania might simply be the natural course of illness.¹⁰

Notably, several reports suggest that antidepressants might pose a greater risk of mood destabilization in people with BD I than with either BD II or other suspected variants on the bipolar spectrum.

DSM-5 advises that a diagnosis of substance-induced mood disorder appropriately describes symptoms that spontaneously dissipate once an antidepressant has been discontinued, whereas a diagnosis of BD can be made when manic or hypomanic symptoms persist at a syndromal level after an antidepressant has been stopped and its physiological effects are no longer present. With respect to time course, the International Society of Bipolar Disorders proposes that, beyond 12 to 16 weeks after an antidepressant has been started or the dosage has been increased, it is unlikely that new-onset mania/hypomania can reasonably be attributed to “triggering” by an antidepressant (although antidepressants should be stopped when symptoms of mania emerge).¹¹ Several clinical features have been linked in the literature with an increased susceptibility to BD after an initial depressive episode, including:

• Early (pre-adolescent) age at onset of first mood disorder episode⁶
• Family history of BD, highly recurrent depression, or psychosis^12,13
• Psychosis when depressed.^7,14

A number of other characteristics of depressive illness—including seasonal depression, atypical depressive features, suicidality, irritability, anxiety or substance use comorbidity, postpartum mood episodes, and brief recurrent depressive episodes—have been described in the literature as potential correlates of a bipolar diathesis; none have proved to be robust or pathognomonic of a BD diagnosis, as opposed to a unipolar diagnosis.

Data from the NIMH Collaborative Depression Study suggest that recurrent mania/hypomania after an antidepressant-associated polarity switch is greater when a family history of BD is present; other clinical variables might hold less predictive value.¹⁵ In addition, although some practitioners consider a history of nonresponse to trials of multiple antidepressants suggestive of an underlying bipolar process, polarity is only one of many variables that must be considered in the differential diagnosis of antidepressantresistant depression. Likewise, molecular genetic studies do not support a link between antidepressant nonresponse and the likelihood of a diagnosis of BD.¹⁶

Indefinite Pharmacotherapy for Bipolar Disorder

An important but nagging issue when diagnosing BD after a first manic (or hypomanic) episode is the implied need for indefinite pharmacotherapy to sustain remission and prevent relapse and recurrence.

The likelihood of subsequent depression or mania/hypomania remains high after an index manic/hypomanic episode, particularly for 6 to 8 months after recovery.^8,17 Natural history data suggest that, during the year that follows a first lifetime mania, approximately 40% of patients experience a second manic episode.⁸ A second lifetime mania might be especially likely in patients whose index episode involved mood-congruent psychosis, low premorbid work functioning, and an initial manic episode, as opposed to a mixed episode or early age at onset.^8,17

In the absence of randomized, placebo-controlled studies of maintenance pharmacotherapy after a first lifetime manic episode, clinical judgment often drives decisions about the duration of continuing pharmacotherapy after initial symptoms resolve. The Texas Medication Algorithm Project for BD advises that:

General practice at this time is lifetime medication following 2 manic episodes, or 1 episode if it was a severe episode and/or significant family history of bipolar or major depressive disorder is present. For a first episode of bipolar mania with no family history of bipolar or major depressive disorders, medication tapering and discontinuation may be considered after the continuation period is completed (usually 6 months in remission), depending on the severity of the first episode, surrounding factors, and prodromal history.¹⁸

Similarly, in the most recent (2004) Expert Consensus Guideline Series for the Treatment of Bipolar Disorder, 84% of practitioner−respondents favored indefinite mood stabilizer therapy after a second lifetime manic episode.¹⁹ No recommendation was made about the duration of maintenance pharmacotherapy after a first lifetime manic/hypomanic episode.

Avoid or Reintroduce an Antidepressant if Depression Recurs After a First Mania?

Controversies surrounding antidepressant use in BD are extensive; detailed discussion is beyond the scope of this review (Goldberg and Ghaemi provided a broader discussion of risks and benefits of antidepressants in BD).²⁰ Although the main clinical concern regarding antidepressant use was, at one time, the potential to induce mania or accelerate the frequency of recurrent episodes, more recent, empirical studies suggest that the greater risk of using antidepressants for BD is lack of efficacy.^10,21

If a careful longitudinal history and clinical evaluation reveal that an initial manic episode heralds the onset of BD, decisions about whether to avoid an antidepressant (as opposed to using other, more evidence-based interventions for bipolar depression) depend on a number of variables, including establishing whether the index episode was manic or hypomanic; ruling out current subthreshold mixed features; and clarifying how recently mania developed. Decisions about future antidepressant use (or avoidance) might be less clear if an index manic/hypomanic episode was brief and self-limited once the antidepressant was stopped.

Although some experts eschew antidepressant monotherapy after such occurrences, there is no body of literature to inform decisions about the safety or efficacy of undertaking a future antidepressant trial in such patients. That said, reasonable judgment probably includes several considerations:

• Re-exposure to the same antidepressant that was associated with an induction of mania is likely riskier than choosing a different antidepressant; in general, purely serotonergic antidepressants or bupropion are considered to pose less risk of mood destabilization than is seen with an SNRI or tricyclic antidepressant.
• After a manic episode, a subsequent antidepressant trial generally shouldn’t be attempted without concurrent anti-manic medication.
• Introducing any antidepressant is probably ill-advised in the recent (~2 months) aftermath of acute manic/hypomanic symptoms.²²
• Patients and their significant other should be apprised of the risk of emerging symptoms of mania or hypomania, or mixed features, and should be familiar with key target symptoms to watch for. Prospective mood charting can be helpful.
• Patients should be monitored closely both for an exacerbation of depression and recurrence of mania/hypomania symptoms.
• Any antidepressant should be discontinued promptly at the first sign of psychomotor acceleration or the emergence of mixed features, as defined by DSM-5

Psychoeducation and Forecasting

Functional recovery from a manic episode can lag behind symptomatic recovery. Subsyndromal symptoms often persist after a full episode subsides.

Mania often is followed by a depressive episode, and questions inevitably arise about how to prevent and treat these episodes. Because the median duration of a manic episode is approximately 13 weeks, it is crucial for patients and their immediate family to recognize that recovery might be gradual, and that it will likely take time before she (he) can resume full-time responsibilities at work or school or in the home.²³

Today, a patient who is hospitalized for severe acute mania (as Ms. J was, in the case vignette) seldom remains an inpatient long enough to achieve remission of symptoms; sometimes, she (he) might continue to manifest significant symptoms, even though decisions about the “medical necessity” of ongoing inpatient care tend to be governed mainly by issues of safety and imminent danger. (See this article at CurrentPsychiatry.com for a Table of considerations when making the transition from the acute phase to the continuation phase of treatment.^20,24,25)

To minimize risk of relapse, psycho-education should include discussion of:

• Psychiatrically deleterious effects of alcohol and illicit drug use
• Suicide risk, including what to do in an emergency
• Protecting a regular sleep schedule and avoiding sleep deprivation
• The potential for poor medication adherence and management of side effects
• The role of adjunctive psychotherapy and effective stress management
• Familiarity with symptoms that serve as warning signs, and how to monitor their onset.

Click here to read the digital edition.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression—sad, empty, or irritable mood accompanied by somatic or cognitive changes—is not a homoge­neous condition. Recognizing subtypes of depressive illness can guide treatment and relieve your patient’s suf­fering. In this 2-part article [April and May 2014 issues], I summarize information about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular sub­groups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonre­sponse or partial response, often hinges on clinical subtyping.

The second part of this article examines “situational,” treat­ment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disor­der; premenstrual dysphoric disorder; and seasonal affective disorder. Treatments for these subtypes for which there is evi­dence, or a clinical rationale, are given in the Table.

‘Situational depression’
In recent decades, the phenomenon of nonsyndromal depres­sion after a life stress has undergone many name changes but little conceptional revision: “situational,” “reactive,” and “neurotic” labels for depression that were used before DSM-III became “adjustment disorders” in DSM-IV-TR and then “stress response syndromes” in DSM-5. These names all connote presentations of depressed mood after an environmental stressor, with­out either the full constellation of symptoms that define major depression or the chronicity of dysthymic disorder.

Paucity of guidance. There has been little research to identify vulnerability variables for adjustment disorders in the aftermath of particular stressors. Similarly, extensive data are lacking on 1) the likely progression of such disorders to a syndromal form of depression or 2) protective factors against developing clinically significant depres­sion after a life stress. The extent to which adjustment disorders lie on a continuum with major mood disorders is not well-established, although subthreshold levels of depression can predispose to major depres­sion or suicidal behaviors.¹

Models of behavioral sensitization posit that stressful life events more often precede first or early episodes of depression than sub­sequent recurrences.² At the same time, non-melancholic depressions that are preceded by “situational stresses” tend to recur in similar fashion.³

Medical therapy of value? Psychotherapy without medication—apart from occa­sional sedative−hypnotic drugs as needed for insomnia, anxiety, or distress—is con­sidered the standard of care for treating an adjustment disorder. No drug has demon­strated superiority to placebo for alleviating symptoms of an adjustment disorder, but some clinicians nonetheless sometimes feel compelled to “up-code” the diagnosis of an adjustment disorder to the status of a major affective disorder, even when syndromal cri­teria for major depressive disorder (MDD) or dysthymia are absent.

Treatment-resistant depression
Disease staging models for depression and other psychiatric disorders^a make note that, elsewhere in medicine, distinct clinical entities often are identified based on their responsivity to treatment (eg, classifying infections as antibiotic-sensitive or -resis­tant). Within the study and management of mood disorders, “treatment resistance” sometimes is a catch-all description of situ­ations in which past treatment 1) yielded no improvement or partial improvement or 2) was marked by intolerance. Poor out­comes due to past medication intolerance or an aborted trial often are commingled with cases of true lack of improvement after an adequate treatment trial.

^aSee “Staging psychiatric disorders: A clinico-biologic model,” Current Psychiatry, May 2013, at CurrentPsychiatry.com.

It is useful, therefore, to define terminology precisely when describing “treatment-resistant depression” and “treatment-refractory depres­sion.” True past nonresponse to appropriate treatment often carries prognostic importance and bears on future treatment decisions.

Few interventions are FDA approved for treatment-resistant depression (Table).

Neuromodulation techniques are attract­ing interest in this area, although repetitive transcranial magnetic stimulation appears inferior to electroconvulsive therapy (ECT) for this indication.⁴

Melancholic depression
Melancholia involves the cardinal symptoms of anhedonia and lack of mood reactivity, alongside such features as distinct quality of mood, diurnal variation, excessive guilt, and severe weight loss. It most closely approxi­mates pre-DSM-III “endogenous depres­sion” and can involve 1) greater genetic loading⁵ and 2) structural and functional abnormalities in frontostriatal pathways.^6,7

Melancholic features do not necessarily recur across successive episodes⁸ but carry an increased risk of psychosis⁹ and high-lethality suicidal behavior.¹⁰ Melancholia implies necessity for pharmacotherapy or ECT rather than psychosocial treatment alone; some researchers have suggested that tricyclic antidepressants (TCAs) might yield better results than selective serotonin reup­take inhibitors (SSRIs).¹¹

Agitated depression
The Research Diagnostic Criteria (a forerun­ner in the 1970s to DSM-III) described agi­tated depression, but the disorder was not included in any DSM editions—although it is a “clinical modification” for MDD in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Agitated depression refers to a major depressive episode involving motor or psy­chic agitation, intense inner tension, and rac­ing or “crowded” thoughts. Some experts believe that it represents a variant of psy­chotic depression or a bipolar mixed state, but the construct does not specify that criteria for a full manic or hypomanic episode exist.

Recovery from agitated depression tends to be slower than in non-agitated depression. Treatment usually entails an antidepressant plus an antipsychotic, although some believe that antidepressants can exacerbate, not alle­viate, symptoms and, instead, favor antipsy­chotics, mood stabilizers, or ECT.¹²

Anxious depression
Anxiety symptoms or syndromes occur in at least one-half of outpatients who have major depression, and might account for a substan­tial percentage of nonresponse to first-line antidepressant therapies.¹³ The construct of a mixed anxiety−depressive disorder is, in fact, well-represented in the literature, particu­larly in primary care medicine, but its poor inter-rater reliability in DSM-5 field trials led to its exclusion there as a formal diagnosis.¹⁴

Serotonergic antidepressants remain the mainstay of treatment for depression with anxiety, although (contrary to popular percep­tion) bupropion exerts an anxiolytic effect that is comparable to the effect of SSRIs.¹⁵ Notably, high somatic anxiety during depression might predict a poor outcome from ECT.¹⁶

Atypical depression
Often closely linked with early onset and chronicity, the construct of atypical depres­sion has been defined in the literature by the symptom constellation of:

• mood reactiveness to environmental circumstances (unlike melancholia)
• heightened interpersonal sensitivity
• hypersomnia
• hyperphagia
• profound fatigue or a sense of physical heaviness.

Some authorities regard atypical fea­tures as being especially common in bipolar depression, or in depression among people who have borderline personality disorder.

Particular interest in this construct grew from studies that suggested that atypical depression is more responsive to a monoamine oxidase inhibitor (MAOI) than to a TCA, but also that SSRIs are not clearly superior to MAOIs.¹⁷ Response to ECT might also be bet­ter in atypical than in typical depression.¹⁸

Depression with a substance use disorder
Although not a distinct diagnostic entity, depression with a coexisting substance use disorder poses special challenges with regard to the source of symptom emergence (that is, when does depression lead to drug or alcohol use to “self medicate,” and when does drug use cause depression?) and treat­ment. Debate continues about whether 1) medicines that treat depression are effec­tive and worthwhile in the setting of active substance use or 2) aggressive treatment of substance misuse is a prerequisite for sub­sequent pharmacotherapy for depression that is “uncontaminated” by the psychotoxic effects of concurrent substances of abuse.

Meta-analysis of controlled trials of antidepressants for patients who have MDD or a dysthymic disorder plus a comorbid alcohol use disorder found that antidepressants were, overall, superior to placebo unless a patient is actively drink­ing.¹⁹ Of the various classes of antidepres­sants, TCAs and nefazodone were found to be superior to placebo but, surprisingly, SSRIs were not. Another meta-analysis of adjunctive antidepressant outcomes for opiate-dependent, depressed patients who are receiving methadone maintenance therapy found no difference between anti­depressants and placebo in their effect on depression symptom outcomes.²⁰

Premenstrual dysphoric disorder
A new category in DSM-5, premenstrual dysphoric disorder (PMDD) represents a variant of premenstrual syndrome that arises during the luteal phase and ends with menstruation. Symptoms include several of those identified with MDD (without duration criteria), as well as mood swings, panic attacks, and physi­cal complaints.

SSRIs—but not bupropion²¹ or TCAs²²— and, sometimes, low-estrogen oral contra­ceptives are mainstays of treatment; so is cognitive-behavioral therapy, as well as life­style modifications (eg, exercise and changes to diet). Phototherapy has not shown robust efficacy for PMDD.²³

Secondary depression
In DSM-5, depressive episodes that arise secondary to a general medical condition (eg, hypothyroidism and other endocrinopa­thies, cerebrovascular accidents, malignan­cies) or iatrogenically from medications (eg, corticosteroids, some anticonvulsants, interinter­feron) are viewed as distinct from MDD in regard to risk of recurrence, genetic under­pinnings, and possible neurodegenerative pathophysiology.^b Unlike MDD, patient-specific risk factors are poorly defined for anticipating that a secondary depression is more or less likely to develop in the context of an exogenous substance or medical illness.

^bFor further discussion, see “Is a medical illness causing your patient’s depression? Current Psychiatry, August 2009, at CurrentPsychiatry.com.

Treating secondary depression involves addressing the underlying condition and might include antidepressant medication.

Seasonal affective disorder
DSM-5 identifies “with seasonal pattern” as a specifier for recurrent major depression. Phototherapy remains a standard treatment, although a Cochrane Review identified comparable outcomes with fluoxetine, but inconclusive data for other, newer antide­pressants.²⁴ Small open trials have suggested that MAOIs and TCAs can be efficacious.

Note: Phototherapy lacks demonstrated efficacy in non-seasonal forms of depression.²⁵

What does the future hold for classifying depressive disorders?
Recent initiatives have attempted to classify depression less by traditional clinical signs and more by focusing on possible underly­ing neurobiological substrates.^c In the future, subtyping of mood disorders might focus on such constructs as:

• positive and negative valence systems and attentional domains
• treatment-responsivity relative to genotypic variants (for example, the sero­tonin transporter gene locus [SLC6A4] or prediction of L-methylfolate-responsive depression based on the genotype of the methylenetetrahydrofolate reductase [MTHFR] polymorphism)
• disrupted neural plasticity in brain cir­cuits believed to regulate emotion.

^cAn example is the Research Domain Criteria [RDoC],www. nimh.nih.gov/research-priorities/rdoc/index.shtml.

Until robust biomarkers for depression are identified and validated, however, such advances in nosology remain experi­mental and speculative.


BOTTOM LINE
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a substance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder, among other classifications. Clinical characteristics vary across subtypes—as do corresponding preferred treatments, which should be tailored to the needs of your patients.


Editor’s note: The first part of Dr. Goldberg’s review of depression subtypes—focusing on major and minor depression, chronicity, polar­ity, severity, and psychosis—appeared in the April 2014 issue.


Related Resources
• Kosinski EC, Rothschild AJ. Monoamine oxidase inhibitors: Forgotten treatment for depression. Current Psychiatry. 2012;11(12):20-26.
• Rodgers S, Grosse Holtforth M, Müller M, et al. Symptom-based subtypes of depression and their psychosocial cor­relates: a person-centered approach focusing on the influ­ence of sex. J Affect Disord. 2014;156:92-103.

Drug Brand Names
Aripiprazole • Abilify               Mirtazapine • Remeron
Bupropion • Wellbutrin            Nefazodone • Serzone
Fluoxetine • Prozac                 Olanzapine/fluoxetine • Symbyax
Ketamine • Ketalar                 Pramipexole • Mirapex
L-Methylfolate • Deplin           Quetiapine • Seroquel
Lamotrigine • Lamictal            Riluzole • Rilutek
Lithium • Eskalith, Lithobid      Vortioxetine • Brintellix
Methadone • Dolophine

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion Pharmaceuticals, Takeda-Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Depression carries a wide differential diagnosis. Practitioners sometimes think polarity is the fundamental distinction when they conceptualize depression as a clinical entity; in fact, many nosologic frameworks have been described for defining and subtyping clinically meaningful forms of depression, and each waxed and waned in popularity.

Kraepelin, writing in the early 20th century, linked manic-depres­sive illness with “the greater part of the morbid states termed mel­ancholia,”¹ but many features other than polarity remain important components of depression, and those features often carry implications for how individual patients respond to treatment.

In this 2-part article [April and May 2014 issues], I summarize in­formation about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular subgroups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonresponse or partial response, often hinges on clinical subtyping.

The first part of this article examines major depressive disorder (MDD), minor depression, chronic depression, depression in bipolar disorder, depression that is severe or mild, and psychotic depression. Treatments for these subtypes for which there is evidence, or a clinical rationale, are given in the Table.

The subtypes of depression that I’ll discuss in the second part of the article are listed on page 47.

Major and minor depression
MDD has been the focus of most drug tri­als seeking FDA approval. As a syndrome, MDD is defined by a constellation of fea­tures that are related not only to mood but also to sleep, energy, cognition, motiva­tion, and motor behavior, persisting for ≥2 weeks.

DSM-5 has imposed few changes to the basic definition of MDD:
   • bereavement (the aftermath of death of a loved one), formerly an exclusion cri­terion, no longer precludes making a diag­nosis of MDD when syndromal criteria are otherwise fulfilled
   • “with anxious distress” is a new course specifier that designates promi­nent anxiety features (feeling worried, restless, tense, or keyed up; fearful of losing control or something terrible happening)
   • “with mixed features” is a new course specifier pertinent when ≥3 mania or hy­pomania symptoms coexist (that is, might be a subsyndromal mania or hypomania) with a depressive syndrome; the mixed features specifier can be applied to de­pressed patients whether or not they have ever had a manic or hypomanic episode, but MDD—rather than bipolar disorder— remains the overarching diagnosis, unless criteria have ever been met for a full mania or hypomania.

More than 2 dozen medications are FDA-approved to treat MDD. Evidence-based psychotherapies (eg, cognitive-behavioral therapy [CBT] and interpersonal therapy), as adjuncts to pharmacotherapy, further improve outcomes, but with only modest additional effect.²

Minor depression. Depressive states that involve 2 to 4 associated symptoms last­ing ≥2 weeks but <2 years are sometimes described as minor depression, captured within DSM-5 as “depression not else­where defined.” The terminology of so-called “minor depression” generally is shunned, in part because it might wrongly connote low severity and therefore dis­courage treatment—even though it con­fers more than a 5-fold increase in risk of MDD.3 

Chronicity
DSM-IV-TR identified long-standing de­pression by 2 constructs:
   • chronic major depression (an episode of MDD lasting ≥2 years in adults, ≥1 year in children and adolescents)
   • dysthymic disorder (2 to 4 depressive symptoms for ≥2 years in adults and ≥1 year in children and adolescents), affecting 3% to 6% of adults and carrying a 2-fold increased risk of MDD, eventually.⁴

Depression that begins as dysthymic disorder and blossoms into syndromal MDD is described as “double depres­sion”—although it is not recognized as a unique condition in any edition of the DSM. Subsequent incomplete recovery may revert to dysthymic disorder. DSM-5 has subsumed chronic major depression and dysthymia under the unified heading of persistent depressive disorder.

There are no FDA-approved drugs for treating dysthymia. A meta-analysis of 9 controlled trials of off-label use of antide­pressants to treat dysthymia revealed an overall response rate of 52.4%, compared with 29.9% for placebo.⁵ Notably, although the active drug response rate in these stud­ies is comparable to what seen in MDD, the placebo response rate was approxi­mately 10% lower than what was seen in major depression.

Positive therapeutic findings (typically, treatment for 6 to 12 weeks) have been reported in so-called “pure” dysthymic disorder with sertraline, fluoxetine, imip­ramine, ritanserin, moclobemide (not ap­proved for use in the United States), and phenelzine; the results of additional, posi­tive placebo-controlled studies support the utility of duloxetine⁶ and paroxetine.⁷ Randomized trials have reported negative findings for desipramine,⁸ fluoxetine,⁹ and escitalopram¹⁰ escitalopram¹⁰—although the sample size in these latter studies might have been too small to detect a drug-placebo difference.

In dysthymic and minor-depressive middle-age and older adult men who have a low serum level of testosterone, hormone replacement was shown to be superior to placebo in several randomized trials.¹¹ Studies of adjunctive atypical antipsy­chotics for dysthymic disorder are scarce; a Cochrane review identified controlled data only with amisulpride (not approved for use in the United States), which yielded a modest therapeutic effect.¹²

Polarity
In recent years, depression in bipolar dis­order (BD) has been contrasted with uni­polar MDD based on a difference in:
   • duration (briefer in BD)
   • severity (worse in BD)
   • risk of suicide (higher)
   • comorbidity (more extensive)
   • family history (often present for BD and highly recurrent depression)
   • treatment outcome (generally less favorable).

DSM-5 has at least somewhat blurred the distinctions in polarity by way of the new construct of “major depression with mixed features” (see the discussion of MDD above), identifiable even when a person has never had a full manic or hypo­manic episode.

No randomized trials have been con­ducted to identify the best treatments for such presentations, which has invited ex­trapolation from the literature in regard to bipolar mixed episodes, and suggesting that 1) some mood stabilizers (eg, divalproex) might have value and 2) antidepres­sants might exacerbate manic symptoms.

Perhaps most noteworthy in regard to treating bipolar depression is the unresolved, but hotly debated, contro­versy over whether and, if so, when, an antidepressant is inappropriate (based on concerns about possible induction or exac­erbation of manic symptoms). In addition, nearly all of the large, randomized con­trolled trials of antidepressants for bipolar depression have shown that they offer no advantage over placebo.

Some authors argue that a lack of re­sponse to antidepressants might, itself, be a “soft” indicator of “bipolarity.” However, nonresponse to antidepressants should prompt a wider assessment of features other than polarity—including psychosis, anxiety, substance abuse, a personality disorder, psychiatric adverse effects from concomitant medications, medical comor­ bidity, adequacy of trials of medical ther­apy, and potential non-adherence to such trials—to account for poor antidepressant outcomes.

Severity
Severity of depression warrants consider­ation when formulating impressions about the nature and treatment of all presenta­tions of depression.

High-severity forms prompt decisions about treatment setting (inpatient or out­patient); suicide assessment; and thera­peutic modalities (eg, electroconvulsive therapy is more appropriate than psycho­therapy for catatonic depression).

Mild forms. A recent meta-analysis of 6 randomized trials (each of >6 weeks’ du­ration) of antidepressants for mild de­pression demonstrated that these agents exert only a modest effect compared with placebo, owing largely to higher placebo-responsivity in mild depressive episodes than in moderate and severe episodes.13 In contrast, another meta-analysis of sub­jects who had “mild” baseline depression severity scores found that antidepressant medication had greater efficacy than pla­cebo in 4 of 6 randomized trials.14 Higher depression severity levels typically dimin­ish the placebo response rate but also re­duce the magnitude of drug efficacy.

Psychosis
Before DSM-III, psychotic (as opposed to neurotic) depression was perhaps the key nosologic distinction when characteriz­ing forms of depression. The presence of psychosis and related components (eg, mood-congruence) is closely linked with the severity of depression (high) and prog­nosis and longitudinal outcome (poorer), and has implications for treatment (Table).

Bottom Line
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including polarity, chronicity, recurrence, psychosis, treatment resistance, comorbidity, and atypicality, among other classifications. Clinical characteristics vary across subtypes—and so do corresponding preferred treatments, which should be tailored to the needs of each of your patients.

Related Resources
• Goldberg JF, Thase ME. Monoamine oxidase inhibi­tors revisited: what you should know. J Clin Psychiatry. 2013;74(2):189-191.
• Goldberg JF. Antidepressants in bipolar disorder: 7 myths and realities. Current Psychiatry. 2010;9(5):41-49.
• Ketamine cousin rapidly lifts depression without side ef­fects. National Institute of Mental Health. http://www. nimh.nih.gov/news/science-news/2013/ketamine-cousin-rapidly-lifts-depression-without-side-effects.shtml. Published May 23, 2013. Accessed March 20, 2014.
• Research Domain Criteria (RDoC). National Institute of Mental Health. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml?u tm_ source = govdelivery&utm_medium=email&utm_campaign= govdelivery. Accessed March 20, 2014.

Drug Brand Names
Amisulpride • Amazeo,                                  Lurasidone • Latuda
Amival, Amipride, Sulpitax                             Mirtazapine • Remeron
   Aripiprazole • Abilify                                   Moclobemide • Amira,
Armodafinil • Nuvigil                                        Aurorix, Clobemix,
Bupropion • Wellbutrin                                     Depnil, Manerix
Desipramine • Norpramin                               Modafinil • Provigil
Divalproex • Depakote,                                  Olanzapine/fluoxetine
Depakene                                                        • Symbyax
Duloxetine • Cymbalta                                    Paroxetine • Paxil
Escitalopram • Lexapro                                   Phenelzine • Nardil
Fluoxetine • Prozac                                         Pramipexole • Mirapex
Imipramine • Tofranil                                     Quetiapine • Seroquel
Ketamine • Ketalar                                         Riluzole • Rilutek
Lamotrigine • Lamictal                                    Sertraline • Zoloft
Lithium • Eskalith, Lithobid                             Vortioxetine • Brintellix

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion
Pharmaceuticals, and Takeda and Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Editor’s note: The second part of Dr. Goldberg’s review of depression subtypes—fo­cusing on “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a sub­stance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder—will appear in the May 2014 issue of Current Psychiatry.

Depression carries a wide differential diagnosis. Practitioners sometimes think polarity is the fundamental distinction when they conceptualize depression as a clinical entity; in fact, many nosologic frameworks have been described for defining and subtyping clinically meaningful forms of depression, and each waxed and waned in popularity.

Kraepelin, writing in the early 20th century, linked manic-depres­sive illness with “the greater part of the morbid states termed mel­ancholia,”¹ but many features other than polarity remain important components of depression, and those features often carry implications for how individual patients respond to treatment.

In this 2-part article [April and May 2014 issues], I summarize in­formation about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular subgroups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonresponse or partial response, often hinges on clinical subtyping.

The first part of this article examines major depressive disorder (MDD), minor depression, chronic depression, depression in bipolar disorder, depression that is severe or mild, and psychotic depression. Treatments for these subtypes for which there is evidence, or a clinical rationale, are given in the Table.

The subtypes of depression that I’ll discuss in the second part of the article are listed on page 47.

Major and minor depression
MDD has been the focus of most drug tri­als seeking FDA approval. As a syndrome, MDD is defined by a constellation of fea­tures that are related not only to mood but also to sleep, energy, cognition, motiva­tion, and motor behavior, persisting for ≥2 weeks.

DSM-5 has imposed few changes to the basic definition of MDD:
   • bereavement (the aftermath of death of a loved one), formerly an exclusion cri­terion, no longer precludes making a diag­nosis of MDD when syndromal criteria are otherwise fulfilled
   • “with anxious distress” is a new course specifier that designates promi­nent anxiety features (feeling worried, restless, tense, or keyed up; fearful of losing control or something terrible happening)
   • “with mixed features” is a new course specifier pertinent when ≥3 mania or hy­pomania symptoms coexist (that is, might be a subsyndromal mania or hypomania) with a depressive syndrome; the mixed features specifier can be applied to de­pressed patients whether or not they have ever had a manic or hypomanic episode, but MDD—rather than bipolar disorder— remains the overarching diagnosis, unless criteria have ever been met for a full mania or hypomania.

More than 2 dozen medications are FDA-approved to treat MDD. Evidence-based psychotherapies (eg, cognitive-behavioral therapy [CBT] and interpersonal therapy), as adjuncts to pharmacotherapy, further improve outcomes, but with only modest additional effect.²

Minor depression. Depressive states that involve 2 to 4 associated symptoms last­ing ≥2 weeks but <2 years are sometimes described as minor depression, captured within DSM-5 as “depression not else­where defined.” The terminology of so-called “minor depression” generally is shunned, in part because it might wrongly connote low severity and therefore dis­courage treatment—even though it con­fers more than a 5-fold increase in risk of MDD.3 

Chronicity
DSM-IV-TR identified long-standing de­pression by 2 constructs:
   • chronic major depression (an episode of MDD lasting ≥2 years in adults, ≥1 year in children and adolescents)
   • dysthymic disorder (2 to 4 depressive symptoms for ≥2 years in adults and ≥1 year in children and adolescents), affecting 3% to 6% of adults and carrying a 2-fold increased risk of MDD, eventually.⁴

Depression that begins as dysthymic disorder and blossoms into syndromal MDD is described as “double depres­sion”—although it is not recognized as a unique condition in any edition of the DSM. Subsequent incomplete recovery may revert to dysthymic disorder. DSM-5 has subsumed chronic major depression and dysthymia under the unified heading of persistent depressive disorder.

There are no FDA-approved drugs for treating dysthymia. A meta-analysis of 9 controlled trials of off-label use of antide­pressants to treat dysthymia revealed an overall response rate of 52.4%, compared with 29.9% for placebo.⁵ Notably, although the active drug response rate in these stud­ies is comparable to what seen in MDD, the placebo response rate was approxi­mately 10% lower than what was seen in major depression.

Positive therapeutic findings (typically, treatment for 6 to 12 weeks) have been reported in so-called “pure” dysthymic disorder with sertraline, fluoxetine, imip­ramine, ritanserin, moclobemide (not ap­proved for use in the United States), and phenelzine; the results of additional, posi­tive placebo-controlled studies support the utility of duloxetine⁶ and paroxetine.⁷ Randomized trials have reported negative findings for desipramine,⁸ fluoxetine,⁹ and escitalopram¹⁰ escitalopram¹⁰—although the sample size in these latter studies might have been too small to detect a drug-placebo difference.

In dysthymic and minor-depressive middle-age and older adult men who have a low serum level of testosterone, hormone replacement was shown to be superior to placebo in several randomized trials.¹¹ Studies of adjunctive atypical antipsy­chotics for dysthymic disorder are scarce; a Cochrane review identified controlled data only with amisulpride (not approved for use in the United States), which yielded a modest therapeutic effect.¹²

Polarity
In recent years, depression in bipolar dis­order (BD) has been contrasted with uni­polar MDD based on a difference in:
   • duration (briefer in BD)
   • severity (worse in BD)
   • risk of suicide (higher)
   • comorbidity (more extensive)
   • family history (often present for BD and highly recurrent depression)
   • treatment outcome (generally less favorable).

DSM-5 has at least somewhat blurred the distinctions in polarity by way of the new construct of “major depression with mixed features” (see the discussion of MDD above), identifiable even when a person has never had a full manic or hypo­manic episode.

No randomized trials have been con­ducted to identify the best treatments for such presentations, which has invited ex­trapolation from the literature in regard to bipolar mixed episodes, and suggesting that 1) some mood stabilizers (eg, divalproex) might have value and 2) antidepres­sants might exacerbate manic symptoms.

Perhaps most noteworthy in regard to treating bipolar depression is the unresolved, but hotly debated, contro­versy over whether and, if so, when, an antidepressant is inappropriate (based on concerns about possible induction or exac­erbation of manic symptoms). In addition, nearly all of the large, randomized con­trolled trials of antidepressants for bipolar depression have shown that they offer no advantage over placebo.

Some authors argue that a lack of re­sponse to antidepressants might, itself, be a “soft” indicator of “bipolarity.” However, nonresponse to antidepressants should prompt a wider assessment of features other than polarity—including psychosis, anxiety, substance abuse, a personality disorder, psychiatric adverse effects from concomitant medications, medical comor­ bidity, adequacy of trials of medical ther­apy, and potential non-adherence to such trials—to account for poor antidepressant outcomes.

Severity
Severity of depression warrants consider­ation when formulating impressions about the nature and treatment of all presenta­tions of depression.

High-severity forms prompt decisions about treatment setting (inpatient or out­patient); suicide assessment; and thera­peutic modalities (eg, electroconvulsive therapy is more appropriate than psycho­therapy for catatonic depression).

Mild forms. A recent meta-analysis of 6 randomized trials (each of >6 weeks’ du­ration) of antidepressants for mild de­pression demonstrated that these agents exert only a modest effect compared with placebo, owing largely to higher placebo-responsivity in mild depressive episodes than in moderate and severe episodes.13 In contrast, another meta-analysis of sub­jects who had “mild” baseline depression severity scores found that antidepressant medication had greater efficacy than pla­cebo in 4 of 6 randomized trials.14 Higher depression severity levels typically dimin­ish the placebo response rate but also re­duce the magnitude of drug efficacy.

Psychosis
Before DSM-III, psychotic (as opposed to neurotic) depression was perhaps the key nosologic distinction when characteriz­ing forms of depression. The presence of psychosis and related components (eg, mood-congruence) is closely linked with the severity of depression (high) and prog­nosis and longitudinal outcome (poorer), and has implications for treatment (Table).

Bottom Line
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including polarity, chronicity, recurrence, psychosis, treatment resistance, comorbidity, and atypicality, among other classifications. Clinical characteristics vary across subtypes—and so do corresponding preferred treatments, which should be tailored to the needs of each of your patients.

Related Resources
• Goldberg JF, Thase ME. Monoamine oxidase inhibi­tors revisited: what you should know. J Clin Psychiatry. 2013;74(2):189-191.
• Goldberg JF. Antidepressants in bipolar disorder: 7 myths and realities. Current Psychiatry. 2010;9(5):41-49.
• Ketamine cousin rapidly lifts depression without side ef­fects. National Institute of Mental Health. http://www. nimh.nih.gov/news/science-news/2013/ketamine-cousin-rapidly-lifts-depression-without-side-effects.shtml. Published May 23, 2013. Accessed March 20, 2014.
• Research Domain Criteria (RDoC). National Institute of Mental Health. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml?u tm_ source = govdelivery&utm_medium=email&utm_campaign= govdelivery. Accessed March 20, 2014.

Drug Brand Names
Amisulpride • Amazeo,                                  Lurasidone • Latuda
Amival, Amipride, Sulpitax                             Mirtazapine • Remeron
   Aripiprazole • Abilify                                   Moclobemide • Amira,
Armodafinil • Nuvigil                                        Aurorix, Clobemix,
Bupropion • Wellbutrin                                     Depnil, Manerix
Desipramine • Norpramin                               Modafinil • Provigil
Divalproex • Depakote,                                  Olanzapine/fluoxetine
Depakene                                                        • Symbyax
Duloxetine • Cymbalta                                    Paroxetine • Paxil
Escitalopram • Lexapro                                   Phenelzine • Nardil
Fluoxetine • Prozac                                         Pramipexole • Mirapex
Imipramine • Tofranil                                     Quetiapine • Seroquel
Ketamine • Ketalar                                         Riluzole • Rilutek
Lamotrigine • Lamictal                                    Sertraline • Zoloft
Lithium • Eskalith, Lithobid                             Vortioxetine • Brintellix

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion
Pharmaceuticals, and Takeda and Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Editor’s note: The second part of Dr. Goldberg’s review of depression subtypes—fo­cusing on “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a sub­stance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder—will appear in the May 2014 issue of Current Psychiatry.

Depression carries a wide differential diagnosis. Practitioners sometimes think polarity is the fundamental distinction when they conceptualize depression as a clinical entity; in fact, many nosologic frameworks have been described for defining and subtyping clinically meaningful forms of depression, and each waxed and waned in popularity.

Kraepelin, writing in the early 20th century, linked manic-depres­sive illness with “the greater part of the morbid states termed mel­ancholia,”¹ but many features other than polarity remain important components of depression, and those features often carry implications for how individual patients respond to treatment.

In this 2-part article [April and May 2014 issues], I summarize in­formation about clinically distinct subtypes of depression, as they are recognized within diagnostic systems or as descriptors of treatment outcomes for particular subgroups of patients. My focus is on practical considerations for assessing and managing depression. Because many forms of the disorder respond inadequately to initial antidepressant treatment, optimal “next-step” pharmacotherapy, after nonresponse or partial response, often hinges on clinical subtyping.

The first part of this article examines major depressive disorder (MDD), minor depression, chronic depression, depression in bipolar disorder, depression that is severe or mild, and psychotic depression. Treatments for these subtypes for which there is evidence, or a clinical rationale, are given in the Table.

The subtypes of depression that I’ll discuss in the second part of the article are listed on page 47.

Major and minor depression
MDD has been the focus of most drug tri­als seeking FDA approval. As a syndrome, MDD is defined by a constellation of fea­tures that are related not only to mood but also to sleep, energy, cognition, motiva­tion, and motor behavior, persisting for ≥2 weeks.

DSM-5 has imposed few changes to the basic definition of MDD:
   • bereavement (the aftermath of death of a loved one), formerly an exclusion cri­terion, no longer precludes making a diag­nosis of MDD when syndromal criteria are otherwise fulfilled
   • “with anxious distress” is a new course specifier that designates promi­nent anxiety features (feeling worried, restless, tense, or keyed up; fearful of losing control or something terrible happening)
   • “with mixed features” is a new course specifier pertinent when ≥3 mania or hy­pomania symptoms coexist (that is, might be a subsyndromal mania or hypomania) with a depressive syndrome; the mixed features specifier can be applied to de­pressed patients whether or not they have ever had a manic or hypomanic episode, but MDD—rather than bipolar disorder— remains the overarching diagnosis, unless criteria have ever been met for a full mania or hypomania.

More than 2 dozen medications are FDA-approved to treat MDD. Evidence-based psychotherapies (eg, cognitive-behavioral therapy [CBT] and interpersonal therapy), as adjuncts to pharmacotherapy, further improve outcomes, but with only modest additional effect.²

Minor depression. Depressive states that involve 2 to 4 associated symptoms last­ing ≥2 weeks but <2 years are sometimes described as minor depression, captured within DSM-5 as “depression not else­where defined.” The terminology of so-called “minor depression” generally is shunned, in part because it might wrongly connote low severity and therefore dis­courage treatment—even though it con­fers more than a 5-fold increase in risk of MDD.3 

Chronicity
DSM-IV-TR identified long-standing de­pression by 2 constructs:
   • chronic major depression (an episode of MDD lasting ≥2 years in adults, ≥1 year in children and adolescents)
   • dysthymic disorder (2 to 4 depressive symptoms for ≥2 years in adults and ≥1 year in children and adolescents), affecting 3% to 6% of adults and carrying a 2-fold increased risk of MDD, eventually.⁴

Depression that begins as dysthymic disorder and blossoms into syndromal MDD is described as “double depres­sion”—although it is not recognized as a unique condition in any edition of the DSM. Subsequent incomplete recovery may revert to dysthymic disorder. DSM-5 has subsumed chronic major depression and dysthymia under the unified heading of persistent depressive disorder.

There are no FDA-approved drugs for treating dysthymia. A meta-analysis of 9 controlled trials of off-label use of antide­pressants to treat dysthymia revealed an overall response rate of 52.4%, compared with 29.9% for placebo.⁵ Notably, although the active drug response rate in these stud­ies is comparable to what seen in MDD, the placebo response rate was approxi­mately 10% lower than what was seen in major depression.

Positive therapeutic findings (typically, treatment for 6 to 12 weeks) have been reported in so-called “pure” dysthymic disorder with sertraline, fluoxetine, imip­ramine, ritanserin, moclobemide (not ap­proved for use in the United States), and phenelzine; the results of additional, posi­tive placebo-controlled studies support the utility of duloxetine⁶ and paroxetine.⁷ Randomized trials have reported negative findings for desipramine,⁸ fluoxetine,⁹ and escitalopram¹⁰ escitalopram¹⁰—although the sample size in these latter studies might have been too small to detect a drug-placebo difference.

In dysthymic and minor-depressive middle-age and older adult men who have a low serum level of testosterone, hormone replacement was shown to be superior to placebo in several randomized trials.¹¹ Studies of adjunctive atypical antipsy­chotics for dysthymic disorder are scarce; a Cochrane review identified controlled data only with amisulpride (not approved for use in the United States), which yielded a modest therapeutic effect.¹²

Polarity
In recent years, depression in bipolar dis­order (BD) has been contrasted with uni­polar MDD based on a difference in:
   • duration (briefer in BD)
   • severity (worse in BD)
   • risk of suicide (higher)
   • comorbidity (more extensive)
   • family history (often present for BD and highly recurrent depression)
   • treatment outcome (generally less favorable).

DSM-5 has at least somewhat blurred the distinctions in polarity by way of the new construct of “major depression with mixed features” (see the discussion of MDD above), identifiable even when a person has never had a full manic or hypo­manic episode.

No randomized trials have been con­ducted to identify the best treatments for such presentations, which has invited ex­trapolation from the literature in regard to bipolar mixed episodes, and suggesting that 1) some mood stabilizers (eg, divalproex) might have value and 2) antidepres­sants might exacerbate manic symptoms.

Perhaps most noteworthy in regard to treating bipolar depression is the unresolved, but hotly debated, contro­versy over whether and, if so, when, an antidepressant is inappropriate (based on concerns about possible induction or exac­erbation of manic symptoms). In addition, nearly all of the large, randomized con­trolled trials of antidepressants for bipolar depression have shown that they offer no advantage over placebo.

Some authors argue that a lack of re­sponse to antidepressants might, itself, be a “soft” indicator of “bipolarity.” However, nonresponse to antidepressants should prompt a wider assessment of features other than polarity—including psychosis, anxiety, substance abuse, a personality disorder, psychiatric adverse effects from concomitant medications, medical comor­ bidity, adequacy of trials of medical ther­apy, and potential non-adherence to such trials—to account for poor antidepressant outcomes.

Severity
Severity of depression warrants consider­ation when formulating impressions about the nature and treatment of all presenta­tions of depression.

High-severity forms prompt decisions about treatment setting (inpatient or out­patient); suicide assessment; and thera­peutic modalities (eg, electroconvulsive therapy is more appropriate than psycho­therapy for catatonic depression).

Mild forms. A recent meta-analysis of 6 randomized trials (each of >6 weeks’ du­ration) of antidepressants for mild de­pression demonstrated that these agents exert only a modest effect compared with placebo, owing largely to higher placebo-responsivity in mild depressive episodes than in moderate and severe episodes.13 In contrast, another meta-analysis of sub­jects who had “mild” baseline depression severity scores found that antidepressant medication had greater efficacy than pla­cebo in 4 of 6 randomized trials.14 Higher depression severity levels typically dimin­ish the placebo response rate but also re­duce the magnitude of drug efficacy.

Psychosis
Before DSM-III, psychotic (as opposed to neurotic) depression was perhaps the key nosologic distinction when characteriz­ing forms of depression. The presence of psychosis and related components (eg, mood-congruence) is closely linked with the severity of depression (high) and prog­nosis and longitudinal outcome (poorer), and has implications for treatment (Table).

Bottom Line
Depressive disorders comprise a range of conditions that can be viewed along many dimensions, including polarity, chronicity, recurrence, psychosis, treatment resistance, comorbidity, and atypicality, among other classifications. Clinical characteristics vary across subtypes—and so do corresponding preferred treatments, which should be tailored to the needs of each of your patients.

Related Resources
• Goldberg JF, Thase ME. Monoamine oxidase inhibi­tors revisited: what you should know. J Clin Psychiatry. 2013;74(2):189-191.
• Goldberg JF. Antidepressants in bipolar disorder: 7 myths and realities. Current Psychiatry. 2010;9(5):41-49.
• Ketamine cousin rapidly lifts depression without side ef­fects. National Institute of Mental Health. http://www. nimh.nih.gov/news/science-news/2013/ketamine-cousin-rapidly-lifts-depression-without-side-effects.shtml. Published May 23, 2013. Accessed March 20, 2014.
• Research Domain Criteria (RDoC). National Institute of Mental Health. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml?u tm_ source = govdelivery&utm_medium=email&utm_campaign= govdelivery. Accessed March 20, 2014.

Drug Brand Names
Amisulpride • Amazeo,                                  Lurasidone • Latuda
Amival, Amipride, Sulpitax                             Mirtazapine • Remeron
   Aripiprazole • Abilify                                   Moclobemide • Amira,
Armodafinil • Nuvigil                                        Aurorix, Clobemix,
Bupropion • Wellbutrin                                     Depnil, Manerix
Desipramine • Norpramin                               Modafinil • Provigil
Divalproex • Depakote,                                  Olanzapine/fluoxetine
Depakene                                                        • Symbyax
Duloxetine • Cymbalta                                    Paroxetine • Paxil
Escitalopram • Lexapro                                   Phenelzine • Nardil
Fluoxetine • Prozac                                         Pramipexole • Mirapex
Imipramine • Tofranil                                     Quetiapine • Seroquel
Ketamine • Ketalar                                         Riluzole • Rilutek
Lamotrigine • Lamictal                                    Sertraline • Zoloft
Lithium • Eskalith, Lithobid                             Vortioxetine • Brintellix

Disclosure
Dr. Goldberg has been a consultant to Avanir Pharmaceuticals and Merck; has served on the speakers’ bureau for AstraZeneca, Merck, Novartis, Sunovion
Pharmaceuticals, and Takeda and Lundbeck; and has received royalties from American Psychiatric Publishing and honoraria from Medscape and WebMD.

Editor’s note: The second part of Dr. Goldberg’s review of depression subtypes—fo­cusing on “situational,” treatment-resistant, melancholic, agitated, anxious, and atypical depression; depression occurring with a sub­stance use disorder; premenstrual dysphoric disorder; and seasonal affective disorder—will appear in the May 2014 issue of Current Psychiatry.

Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.

This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.

Imprecise nomenclature

Post et al¹ coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.

In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.² Geller and colleagues³ proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.

Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.⁴

A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.

Table 1

Differential diagnosis in suspected URC

Duration criteria

Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.⁵ More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.⁶ Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.⁷ In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)⁸ that involve continual (ultradian) mood cycling in as many as 80% of cases.⁹

Is URC a valid construct?

A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.

Studies by our group¹⁰ and others¹¹ have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.

A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.

Borderline personality disorder

A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,¹² others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.

Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,¹³ in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.

Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation¹⁴; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.¹⁵ Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,¹⁶ whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.

See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.

Treatment considerations

No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.

Broadly speaking, treatment for URC, similar to RC, pragmatically involves:

• identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
• treating medical comorbidities such as hypothyroidism
• optimizing treatment with mood stabilizing agents
• exercising caution when using antidepressants (see below).

Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group¹⁷ compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.

Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al¹⁸) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al¹⁹ found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.

Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).^19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.

Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.²⁷ No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.

Table 2

Evidence-based treatments for ultra-rapid cycling BD

Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:

• number of days euthymic
• number of days with depression
• number of days with abnormal mood elevation
• number of occasions in which moods of both polarities occur on the same day.

Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.

Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.

Table 3

Tips for managing suspected ultra-rapid cycling BD

Table

Rapid cycling and ultra-rapid cycling BD: A comparison

Box

Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time

In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression

Related Resources

• American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
• Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.

Drug Brand Names

• Carbamazepine • Equetro, Tegretol
• Divalproex • Depakote
• Lamotrigine • Lamictal
• Levothyroxine • Synthroid
• Lithium • Lithobid
• Nimodipine • Nimotop
• Topiramate • Topamax

Disclosures

Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.

Acknowledgment

The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.

Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.

This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.

Imprecise nomenclature

Post et al¹ coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.

In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.² Geller and colleagues³ proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.

Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.⁴

A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.

Table 1

Differential diagnosis in suspected URC

Duration criteria

Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.⁵ More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.⁶ Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.⁷ In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)⁸ that involve continual (ultradian) mood cycling in as many as 80% of cases.⁹

Is URC a valid construct?

A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.

Studies by our group¹⁰ and others¹¹ have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.

A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.

Borderline personality disorder

A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,¹² others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.

Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,¹³ in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.

Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation¹⁴; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.¹⁵ Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,¹⁶ whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.

See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.

Treatment considerations

No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.

Broadly speaking, treatment for URC, similar to RC, pragmatically involves:

• identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
• treating medical comorbidities such as hypothyroidism
• optimizing treatment with mood stabilizing agents
• exercising caution when using antidepressants (see below).

Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group¹⁷ compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.

Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al¹⁸) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al¹⁹ found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.

Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).^19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.

Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.²⁷ No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.

Table 2

Evidence-based treatments for ultra-rapid cycling BD

Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:

• number of days euthymic
• number of days with depression
• number of days with abnormal mood elevation
• number of occasions in which moods of both polarities occur on the same day.

Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.

Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.

Table 3

Tips for managing suspected ultra-rapid cycling BD

Table

Rapid cycling and ultra-rapid cycling BD: A comparison

Box

Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time

In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression

Related Resources

• American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
• Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.

Drug Brand Names

• Carbamazepine • Equetro, Tegretol
• Divalproex • Depakote
• Lamotrigine • Lamictal
• Levothyroxine • Synthroid
• Lithium • Lithobid
• Nimodipine • Nimotop
• Topiramate • Topamax

Disclosures

Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.

Acknowledgment

The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.

Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.

This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.

Imprecise nomenclature

Post et al¹ coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.

In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.² Geller and colleagues³ proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.

Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.⁴

A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.

Table 1

Differential diagnosis in suspected URC

Duration criteria

Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.⁵ More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.⁶ Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.⁷ In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)⁸ that involve continual (ultradian) mood cycling in as many as 80% of cases.⁹

Is URC a valid construct?

A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.

Studies by our group¹⁰ and others¹¹ have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.

A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.

Borderline personality disorder

A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,¹² others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.

Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,¹³ in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.

Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation¹⁴; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.¹⁵ Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,¹⁶ whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.

See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.

Treatment considerations

No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.

Broadly speaking, treatment for URC, similar to RC, pragmatically involves:

• identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
• treating medical comorbidities such as hypothyroidism
• optimizing treatment with mood stabilizing agents
• exercising caution when using antidepressants (see below).

Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group¹⁷ compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.

Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al¹⁸) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al¹⁹ found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.

Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).^19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.

Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.²⁷ No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.

Table 2

Evidence-based treatments for ultra-rapid cycling BD

Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:

• number of days euthymic
• number of days with depression
• number of days with abnormal mood elevation
• number of occasions in which moods of both polarities occur on the same day.

Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.

Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.

Table 3

Tips for managing suspected ultra-rapid cycling BD

Table

Rapid cycling and ultra-rapid cycling BD: A comparison

Box

Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time

In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression

Related Resources

• American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
• Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.

Drug Brand Names

• Carbamazepine • Equetro, Tegretol
• Divalproex • Depakote
• Lamotrigine • Lamictal
• Levothyroxine • Synthroid
• Lithium • Lithobid
• Nimodipine • Nimotop
• Topiramate • Topamax

Disclosures

Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.

Acknowledgment

The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.