Serotonin Transporter Occupancy Predicts Treatment Response to SSRIs

AMSTERDAM – A significant relationship was observed between treatment response to selective serotonin reuptake inhibitors and serotonin transporter availability and occupancy in a study that used positron emission tomography in patients with major depressive disorder. Dr. Elena Akimova of the Medical University of Vienna presented the findings at the annual congress of the European College of Neuropsychopharmacology.

“We found no correlation between plasma drug level and clinical improvement, but we found that the higher the plasma level, the higher the SERT occupancy, and that lower availability and higher occupancy in the raphe and midbrain regions were related to treatment response,” Dr. Akimova said in an interview.

Impaired serotonin neurotransmission is implicated in the pathophysiology of affective disorders. As an underlying mechanism involved in the effects of selective serotonin reuptake inhibitors (SSRIs), evidence points to a key role for the serotonin transporter (SERT) in high concentrations in the raphe nuclei. The SSRIs bind to SERT, thereby blocking the reuptake of serotonin from the synaptic cleft.

The predictive value of SERT availability in the clinical response to antidepressants is a new research interest. Looking into this question, these investigators conducted a double-blind, randomized longitudinal study with two parallel treatment groups of 18 patients with MDD receiving 10 mg/day escitalopram or 20 mg/day citalopram (which are equivalent doses). Patients underwent PET scanning with [11C] DASB, a new, highly selective PET radiotracer that shows high affinity for SERT. Superior to other PET radioligands for SERT, [11C] DASB permits reliable quantification of subcortical and cortical SERT binding, according to the investigators, whose study earned them a “travel award” to the meeting.

Patients were measured three times to assess SERT availability in the unmedicated state and SERT occupancy 4 hours after a single dose and after the first 3 weeks of treatment with SSRIs. The Hamilton Depression Rating Scale (HAM-D, 17 items) was administered at the screening visit and before each PET scan. SERT availability at baseline and SSRI treatment-induced occupancies of SERT were quantified in 10 brain regions in which high to medium SERT availability might be expected: nucleus caudatus, putamen, midbrain, thalamus, dorsal raphe nucleus, median raphe nucleus, nucleus accumbens, amygdala, anterior cingulated cortex insula. This was correlated with treatment response assessed by the HAM-D.

There were 10 responders and 8 nonresponders to 3 weeks of SSRI treatment. The study found no significant interaction between drug plasma levels and treatment response after either the single dose or prolonged treatment but did find that lower pretreatment SERT availability in raphe regions and midbrain indicated improved treatment responses 3 weeks later, Dr. Akimova reported.

“Our results show that lower availability of SERT before treatment in the midbrain and raphe regions may indicate better treatment outcome in response to SSRIs,” she said.

In the brain regions, pretreatment SERT availability significantly explained the variability in the proportional decrease of HAM-D scores in the midbrain and raphe regions only. Significant correlations between the decrease in HAM-D scores and SERT availability were found in the midbrain (P = .004), median raphe nucleus (P = .002) and dorsal raphe nucleus (P = .011).

“In other words, lower pretreatment SERT availability in these regions indicated improved treatment response 3 weeks later,” she said.

A significant relationship between treatment response and transporter occupancy (second PET) was also observed in the median raphe nucleus (P = .012).

A single dose of SSRIs led to a considerable transporter blockage, resulting in relatively high mean brain occupancy of 74.8%. Continuous SSRI treatment over 3 weeks raised the occupancy to 84.0%, she added.

“To our knowledge, this is the first PET study with [11C] DASB demonstrating a significant relationship between treatment response and SERT availability and occupancy,” she said. “Some investigators suggest that availability and occupancy of SERT may be a key component in the response to SSRIs. In our sample, we were able to show this for the raphe and midbrain regions. With our study, we aim to contribute to the controversial research topic of biological markers.”

Dr. Akimova reported no conflicts of interest.

AMSTERDAM – A significant relationship was observed between treatment response to selective serotonin reuptake inhibitors and serotonin transporter availability and occupancy in a study that used positron emission tomography in patients with major depressive disorder. Dr. Elena Akimova of the Medical University of Vienna presented the findings at the annual congress of the European College of Neuropsychopharmacology.

“We found no correlation between plasma drug level and clinical improvement, but we found that the higher the plasma level, the higher the SERT occupancy, and that lower availability and higher occupancy in the raphe and midbrain regions were related to treatment response,” Dr. Akimova said in an interview.

Impaired serotonin neurotransmission is implicated in the pathophysiology of affective disorders. As an underlying mechanism involved in the effects of selective serotonin reuptake inhibitors (SSRIs), evidence points to a key role for the serotonin transporter (SERT) in high concentrations in the raphe nuclei. The SSRIs bind to SERT, thereby blocking the reuptake of serotonin from the synaptic cleft.

The predictive value of SERT availability in the clinical response to antidepressants is a new research interest. Looking into this question, these investigators conducted a double-blind, randomized longitudinal study with two parallel treatment groups of 18 patients with MDD receiving 10 mg/day escitalopram or 20 mg/day citalopram (which are equivalent doses). Patients underwent PET scanning with [11C] DASB, a new, highly selective PET radiotracer that shows high affinity for SERT. Superior to other PET radioligands for SERT, [11C] DASB permits reliable quantification of subcortical and cortical SERT binding, according to the investigators, whose study earned them a “travel award” to the meeting.

Patients were measured three times to assess SERT availability in the unmedicated state and SERT occupancy 4 hours after a single dose and after the first 3 weeks of treatment with SSRIs. The Hamilton Depression Rating Scale (HAM-D, 17 items) was administered at the screening visit and before each PET scan. SERT availability at baseline and SSRI treatment-induced occupancies of SERT were quantified in 10 brain regions in which high to medium SERT availability might be expected: nucleus caudatus, putamen, midbrain, thalamus, dorsal raphe nucleus, median raphe nucleus, nucleus accumbens, amygdala, anterior cingulated cortex insula. This was correlated with treatment response assessed by the HAM-D.

There were 10 responders and 8 nonresponders to 3 weeks of SSRI treatment. The study found no significant interaction between drug plasma levels and treatment response after either the single dose or prolonged treatment but did find that lower pretreatment SERT availability in raphe regions and midbrain indicated improved treatment responses 3 weeks later, Dr. Akimova reported.

“Our results show that lower availability of SERT before treatment in the midbrain and raphe regions may indicate better treatment outcome in response to SSRIs,” she said.

In the brain regions, pretreatment SERT availability significantly explained the variability in the proportional decrease of HAM-D scores in the midbrain and raphe regions only. Significant correlations between the decrease in HAM-D scores and SERT availability were found in the midbrain (P = .004), median raphe nucleus (P = .002) and dorsal raphe nucleus (P = .011).

“In other words, lower pretreatment SERT availability in these regions indicated improved treatment response 3 weeks later,” she said.

A significant relationship between treatment response and transporter occupancy (second PET) was also observed in the median raphe nucleus (P = .012).

A single dose of SSRIs led to a considerable transporter blockage, resulting in relatively high mean brain occupancy of 74.8%. Continuous SSRI treatment over 3 weeks raised the occupancy to 84.0%, she added.

“To our knowledge, this is the first PET study with [11C] DASB demonstrating a significant relationship between treatment response and SERT availability and occupancy,” she said. “Some investigators suggest that availability and occupancy of SERT may be a key component in the response to SSRIs. In our sample, we were able to show this for the raphe and midbrain regions. With our study, we aim to contribute to the controversial research topic of biological markers.”

Dr. Akimova reported no conflicts of interest.

AMSTERDAM – A significant relationship was observed between treatment response to selective serotonin reuptake inhibitors and serotonin transporter availability and occupancy in a study that used positron emission tomography in patients with major depressive disorder. Dr. Elena Akimova of the Medical University of Vienna presented the findings at the annual congress of the European College of Neuropsychopharmacology.

“We found no correlation between plasma drug level and clinical improvement, but we found that the higher the plasma level, the higher the SERT occupancy, and that lower availability and higher occupancy in the raphe and midbrain regions were related to treatment response,” Dr. Akimova said in an interview.

Impaired serotonin neurotransmission is implicated in the pathophysiology of affective disorders. As an underlying mechanism involved in the effects of selective serotonin reuptake inhibitors (SSRIs), evidence points to a key role for the serotonin transporter (SERT) in high concentrations in the raphe nuclei. The SSRIs bind to SERT, thereby blocking the reuptake of serotonin from the synaptic cleft.

The predictive value of SERT availability in the clinical response to antidepressants is a new research interest. Looking into this question, these investigators conducted a double-blind, randomized longitudinal study with two parallel treatment groups of 18 patients with MDD receiving 10 mg/day escitalopram or 20 mg/day citalopram (which are equivalent doses). Patients underwent PET scanning with [11C] DASB, a new, highly selective PET radiotracer that shows high affinity for SERT. Superior to other PET radioligands for SERT, [11C] DASB permits reliable quantification of subcortical and cortical SERT binding, according to the investigators, whose study earned them a “travel award” to the meeting.

Patients were measured three times to assess SERT availability in the unmedicated state and SERT occupancy 4 hours after a single dose and after the first 3 weeks of treatment with SSRIs. The Hamilton Depression Rating Scale (HAM-D, 17 items) was administered at the screening visit and before each PET scan. SERT availability at baseline and SSRI treatment-induced occupancies of SERT were quantified in 10 brain regions in which high to medium SERT availability might be expected: nucleus caudatus, putamen, midbrain, thalamus, dorsal raphe nucleus, median raphe nucleus, nucleus accumbens, amygdala, anterior cingulated cortex insula. This was correlated with treatment response assessed by the HAM-D.

There were 10 responders and 8 nonresponders to 3 weeks of SSRI treatment. The study found no significant interaction between drug plasma levels and treatment response after either the single dose or prolonged treatment but did find that lower pretreatment SERT availability in raphe regions and midbrain indicated improved treatment responses 3 weeks later, Dr. Akimova reported.

“Our results show that lower availability of SERT before treatment in the midbrain and raphe regions may indicate better treatment outcome in response to SSRIs,” she said.

In the brain regions, pretreatment SERT availability significantly explained the variability in the proportional decrease of HAM-D scores in the midbrain and raphe regions only. Significant correlations between the decrease in HAM-D scores and SERT availability were found in the midbrain (P = .004), median raphe nucleus (P = .002) and dorsal raphe nucleus (P = .011).

“In other words, lower pretreatment SERT availability in these regions indicated improved treatment response 3 weeks later,” she said.

A significant relationship between treatment response and transporter occupancy (second PET) was also observed in the median raphe nucleus (P = .012).

A single dose of SSRIs led to a considerable transporter blockage, resulting in relatively high mean brain occupancy of 74.8%. Continuous SSRI treatment over 3 weeks raised the occupancy to 84.0%, she added.

“To our knowledge, this is the first PET study with [11C] DASB demonstrating a significant relationship between treatment response and SERT availability and occupancy,” she said. “Some investigators suggest that availability and occupancy of SERT may be a key component in the response to SSRIs. In our sample, we were able to show this for the raphe and midbrain regions. With our study, we aim to contribute to the controversial research topic of biological markers.”

Dr. Akimova reported no conflicts of interest.