Association of dopamine D2/3 receptor binding potential measured using PET and [11C]-(+)-PHNO with post-mortem DRD2/3 gene expression in the human brain.

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D2 and D3 dopamine receptor distribution by applying the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and human gene expression data. Since [11C]-(+)-PHNO has a higher affinity for D3 compared to D2 receptors, we hypothesized that there is a stronger relationship between D2/3 non-displaceable binding potentials (BPND) and D3 mRNA expression. To investigate the relationship between D2/3 BPND and mRNA expression of DRD2 and DRD3 we performed [11C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D2/D3 mRNA expression ratios to imitate the mixed D2/3 signal of [11C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [11C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D2/D3 mRNA expression ratios also showed a positive correlation with [11C]-(+)-PHNO binding, reflecting the mixed D2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.

Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence.

Since 2006, reprogrammed cells have increasingly been used as a biomedical research technique in addition to neuro-psychiatric methods. These rapidly evolving techniques allow for the generation of neuronal sub-populations, and have sparked interest not only in monogenetic neuro-psychiatric diseases, but also in poly-genetic and poly-aetiological disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). This review provides a summary of 19 publications on reprogrammed adult somatic cells derived from patients with SCZ, and five publications using this technique in patients with BPD. As both disorders are complex and heterogeneous, there is a plurality of hypotheses to be tested in vitro. In SCZ, data on alterations of dopaminergic transmission in vitro are sparse, despite the great explanatory power of the so-called DA hypothesis of SCZ. Some findings correspond to perturbations of cell energy metabolism, and observations in reprogrammed cells suggest neuro-developmental alterations. Some studies also report on the efficacy of medicinal compounds to revert alterations observed in cellular models. However, due to the paucity of replication studies, no comprehensive conclusions can be drawn from studies using reprogrammed cells at the present time. In the future, findings from cell culture methods need to be integrated with clinical, epidemiological, pharmacological and imaging data in order to generate a more comprehensive picture of SCZ and BPD.

Making Sense of: Sensitization in Schizophrenia.

Sensitization is defined as a process whereby repeated intermittent exposure to a given stimulus results in an enhanced response at subsequent exposures. Next to robust findings of an increased dopamine synthesis capacity in schizophrenia, empirical data and neuroimaging studies support the notion that the mesolimbic dopamine system of patients with schizophrenia is more reactive compared with healthy controls. These studies led to the conceptualization of schizophrenia as a state of endogenous sensitization, as stronger behavioral response and increased dopamine release after amphetamine administration or exposure to stress have been observed in patients with schizophrenia. These findings have also been integrated into the neurodevelopmental model of the disorder, which assumes that vulnerable neuronal circuits undergo progressive changes during puberty and young adulthood that lead to manifest psychosis. Rodent and human studies have made an attempt to identify the exact mechanisms of sensitization of the dopaminergic system and its association with psychosis. Doing so, several epigenetic and molecular alterations associated with dopamine release, neuroplasticity, and cellular energy metabolism have been discovered. Future research aims at targeting these key proteins associated with sensitization in schizophrenia to enhance the knowledge of the pathophysiology of the illness and pave the way for an improved treatment or even prevention of this severe psychiatric disorder.

Additive gene-environment effects on hippocampal structure in healthy humans.

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

Case report: Hyperactive delirium after a single dose of zolpidem administered additionally to psychopharmacotherapy including clozapine.

The non-benzodiazepine hypnotic zolpidem is frequently administered as a short term psychopharmacotherapy for insomnia. Although it is well-established in a broad clinical routine and often well-tolerated, severe delirium and complex sleep behavior were reported in rare cases. Hereby, it remains unclear whether zolpidem's potential for delirium might be enhanced when combined with further psychopharmacotherapeutics. The present case report portrays a young male Caucasian inpatient with schizoaffective disorder, who was admitted due to severe hyperactive delirium after a single dose of zolpidem 10 mg that was administered in addition to already established psychopharmacotherapy including clozapine 200 mg/day, aripiprazole 15 mg/day and cariprazine 4.5 mg/day. In detail, disorientation, agitation, confabulations, bizarre behavior, and anterograde amnesia occurred shortly after ingestion of zolpidem and gained in intensity within a couple of hours. Once zolpidem was discontinued, the abovementioned symptoms subsided completely and did not reoccur. Since a clear temporal association could be drawn between the intake of zolpidem and the onset of hyperactive delirium, the present clinical experience should serve as a cautionary note for combining potent sedative-hypnotics and substances with anticholinergic properties, even in young adults in a good general condition. Moreover, our case argues for the necessity of further research into the pathomechanism of the interaction potential of non-benzodiazepines as zolpidem, especially with substances exerting anticholinergic properties, which are known for their potential to precipitate delirium. Therefore, the metabolic pathways of the concurrently administered substances should be further taken into account.

Effects of sunshine on suicide rates.

OBJECTIVES: Seasonal spring peaks of suicide are well described in epidemiological studies, but their origin is poorly understood. More recent evidence suggests that this peak may be associated with the increase in the duration of sunshine in spring. We investigated the effect of number of sunshine hours per month on suicide rates in Austria between 1996 and 2006. METHODS: Suicide data, differentiated by month of suicide, sex, and method of suicide (violent vs nonviolent methods), were provided by Statistics Austria. Data on the average number of sunshine hours per month were calculated from 39 representative meteorological stations (provided by the Austrian Central Institute for Meteorology and Geodynamics). For statistical analysis, analysis of variance tests, Kruskal-Wallis tests, and Pearson correlation tests were used. RESULTS: A total of 16,673 suicides with a median of 126 ± 19.8 suicides per month occurred in the examined period. A clear seasonal pattern was observed, with suicide frequencies being highest between March and May and lowest between November and January (df = 11, F = 5.2, P < .0001) for men (df = 11, F = 4.9, P < .0001) and women (df = 11, F = 2.4, P = .008). The average number of sunshine hours per month was significantly correlated with the number of suicides among both sexes (r = .43, P < .0001), violent methods (r = .48, P < .0001) but not with nonviolent methods (r = .03, P = .707). CONCLUSIONS: This study shows that seasonal changes in sunshine account for variations in the number of suicides and especially violent suicides. We propose that sunshine, via interactions with serotonin neurotransmission, may trigger increased impulsivity and promote suicidal acts. However, because of the hypothesis-generating design of this study, more research is needed to further clarify the role of sunshine in triggering neurobiologic changes, which might contribute to suicidal behavior.

Intravenous esketamine leads to an increase in impulsive and suicidal behaviour in a patient with recurrent major depression and borderline personality disorder.

Objectives: As clinical studies demonstrated that ketamine possesses rapid-acting antidepressant and antisuicidal effects, it is increasingly used in affective disorders. The neuroplastic properties of ketamine are well described in preclinical and imaging studies, and are highly related to its antidepressive mechanism of action.Methods: Here, we report on a female patient with recurrent major depression and borderline personality disorder (BPD) who was treated with intravenous (i.v.) esketamine as rapid-acting augmentation therapy to improve severe and acute depressive symptoms and suicidal behaviour.Results: Esketamine led to an initial improvement of these symptoms. However, during the course of treatment, loosened and disinhibited behaviour and severe suicidal ideation occurred during and immediately after esketamine application. Hence, i.v. esketamine was discontinued, and she further received treatment as usual, which demonstrated to be beneficial.Conclusions: With current knowledge at hand, one cannot exclude esketamine's effects on the equilibrium of neural plasticity in brain networks, potentially initiating undesirable symptoms as impulsive behaviour and emotional dysregulation. Therefore, until investigations focus on efficacy and side effects profile of esketamine in depressed patients with (comorbid) BPD, treatment with this fast-acting medication should be considered with caution in this patient group.

Lithium in drinking water and suicide mortality.

BACKGROUND: There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. AIMS: To evaluate the association between local lithium levels in drinking water and suicide mortality at district level in Austria. METHOD: A nationwide sample of 6460 lithium measurements was examined for association with suicide rates per 100,000 population and suicide standardised mortality ratios across all 99 Austrian districts. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Austria (population density, per capita income, proportion of Roman Catholics, as well as the availability of mental health service providers). Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results. RESULTS: The overall suicide rate (R(2) = 0.15, ß = -0.39, t = -4.14, P = 0.000073) as well as the suicide mortality ratio (R(2) = 0.17, ß = -0.41, t = -4.38, P = 0.000030) were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors. CONCLUSIONS: In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates.

Bright-light therapy in the treatment of mood disorders.

Bright-light therapy (BLT) is established as the treatment of choice for seasonal affective disorder/winter type (SAD). In the last two decades, the use of BLT has expanded beyond SAD: there is evidence for efficacy in chronic depression, antepartum depression, premenstrual depression, bipolar depression and disturbances of the sleep-wake cycle. Data on the usefulness of BLT in non-seasonal depression are promising; however, further systematic studies are still warranted. In this review, the authors present a comprehensive overview of the literature on BLT in mood disorders. The first part elucidates the neurobiology of circadian and seasonal adaptive mechanisms focusing on the suprachiasmatic nucleus (SCN), the indolamines melatonin and serotonin, and the chronobiology of mood disorders. The SCN is the primary oscillator in humans. Indolamines are known to transduce light signals into cells and organisms since early in evolution, and their role in signalling change of season is still preserved in humans: melatonin is synthesized primarily in the pineal gland and is the central hormone for internal clock circuitries. The melatonin precursor serotonin is known to modulate many behaviours that vary with season. The second part discusses the pathophysiology and clinical specifiers of SAD, which can be seen as a model disorder for chronobiological disturbances and the mechanism of action of BLT. In the third part, the mode of action, application, efficacy, tolerability and safety of BLT in SAD and other mood disorders are explored.

Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: A review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry.

Imaging genetics is a research field that describes the impact of genetic risk variants on brain structure and function. While magnetic resonance based imaging techniques are able to provide complex information on a system level, positron emission tomography (PET) and single photon emission computer tomography (SPECT) allow for determination of distribution and density of single receptor molecules in the human brain. Major psychiatric disorders are highly heritable, and have been associated with a dysregulation in brain dopamine and serotonin systems. Understanding the role of genetic polymorphisms within these neurotransmitter systems on brain phenotype is essential. This review tries to cover the literature on the impact of gene variants implicated in psychiatric disorders on serotonin, dopamine, and MAO-A radioligand binding in living humans. The majority of PET and SPECT studies investigated the role of polymorphisms within genes coding for the serotonin and dopamine transporters, the serotonin 1A receptor, and the dopamine D2 receptor on G protein coupled receptors or transporter proteins critically involved in serotonin or dopamine neurotransmission. Other studies investigated the impact of variants in genes for monoamine oxidase-A (MAO-A) or brain derived neurotrophic factor on monoamine transporters, receptors, or MAO-A activity. Two main findings in healthy subjects emerge from the current literature: one is an increased binding of the selective ligand [(11)C]DASB to serotonin transporters in subjects homozygous for the triallelic 5-HTTLPR LA allele. The other one is decreased binding of the radioligand [(11)C]raclopride to dopamine D2 receptors in D2 Taq1 A1 allele carriers. Other findings reported are highly interesting but require independent replication.

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.

Enhanced serotonin transporter function during depression in seasonal affective disorder.

Decreased synaptic serotonin during depressive episodes is a central element of the monoamine hypothesis of depression. The serotonin transporter (5-HTT, SERT) is a key molecule for the control of synaptic serotonin levels. Here we aimed to detect state-related alterations in the efficiency of 5-HTT-mediated inward and outward transport in platelets of drug-free depressed patients suffering from seasonal affective disorder (SAD). 5-HTT turnover rate, a measure for the number of inward transport events per minute, and tyramine-induced, 5-HTT-mediated outward transport were assessed at baseline, after 4 weeks of bright light therapy, and in summer using a case-control design in a consecutive sample of 73 drug-free depressed patients with SAD and 70 nonseasonal healthy controls. Patients were drug-naive or medication-free for at least 6 months prior to study inclusion, females patients were studied in the follicular phase of the menstrual cycle. All participants were genotyped for a 5-HTT-promoter polymorphism (5-HTTLPR) to assess the influence of this polymorphism on 5-HTT parameters. Efficiency of 5-HTT-mediated inward (p=0.014) and outward (p=0.003) transport was enhanced in depressed patients. Both measures normalized toward control levels after therapy and in natural summer remission. Changes in outward transport showed a clear correlation with treatment response (rho=0.421, p=0.001). Changes in inward transport were mediated by changes in 5-HTT transport efficiency rather than affinity or density. 5-HTTLPR was not associated with any of the 5-HTT parameters. In sum, we conclude that the 5-HTT is in a hyperfunctional state during depression in SAD and normalizes after light therapy and in natural summer remission.

Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study.

BACKGROUND: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS: The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.

Agomelatine in the treatment of seasonal affective disorder.

RATIONALE: The novel antidepressant agomelatine acts as a melatonergic (MT(1) and MT(2)) receptor agonist and as a serotonin-2C receptor antagonist. Previous studies showed that agomelatine is able to restore disrupted circadian rhythms, which were implicated in the pathophysiology of seasonal affective disorder (SAD). OBJECTIVES: The aim of this study was to investigate the efficacy and tolerability of agomelatine in the treatment of SAD. MATERIALS AND METHODS: Thirty-seven acutely depressed SAD patients were included in an open study with agomelatine (25 mg/day in the evening) over 14 weeks. Efficacy assessments included the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD), the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I), the Circscreen, a self-rating scale for the assessment of sleep and circadian rhythm disorders, and the Hypomania Scale. RESULTS: Agomelatine led to a progressive and statistically significant decrease of SIGH-SAD, CGI-S, and CGI-I scores from week 2 onward (p < 0.001). Furthermore, scores on the Circscreen improved significantly during the study (p < 0.001). Treatment with agomelatine over 14 weeks yielded a response rate of 75.7% (SIGH-SAD <50% of baseline value) and a remission rate (SIGH-SAD <8) of 70.3% in the intention to treat sample. Scores on the Hypomania Scale were consistently low during the study. Agomelatine showed good overall tolerability: throughout the study only one adverse event (mild fatigue) was related to the study drug. CONCLUSIONS: The results of this study suggest that seasonal depression may be effectively and safely treated with agomelatine.

Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression.

CONTEXT: The monoamine theory of depression proposes that monoamine levels are lowered, but there is no explanation for how monoamine loss occurs. Monoamine oxidase A (MAO-A) is an enzyme that metabolizes monoamines, such as serotonin, norepinephrine, and dopamine. OBJECTIVE: To determine whether MAO-A levels in the brain are elevated during untreated depression. SETTING: Tertiary care psychiatric hospital. PATIENTS: Seventeen healthy and 17 depressed individuals with major depressive disorder that met entry criteria were recruited from the care of general practitioners and psychiatrists. All study participants were otherwise healthy and nonsmoking. Depressed individuals had been medication free for at least 5 months. MAIN OUTCOME MEASURE: Harmine labeled with carbon 11, a radioligand selective for MAO-A and positron emission tomography, was used to measure MAO-A DVS (specific distribution volume), an index of MAO-A density, in different brain regions (prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, caudate, putamen, thalamus, anterior temporal cortex, midbrain, hippocampus, and parahippocampus). RESULTS: The MAO-A DVS was highly significantly elevated in every brain region assessed (t test; P=.001 to 3x10(-7)). The MAO-A DVS was elevated on average by 34% (2 SDs) throughout the brain during major depression. CONCLUSIONS: The sizable magnitude of this finding and the absence of other compelling explanations for monoamine loss during major depressive episodes led to the conclusion that elevated MAO-A density is the primary monoamine-lowering process during major depression.

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.

Actigraphy in patients with seasonal affective disorder and healthy control subjects treated with light therapy.

BACKGROUND: Abnormalities of the circadian rest-activity cycle are hypothesized to accompany the clinical picture of seasonal affective disorder (SAD). The purpose of this study was to investigate if bright light therapy (BLT) is able to reverse these disturbances. METHODS: Seventeen SAD outpatients and 17 sex- and age-matched healthy control subjects were treated with BLT administered in the morning for 4 weeks. Activity levels were measured with wrist actigraphy. RESULTS: SAD patients had 33% lower total (p = .031) and 43% lower daylight activity (p = .006) in week 1 compared with control subjects. The relative amplitude of the sleep-wake cycle was attenuated by 6% in patients (p = .025); they were phase delayed by 55 minutes (p = .023) and had significantly lower sleep efficiency (p = .030). Total (p = .002) and daylight activity (p = .001) increased after 4 weeks of treatment in SAD patients. Moreover, BLT led to increase of relative amplitude (p = .005), advance of delayed rhythms (p = .036), and improved sleep efficiency (p = .011) in patients. Intradaily stability, measuring the strength of coupling of the rhythm to external zeitgebers, increased by 9% both in patients and healthy control subjects (p = .032). CONCLUSIONS: Treatment with BLT normalizes disturbed activity patterns and restores circadian rhythms in SAD patients. BLT might also stabilize the circadian rhythm in nondepressed individuals during the fall-winter season.

Effects of tryptophan depletion on the serotonin transporter in healthy humans.

BACKGROUND: Lowering of brain serotonin by acute tryptophan depletion (TD) frequently leads to transient symptoms of depression in vulnerable individuals but not in euthymic healthy subjects with a negative family history of depression. The effects of TD on regional serotonin transporter binding potential (5-HTT BP), an index of 5-HTT density and affinity, were studied in healthy individuals using 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ([11C]DASB) positron emission tomography (PET). Adaptive decreases in 5-HTT density and/or affinity during TD would be a possible compensatory mechanism to maintain sufficient extracellular serotonin levels during TD, thereby preventing a depressive relapse. METHODS: Regional noninvasive 5-HTT BP was found in 25 healthy subjects using [11C]DASB PET. Fourteen subjects were scanned twice, once after TD and once after sham depletion, and 11 other healthy subjects were scanned twice to measure test-retest reliability of the method. RESULTS: None of the healthy subjects experienced depressive symptoms during TD and there was no difference in regional 5-HTT BP during TD as compared with sham depletion. CONCLUSIONS: Acute changes in 5-HTT density or affinity are unlikely to play a role in protecting healthy subjects against mood symptoms during TD. Other mechanisms that may be associated with greater resilience against acute lowering of extracellular serotonin should be explored to gain further insight into the neurochemical basis of different vulnerabilities to short-term depressive relapse.