Early life adversity and telomere length: a meta-analysis.

Early adversity, in the form of abuse, neglect, socioeconomic status and other adverse experiences, is associated with poor physical and mental health outcomes. To understand the biologic mechanisms underlying these associations, studies have evaluated the relationship between early adversity and telomere length, a marker of cellular senescence. Such results have varied in regard to the size and significance of this relationship. Using meta-analytic techniques, we aimed to clarify the relationship between early adversity and telomere length while exploring factors affecting the association, including adversity type, timing and study design. A comprehensive search in July 2016 of PubMed/MEDLINE, PsycINFO and Web of Science identified 2462 studies. Multiple reviewers appraised studies for inclusion or exclusion using a priori criteria; 3.9% met inclusion criteria. Data were extracted into a structured form; the Newcastle-Ottawa Scale assessed study quality, validity and bias. Forty-one studies (N=30 773) met inclusion criteria. Early adversity and telomere length were significantly associated (Cohen's d effect size=-0.35; 95% CI, -0.46 to -0.24; P<0.0001). Sensitivity analyses revealed no outlier effects. Adversity type and timing significantly impacted the association with telomere length (P<0.0001 and P=0.0025, respectively). Subgroup and meta-regression analyses revealed that medication use, medical or psychiatric conditions, case-control vs longitudinal study design, methodological factors, age and smoking significantly affected the relationship. Comprehensive evaluations of adversity demonstrated more extensive telomere length changes. These results suggest that early adversity may have long-lasting physiological consequences contributing to disease risk and biological aging.

Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to examine whether gender differences may have affected treatment response to S-adenosyl methionine (SAMe) in a recent failed randomized clinical trial (RCT) for adults with major depressive disorder. METHODS: Data from a 2-site, 12-week, double-blind RCT (n=189) assessing the efficacy of SAMe vs. placebo and a comparator selective serotonin reuptake inhibitor (escitalopram) were subjected to post-hoc analyses to evaluate effects of patient gender on treatment response. RESULTS: When assessing the efficacy outcomes within each gender separately, SAMe was superior to placebo among males (n=51), but not among females (n=62). Males showed a significant reduction of depression severity from baseline to study endpoint on the 17-item Hamilton Depression Rating Scale (4.3 point difference; p=0.034; d=0.95), while females did not show significant change. This finding emerged despite equivalence on baseline measures of depression severity between the gender groups. CONCLUSION: RESULTS of this secondary data analysis suggest that gender might impact the antidepressant efficacy of SAMe, with greater therapeutic effect found in males. The underlying mechanism is still relatively unknown. Further work is needed to replicate this observation in independent samples.Clinicaltrials.gov identifier: NCT00101452.

The neurobiological correlates of childhood adversity and implications for treatment.

OBJECTIVE: This article provides an overview of research on the neurobiological correlates of childhood adversity and a selective review of treatment implications. METHOD: Findings from a broad array of human and animal studies of early adversity were reviewed. RESULTS: Topics reviewed include neuroendocrine, neurotrophic, neuroimaging, and cognitive effects of adversity, as well as genetic and epigenetic influences. Effects of early-life stress on treatment outcome are considered, and development of treatments designed to address the neurobiological abnormalities is discussed. CONCLUSION: Early adversity is associated with abnormalities of several neurobiological systems that are implicated in the development of psychopathology and other medical conditions. Early-life stress negatively impacts treatment outcome, and individuals may require treatments that are specific to this condition.

Altered response to neuroendocrine challenge linked to indices of the metabolic syndrome in healthy adults.

Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p<0.001) and blood pressure (p<0.01), and positively associated with HDL cholesterol (p<0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease.

C-reactive protein, early life stress, and wellbeing in healthy adults.

OBJECTIVE: To determine whether C-reactive protein (CRP) can serve as a marker for alterations in immune function prior to the manifestation of significant psychiatric and medical disorders. METHOD: Ninety-two healthy adults were recruited from the community and determined to be free of psychiatric or medical disorders. The concentration of plasma CRP from a single resting sample was examined in relation to current mental and physical health as well as to self-reported history of early life adversity. RESULTS: C-reactive protein showed a significant positive correlation with body mass index (BMI; r = 0.477, P < 0.001). Non-specific pain, fatigue, and lower overall quality of physical health were all associated with higher CRP concentrations (all P < 0.05 or P < 0.01), after controlling for effect of BMI and other relevant covariates. Subthreshold depression symptoms and other indices of mental/emotional wellbeing were not associated with CRP, nor was CRP significantly linked to any measures of early life adversity. CONCLUSION: Lower-quality physical health and wellbeing, but not the presence of mood/anxiety symptoms or early life stress (ELS), were significantly related to plasma CRP. Elevated CRP does not appear to be a fundamental consequence of ELS among healthy adults.

Vagus nerve stimulation for depression: rationale, anatomical and physiological basis of efficacy and future prospects.

Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the vagus nerve stimulation (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication-resistant epilepsy and has recently been approved as an adjunct long-term treatment for chronic or recurrent depression. There is considerable evidence from both animal and human neurochemical and neuroimaging studies, that the vagus nerve and its stimulation influence limbic and higher cortical brain regions implicated in mood disorders, providing a rationale for its possible role in the treatment of psychiatric disorders. Clinical studies (open-label and comparator with treatment in naturalistic setting) in patients with TRD have produced promising results, especially when the response rates at longer-term (one- and two-year) follow-up time points are considered. Ongoing research efforts will help determine the place of VNS in the armament of therapeutic modalities available for major depression.

Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: associations with early adversity and depressive, anxiety and substance-use disorders.

Early adversity increases risk for developing psychopathology. Epigenetic modification of stress reactivity genes is a likely mechanism contributing to this risk. The glucocorticoid receptor (GR) gene is of particular interest because of the regulatory role of the GR in hypothalamic-pituitary-adrenal (HPA) axis function. Mounting evidence suggests that early adversity is associated with GR promoter methylation and gene expression. Few studies have examined links between GR promoter methylation and psychopathology, and findings to date have been mixed. Healthy adult participants (N=340) who were free of psychotropic medications reported on their childhood experiences of maltreatment and parental death and desertion. Lifetime depressive and anxiety disorders and past substance-use disorders were assessed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Methylation of exon 1F of the GR gene (NR3C1) was examined in leukocyte DNA via pyrosequencing. On a separate day, a subset of the participants (n=231) completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Childhood adversity and a history of past substance-use disorder and current or past depressive or anxiety disorders were associated with lower levels of NR3C1 promoter methylation across the region as a whole and at individual CpG sites (P<0.05). The number of adversities was negatively associated with NR3C1 methylation in participants with no lifetime disorder (P=0.018), but not in those with a lifetime disorder. GR promoter methylation was linked to altered cortisol responses to the Dex/CRH test (P<0.05). This study presents evidence of reduced methylation of NR3C1 in association with childhood maltreatment and depressive, anxiety and substance-use disorders in adults. This finding stands in contrast to our prior work, but is consistent with emerging findings, suggesting complexity in the regulation of this gene.

Reliability and validity of the symptoms of major depressive illness.

In two consecutive studies, we examined the interrater reliability and then the concurrent validity of interview ratings for individual symptoms of major depressive illness. The concurrent validity of symptoms was determined by assessing the degree to which symptoms observed or reported during an interview were observed in daily behavior. Results indicated that most signs and symptoms of major depression and melancholia can be reliably rated by clinicians during a semistructured interview. Ratings of observable symptoms (signs) assessed during the interview were valid indicators of dysfunction observed in daily behavior. Several but not all ratings based on patient report of symptoms were at variance with observation. These discordant patient-reported symptoms may have value as subjective reports but were not accurate descriptions of observed dysfunction.

alpha 2-Adrenergic receptor sensitivity in depression. The plasma MHPG, behavioral, and cardiovascular responses to yohimbine.

alpha 2-Adrenergic receptors play a major role in the regulation of the noradrenergic system. To assess the function of these receptors relative to possible abnormalities in noradrenergic function in depression, responses to the alpha 2-antagonist yohimbine hydrochloride were investigated in 45 depressed patients and 20 healthy control subjects. Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure (BP), pulse, subjective mood, and somatic symptoms were measured before and during yohimbine and placebo administration. The 25% increase in plasma MHPG levels produced by yohimbine did not differ between patients and controls. Mood responses also tended to be similar between groups, with patients reporting only minor improvement in depression following yohimbine. However, yohimbine caused significantly greater increases in somatic symptoms and tended to produce a greater increase in BP in patients than in controls. Evaluation of patient subgroups divided by the presence or absence of melancholia, psychosis, prominent anxiety, or personality disorder did not demonstrate consistent differences. In contrast, comparison of these findings with a prior study showed that patients with panic disorder and agoraphobia who received yohimbine manifested significantly greater increases in MHPG levels and ratings of anxiety, nervousness, and depression than depressed patients. These findings suggest that patients with major depression do not demonstrate marked abnormalities in alpha 2-adrenergic autoreceptor function.

Desipramine-yohimbine combination treatment of refractory depression. Implications for the beta-adrenergic receptor hypothesis of antidepressant action.

Preclinical investigations have shown that combined administration of the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the tricyclic antidepressant desipramine hydrochloride produces a reduction in brain beta-adrenergic receptor function within four days. Since the ability of antidepressant treatments to reduce beta-adrenergic receptor function has been hypothesized to mediate antidepressant efficacy, it was predicted that combined desipramine-yohimbine treatment would be a more rapid-acting and potent antidepressant regimen than desipramine alone. In the present investigation, the effects of desipramine (N = 11) and desipramine-yohimbine (N = 10) treatment on depressive symptoms, norepinephrine turnover, and blood pressure were determined in patients with major depression who had a history of nonresponse to standard antidepressant treatments. Neither desipramine nor desipramine-yohimbine proved to be an effective treatment, although concomitant yohimbine administration did attenuate the ability of desipramine to decrease plasma free and 24-hour urinary 3-methoxy-4-hydroxyphenyl-ethyleneglycol levels and blood pressure. Fifteen of the 21 patients eventually had a good response to pharmacologic treatments, particularly a desipramine-lithium carbonate or lithium carbonate-tranylcypromine sulfate combination treatment (11 of 14 responded). This study provides evidence against the beta-adrenergic receptor hypothesis of antidepressant action.

A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.

BACKGROUND: To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone. METHODS: Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition. RESULTS: For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personalty disorder. Other than mild, transient sedation, risperidone was well tolerated. CONCLUSION: These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy.

Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine (MDMA) users. Preliminary observations.

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on 5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous L-tryptophan were measured in nine recreational users of MDMA and compared with findings from nine matched healthy controls. L-Tryptophan induced a rise in the PRL concentration in controls, but not in MDMA users. Peak change and the area under the curve of the PRL response appeared to be blunted in MDMA users, but the difference from controls did not reach statistical significance. This study provides suggestive evidence of altered 5-HT function in MDMA users, but more definitive studies clearly are needed.

Effects of desipramine and fluvoxamine treatment on the prolactin response to tryptophan. Serotonergic function and the mechanism of antidepressant action.

It has been hypothesized that enhancement of brain serotoninergic (5-HT) function is involved in the mechanism of action of some antidepressants. To test this, the prolactin response to intravenously administered tryptophan, a clinical measurement of 5-HT function, was assessed before and during antidepressant treatment. Depressed patients received the tricyclic desipramine hydrochloride (N = 24) or the 5-HT reuptake inhibitor fluvoxamine maleate (N = 30). The prolactin response was significantly enhanced after long-term treatment (4 weeks) but not as reliably increased after short-term (1-week) desipramine treatment. Fluvoxamine enhanced the prolactin response after both short- and long-term treatment. Enhancement of the prolactin response was not clearly correlated with clinical improvement. The results of this study are consistent with preclinical evidence of enhanced 5-HT function during treatment with these classes of antidepressants, but also indicate that enhanced 5-HT function is not a sufficient condition for antidepressant efficacy.

Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan.

Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.

Lithium treatment and serotoninergic function. Neuroendocrine and behavioral responses to intravenous tryptophan in affective disorder.

Evidence suggests that lithium treatment alters serotoninergic (5-HT) function in laboratory animals and humans. Since 5-HT function may be abnormal in patients with affective disorders, we studied 23 such patients by measuring responses to intravenous infusion of the 5-HT precursor tryptophan before and during short-term (less than one week) or long-term (greater than three weeks) lithium treatment. The prolactin response to tryptophan was significantly enhanced after short-term lithium treatment; long-term lithium treatment had no effect. Other studies have shown that the prolactin response to tryptophan is also enhanced after long-term tricyclic antidepressant treatment in depressed patients and after short- and long-term lithium treatment in healthy subjects. The present findings suggest that lithium treatment enhances 5-HT function, but that homeostatic responses of the 5-HT system to long-term lithium treatment may differ in patients with affective disorder and healthy subjects.

Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine.

There is evidence that the abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function observed in patients with depression may be related to changes in central neurotransmitter receptor function. To evaluate this possibility further, the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride, which increases brain norepinephrine turnover, was administered to 40 patients with DSM-III major depression (18 melancholic, 22 nonmelancholic) and 16 healthy controls. Plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) level was measured as an index of noradrenergic function, and plasma cortisol level was used to assess the HPA response. Baseline cortisol levels were elevated in melancholic depressed patients, but not in nonmelancholic patients, when compared with healthy controls. The cortisol response to yohimbine was significantly greater in depressed patients than in controls, despite similar MHPG responses between groups. Since there is evidence that stimulation of postsynaptic alpha 2-adrenergic receptors inhibits HPA axis function, the abnormally increased cortisol response to the alpha 2-antagonist yohimbine suggests a relative subsensitivity of postsynaptic alpha 2-adrenergic receptors in depression.

Noradrenergic dysregulation during discontinuation of cocaine use in addicts.

BACKGROUND: The primary objective of the study was to prospectively determine possible noradrenergic dysregulation in cocaine addicts by assessing biochemical, behavioral, and cardiovascular responses to intravenous yohimbine hydrochloride during early and late discontinuation of cocaine use. METHODS: Twelve male and two female hospitalized cocaine-dependent subjects (mean +/- SD age, 30.9 +/- 7.3 years) who were not seeking primary treatment for addiction participated voluntarily for monetary remuneration. Following an initial test dose of intranasal cocaine, 2 mg/kg, cocaine addicts received single-blind, monitored cocaine insufflation, 2 mg/kg three times each day, for 3 consecutive days. One to two days (early discontinuation) and 15 to 16 days (late discontinuation) after the last dose of cocaine, subjects received double-blind, randomized intravenous infusions of yohimbine hydrochloride, 0.4 mg/kg, or placebo. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and plasma cortisol levels, anxiety-related symptoms on clinician- and subject-rated scales, blood pressure, and heart rate were measured throughout each test day. Ten of 14 subjects completed the entire study. RESULTS: Subjects had a significantly greater placebo-corrected MHPG response to yohimbine during early compared with late discontinuation. Subjects rated themselves significantly more nervous following yohimbine administration during early compared with late discontinuation. Seventy-one percent of subjects experienced a yohimbine-induced panic attack during early discontinuation compared with none during late discontinuation. CONCLUSIONS: The results of this study provide evidence of an underlying dysregulation in noradrenergic function and a vulnerability to panic anxiety during early discontinuation of cocaine use in addicts. Additional investigations of noradrenergic function appear warranted to further clarify derangements associated with cocaine addiction.

m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia.

OBJECTIVE: This study evaluated whether alterations in serotonin function in schizophrenic patients could be demonstrated by comparing the reactivity to a serotonin partial agonist, m-chlorophenylpiperazine (MCPP) in patients and healthy subjects. This study also assessed whether stimulation of serotonin receptors influenced the symptoms of schizophrenia. DESIGN: Double-blind randomized comparison of MCPP (0.1 mg/kg, intravenously, administered over 20 minutes) and placebo effects in patients and healthy subjects. SETTING: Department of Veterans Affairs Medical Center, West Haven, Conn. PATIENTS AND HEALTHY SUBJECTS: Fifteen healthy subjects recruited by public advertisement and 12 schizophrenic inpatients who had been neuroleptic free for at least 2 weeks prior to entry into the study. MAIN OUTCOME MEASURES: The principal outcome variable was the positive symptoms of schizophrenia operationally defined as the sum of scores on the four key items for schizophrenia on the Brief Psychiatric Rating Scale and the Brief Psychiatric Rating Scale thought disorder factor. Anxiety was assessed with a clinician-rated visual analog scale and plasma hormone levels were measured. RESULTS: m-Chlorophenylpiperazine significantly increased the positive symptoms of schizophrenia in patients but not healthy subjects. Patients and healthy subjects exhibited anxiety increases of comparable magnitude following MCPP. However, patients had higher baseline levels of anxiety and exhibited more prolonged anxiogenic responses to MCPP. Anxiety elevations did not correlate with increases in the four key symptoms in patients. Patients exhibited lower baseline prolactin levels compared with healthy subjects, but the two groups did not differ in their prolactin, growth hormone, and cortisol responses to MCPP. CONCLUSIONS: Schizophrenics, the only psychotic patient group studied to date, are the first patient group to exhibit propsychotic responses to MCPP. These data provide further evidence that serotonin systems modulate positive symptoms in some schizophrenic patients.

Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients.

OBJECTIVE: To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response. METHOD: Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebo-controlled cross-over study. After testing, they received open sequential antidepressant treatment. RESULTS: Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greater decrease in Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greater increase in Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvement were more likely to respond. CONCLUSIONS: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.

Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects.

To evaluate the role of serotonin (5-HT) function in obsessive-compulsive disorder (OCD), behavioral and biochemical responses to the 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) and the 5-HT precursor tryptophan were examined in healthy subjects and patients with OCD. Baseline prolactin levels and the prolactin rise following MCPP were significantly reduced in female patients compared with female healthy subjects. In contrast, the increase in prolactin level following tryptophan administration was not significantly different between male or female patients with OCD and the respective sex-matched healthy subjects. The prolactin responses to MCPP and tryptophan were both significantly higher in female patients and healthy subjects than in their male counterparts. The cortisol and growth hormone responses to MCPP and tryptophan were similar in the patients and healthy subjects and were not related to gender. The behavioral responses to MCPP or tryptophan were not consistently different between patients and healthy subjects, and neither MCPP nor tryptophan had effects on obsessive or compulsive symptoms. These results lend only partial support to the hypothesis that 5-HT dysfunction may be linked to the pathophysiology of OCD and point to the need for the evaluation of other neurotransmitter systems in future investigations of OCD.