Short-Term Psychodynamic Psychotherapy for Functional Somatic Disorders: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Functionalsomatic disorders (FSD) are common and costly, thereby driving the need for the development of effective brief treatment options. Short-term psychodynamic psychotherapy (STPP) is one candidate treatment method. OBJECTIVE: To review and meta-analyze, where possible, randomized controlled trials (RCTs) of STPP for FSD. METHODS: Following a systematic search of the literature, we performed a meta-analysis of available RCT groups to determine the effects of STPP on a range of outcomes after treatment, and medium- and long-term follow-ups. RESULTS: In meta-analyses of 17 RCTs, STPP significantly outperformed minimal treatment, treatment as usual, or waiting list controls on somatic symptom measures at all time frames, with small to large magnitude effect sizes. Descriptive reviews of 5 RCTs suggest that STPP performed at least as well as other bona fide psychological therapies. Limitations of this meta-analysis include small samples of studies and possible publication bias. CONCLUSIONS: STPP is a valid treatment option for diverse FSD conditions resulting in somatic symptom reductions that persist over time. STPP should be included in FSD treatment guidelines.

Efficacy and cost-effectiveness of intensive short-term dynamic psychotherapy for treatment resistant depression: 18-Month follow-up of the Halifax depression trial.

BACKGROUND: Depressed patients with chronic and complex health issues commonly relapse; therefore, examining longer-term outcomes is an important consideration. For treatment resistant depression (TRD), the post-treatment efficacy of time-limited Intensive Short-Term Dynamic Psychotherapy (ISTDP) has been demonstrated but longer-term outcomes and cost-effectiveness are unclear. METHOD: In this superiority trial, 60 patients referred to Community Mental Health Teams (CMHT) were randomised to 2 groups (ISTDP=30 and CMHT=30). The primary outcome was Hamilton Depression Rating scale (HAM-D) scores at 18 months. Secondary outcomes included Patient Health Questionnaire (PHQ-9) depression scores and dichotomous measure remission. A health economic evaluation examined mental health costs with quality-adjusted life years (QALYs). RESULTS: Statistically significant treatment differences in depression previously found at 6 months favouring ISTDP were maintained at 18-month follow-up. Group differences in depression were in the moderate to large range on both the observer rated (Cohen's d = .64) and self-report measures (Cohen's d = .70). At 18 months follow-up the remission rate in ISTDP patients was 40.0%, and 23.4% had discontinued antidepressants. Health economic analysis suggests that ISTDP was more cost-effective than CMHT at 18 months. Probabilistic analysis suggests that there is a 64.5% probability of ISTDP being cost-effective at a willingness to pay for a QALY of $25,000 compared to CMHT at 18 months. LIMITATIONS: Replication of these findings is necessary in larger samples and future cost analyses should also consider indirect costs. CONCLUSIONS: ISTDP demonstrates long-term efficacy and cost-effectiveness in TRD.

Microstructural Findings in White Matter Associated with Cannabis and Alcohol Use in Early-Phase Psychosis: A Diffusion Tensor Imaging and Relaxometry Study.

Accumulating evidence suggests that brain white matter (WM) abnormalities may be central to the pathophysiology of psychotic disorders. In addition, there is evidence that cannabis use and alcohol use each is associated with WM abnormalities. However, there are very limited data on the effects of these substances on WM microstructure in patients with psychosis, especially for those at the early phase of illness. This project aimed to examine the impact of cannabis use and alcohol use on WM tissue in early-phase psychosis (EPP). WM was investigated in 21 patients with EPP using diffusion tensor imaging (DTI) and transverse relaxation time of tissue water (T2), with the primary outcomes being mean fractional anisotropy (FA) and T2. DTI analyses were performed at the full-brain level using tract-based spatial statistics with both DTI and T2 analysis done within a WM volume of interest (VOI) implicated in psychosis (containing the left superior longitudinal fasciculus). Our findings revealed that younger age of onset of regular alcohol use (more than one drink per week) was associated with lower FA values in the left thalamic radiation and left parahippocampal and left amygdalar WM. More frequent lifetime cannabis use was correlated with increased mean full-brain FA. There was no significant relationship found between FA and alcohol or cannabis use within the VOI. Relaxometry analysis revealed trend-level evidence of shortened T2 with later onset of regular alcohol use and with more frequent cannabis use. This study provides novel data demonstrating cortical and subcortical WM findings related to alcohol use in EPP and is the first to combine DTI and relaxometry, relating to this patient population.

A randomised controlled trial of Intensive Short-Term Dynamic Psychotherapy for treatment resistant depression: the Halifax Depression Study.

BACKGROUND: While short-term psychodynamic psychotherapies have been shown effective for major depression, it is unclear if this could be a treatment of choice for depressed patients, many of whom have chronic and complex health issues, who have not sufficiently responded to treatment. METHOD: This superiority trial used a single blind randomised parallel group design to test the efficacy of time-limited Intensive Short-Term Dynamic Psychotherapy (ISTDP) for treatment resistant depression (TRD). Patients referred to secondary care community mental health teams (CMHT) who met DSM-IV criteria for major depressive episode, had received antidepressant treatment ≥6 weeks, and had Hamilton Depression Rating Scale (HAM-D) scores of ≥16 were recruited. The effects of 20 sessions of ISTDP were judged through comparison against secondary care CMHT treatment as usual (TAU). The primary outcome was HAM-D scores at 6 months. Secondary outcomes included the Patient Health Questionnaire (PHQ-9) self-report measures for depression and dichotomous measures of both remission (defined as HAM-D score ≤7) and partial remission (defined as HAM-D score ≤12). RESULTS: Sixty patients were randomised to 2 groups (ISTDP=30 and TAU=30), with data collected at baseline, 3, and 6 months. Multi-level linear regression modelling showed that change over time on both depression scales was significantly greater in the ISTDP group in comparison to TAU. Statistically significant between-group treatment differences, in the moderate to large range, favouring ISTDP, were observed on both the observer rated (Cohen's d=0.75) and self-report measures (Cohen's d=0.85) of depression. Relative to TAU, patients in the ISTDP group were significantly more likely after 6 months to achieve complete remission (36.0% vs. 3.7%) and partial remission (48.0% vs. 18.5%). LIMITATIONS: It is unclear if the results are generalizable to other providers, geographical locations and cultures. CONCLUSIONS: Time-limited ISTDP appears an effective treatment option for TRD, showing large advantages over routine treatment delivered by secondary care services.

Illness versus substance use effects on the frontal white matter in early phase schizophrenia: A 4Tesla (1)H-MRS study.

OBJECTIVE: Young adults with early phase schizophrenia often report a past or current pattern of illicit substance use and/or alcohol misuse. Still, little is known about the cumulative and separate effects of each stressor on white matter tissue, at this vulnerable period of brain development. METHODS: Participants involved 24 healthy controls with a past or current history of sustained illicit drug use and/or alcohol misuse (users), 23 healthy controls without such history (normative data), and 27 users with early phase schizophrenia. (1)H-MRS data were acquired from a large frontal volume encompassing 95% of white matter, using a 4Tesla scanner (LASER sequence, TR/TE 3200/46ms). RESULTS: Reduced levels of choline-containing compounds (Cho) were specific to the effect of illness (Cohen's d=0.68), with 22% of the variance in Cho levels accounted for by duration of illness. Reduced levels of myoInositol (d=1.10) and creatine plus phosphocreatine (d=1.07) were specific to the effects of illness plus substance use. Effect of substance use on its own was revealed by reductions in levels of glutamate plus glutamine (d=0.83) in control users relative to normative data. CONCLUSIONS: The specific effect of illness on white matter might indicate a decreased synthesis of membrane phospholipids or alternatively, reduced membrane cellular density. In terms of limitations, this study did not include patients without a lifetime history of substance use (non-users), and the specific effect of each substance used could not be studied separately.

Sustained reduction in health care costs after adjunctive treatment of graded intensive short-term dynamic psychotherapy in patients with psychotic disorders.

The aim of this pilot study was to evaluate the changes in symptom severity and long-term health care cost after intensive short-term dynamic psychotherapy (ISTDP) individually tailored and administered to patients with psychotic disorders undergoing standard psychiatric care. Eleven therapists with different levels of expertise delivered an average of 13 one-hour sessions of graded ISTDP to 38 patients with psychotic disorders. Costs for health care services were compiled for a one-year period prior to the start of ISTDP (baseline) along with four one-year periods after termination. Two validated self-report scales, the Brief Symptom Inventory and the Inventory of Interpersonal Problems, were administered at intake and termination of ISTDP. Results revealed that health care cost reductions were significant for the one-year post-treatment period relative to baseline year, for both physician costs and hospital costs, and the reductions were sustained for the follow-up period of four post-treatment years. Furthermore, at treatment termination self-reported symptoms and interpersonal problems were significantly reduced. These preliminary findings suggest that this brief adjunctive psychotherapy may be beneficial and reduce costs in selected patients with psychotic disorders, and that gains are sustained in long-term follow-up. Future research directions are discussed.

Cortical Thickness in Young Treatment-Naive Children With ADHD.

OBJECTIVE: This study aimed to investigate the cortical thickness in areas of the brain that are hypothesized to be involved in response inhibition and error-monitoring behaviors. The authors hypothesized that children with ADHD would have a thinner prefrontal cortex (PFC) and anterior cingulate cortex (ACC) than healthy children. METHOD: In all, 25 ADHD and 25 healthy control male children (5-12 years) underwent magnetic resonance imaging. RESULTS: The authors found thinner right superior frontal gyrus in ADHD patients compared with controls (t = 2.01, df = 45, p = .049). The older children with ADHD drove this effect when participants were further subdivided into a younger and older age group (older participants: p = .004; younger participants: p = ns). CONCLUSION: These findings have implications for the developmental trajectory of the frontal lobe in ADHD.

Prefrontal glutamate levels differentiate early phase schizophrenia and methamphetamine addiction: a (1)H MRS study at 3Tesla.

Acute symptoms of methamphetamine-induced psychosis are similar to those of primary schizophrenia. Understanding similarities or differences in the biological substrate of these psychoses could lead to early differentiation of these two clinical conditions resulting in more efficient treatment strategies. Proton magnetic resonance spectroscopy was acquired from the medial prefrontal cortex in 29 unmedicated patients with first episode of psychosis (FEP), 29 abstinent methamphetamine-addicted people (METH) and 45 healthy controls (HCs) (age range 17.3 to 29.9years old). The METH group displayed robust reductions in concentration levels of glutamate (Glu) relative to FEP (Cohen's d=1.20) and HC (d=0.87). The METH group also displayed reduced levels of N-acetylaspartate (NAA) relative to FEP (d=0.53) and HC (d=0.76). The HC group displayed a positive association between levels of Glu and NAA, r(45)=0.52, p<0.001, while the two clinical groups failed to show this normal association. This suggests that the cellular metabolism is altered in both conditions. These data support the assumption that cellular abnormalities differ between primary schizophrenia and methamphetamine addiction despite the overlap in clinical presentation.

White matter changes in early phase schizophrenia and cannabis use: an update and systematic review of diffusion tensor imaging studies.

OBJECTIVES: The impact of cannabis use on the brain tissue is still unclear, both in the healthy developing brain and in people with schizophrenia. The focus of this review is on white matter, the primary connective infrastructure of the brain. METHODS: We systematically reviewed diffusion tensor imaging (DTI) studies of early phase schizophrenia (illness effect), of cannabis use in otherwise healthy brains (drug effect), and of early phase schizophrenia with cannabis use (combined effects). Studies had to include a healthy, non-cannabis using, control group as well as report on fractional anisotropy as it is the most commonly used DTI index. We excluded cohorts with heavy alcohol or illicit drug use and studies with a sample size of less than 20 in the clinical group. RESULTS: We retained 17 studies of early phase schizophrenia, which together indicate deficits in white matter integrity observed in all fiber tract families, but most frequently in association, callosal and projection fibers. In otherwise healthy cannabis users (2 studies), deficits in white matter tracts were reported mainly in callosal fibers, but also in projection and limbic fibers. In cannabis users with early phase schizophrenia (1 study), deficits in white matter integrity were also observed in all fiber tract families, except for limbic fibers. CONCLUSIONS: The current literature points to several families of white matter tracts being differentially affected in early phase schizophrenia. Further work is required to reveal the impact of cannabis use in otherwise healthy people as well as those with schizophrenia. LIMITATIONS: Paucity of available studies as well as restricting analysis to FA values represent the main limitations of this review.

Review of psychodynamic psychotherapy neuroimaging studies.

The clinical efficacy of psychodynamic psychotherapy (PDT) has undergone extensive study and review. Recently, researchers have studied the effects of this treatment on brain metabolic or synaptic activity, but the collective findings have never been reviewed. The objective of this review was to describe the findings of all neuroimaging studies of any form of PDT treatment. An extensive literature search through databases along with surveying of research groups were undertaken to acquire all available published studies. Eleven series were included in the final sample, consisting of 2 randomized controlled trials, 5 controlled trials and 4 case series, altogether involving 210 people: 94 healthy controls and 116 people with mood disorders, panic disorder, somatoform disorders and borderline personality disorder. A variety of neuroimaging techniques were used to examine regional metabolic activity and synaptic neurotransmission before and after treatment. The common finding was normalization of synaptic or metabolic activity in limbic, midbrain and prefrontal regions, occurring in association with improved clinical outcomes. PDT has demonstrable effects on brain function in diverse clinical populations as evidenced by a modest group of mixed neuroimaging studies.

NPAS3 variants in schizophrenia: a neuroimaging study.

BACKGROUND: This research is a one-site neuroimaging component of a two-site genetic study involving patients with schizophrenia at early and later stages of illness. Studies support a role for the neuronal Per-Arnt-Sim 3 (NPAS3) gene in processes that are essential for normal brain development. Specific NPAS3 variants have been observed at an increased frequency in schizophrenia. In humans, NPAS3 protein was detected in the hippocampus from the first trimester of gestation. In addition, NPAS3 protein levels were reduced in the dorsolateral prefrontal cortex of some patients with schizophrenia. Npas3 knockout mice display behavioural, neuroanatomical and structural changes with associated severe reductions in neural precursor cell proliferation in the hippocampal dentate gyrus. This study will evaluate the hypothesis that the severe reductions in neural precursor cell proliferation in the dentate gyrus will be present to some degree in patients carrying schizophrenia-associated NPAS3 variants and less so in other patients. METHODS/DESIGN: Patients enrolled in the larger genetic study (n = 150) will be invited to participate in this neuroimaging arm. The genetic data will be used to ensure a sample size of 45 participants in each genetic subgroup of patients (with and without NPAS3 variants). In addition, we will recruit 60 healthy controls for acquisition of normative data. The following neuroimaging measures will be acquired from the medial temporal region: a) an index of the microcellular environment; b) a macro-structural volumetric measure of the hippocampus; and c) concentration levels of N-acetylaspartate, a marker of neuronal health. DISCUSSION: This study will help to establish the contribution of the NPAS3 gene and its variants to brain tissue abnormalities in schizophrenia. Given the genetic and phenotypic heterogeneity of the disorder and the large variation in outcomes, the identification of biological subgroups may in future support tailoring of treatment approaches in order to optimize recovery.

Multimodal neuroimaging of frontal white matter microstructure in early phase schizophrenia: the impact of early adolescent cannabis use.

BACKGROUND: A disturbance in connectivity between different brain regions, rather than abnormalities within the separate regions themselves, could be responsible for the clinical symptoms and cognitive dysfunctions observed in schizophrenia. White matter, which comprises axons and their myelin sheaths, provides the physical foundation for functional connectivity in the brain. Myelin sheaths are located around the axons and provide insulation through the lipid membranes of oligodendrocytes. Empirical data suggests oligodendroglial dysfunction in schizophrenia, based on findings of abnormal myelin maintenance and repair in regions of deep white matter. The aim of this in vivo neuroimaging project is to assess the impact of early adolescent onset of regular cannabis use on brain white matter tissue integrity, and to differentiate this impact from the white matter abnormalities associated with schizophrenia. The ultimate goal is to determine the liability of early adolescent use of cannabis on brain white matter, in a vulnerable brain. METHODS/DESIGN: Young adults with schizophrenia at the early stage of the illness (less than 5 years since diagnosis) will be the focus of this project. Four magnetic resonance imaging measurements will be used to assess different cellular aspects of white matter: a) diffusion tensor imaging, b) localized proton magnetic resonance spectroscopy with a focus on the neurochemical N-acetylaspartate, c) the transverse relaxation time constants of regional tissue water, d) and of N-acetylaspartate. These four neuroimaging indices will be assessed within the same brain region of interest, that is, a large white matter fibre bundle located in the frontal region, the left superior longitudinal fasciculus. DISCUSSION: We will expand our knowledge regarding current theoretical models of schizophrenia with a more comprehensive multimodal neuroimaging approach to studying the underlying cellular abnormalities of white matter, while taking into consideration the important confounding variable of early adolescent onset of regular cannabis use.

Effectiveness and cost effectiveness of Davanloo's intensive short-term dynamic psychotherapy: does unlocking the unconscious make a difference?

More than 20 years ago Habib Davanloo coined the term unlocking of the unconscious to describe how the psychodynamic concept of the human unconscious can become accessible using the technique of Intensive Short-Term Dynamic Psychotherapy (ISTDP). According to Davanloo, the possibility that unconscious material will be revealed is greatly increased when therapeutic efforts promote dominance of the unconscious therapeutic alliance over unconscious resistance. When these ingredients are present there is a psychic shift that allows unacceptable painful feelings to come to the surface. Toward adding further empirical support for the concept, in this article we compare outcomes between patients who experienced one or more major unlocking of the unconscious (N = 57) to those who did not experience major unlocking (N = 32) during ISTDP treatment. Significant and widespread differences were seen between these two groups, those with major unlocking had greater symptom reduction, interpersonal gains, and cost reduction for treatment. The relevance of this to clinical practice and healthcare utilization will be discussed.

3-T proton magnetic spectroscopy in unmedicated first episode psychosis: a focus on creatine.

Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy ((1) H-MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr(240)), mainly Cr was detectable. The target region was an 18 cm(3) prefrontal volume. A negative association was found between age of patients and tCr(240) levels referenced to internal water, with 20% of the variance in tCr(240) accounted for by Age. A secondary finding revealed 16% reduction of tCr(240) levels in patients, solely when comparing participants older than the median age of patients. No association existed between tCr(240) levels and clinical variables. These findings support previous data reporting abnormalities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implications of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr(240) signal, and of potential group differences in T(2) times.

Smaller volumes of caudate nuclei in prepubertal children with ADHD: impact of age.

OBJECTIVE: Age-related abnormalities in caudate volumes have been reported to differ across the periods of childhood and puberty in children with ADHD. This study assessed caudate volumetric abnormalities across two narrow age clusters within the childhood period. METHOD: Three-dimensional manual tracings of the head and body of the caudate nucleus and of the cerebrum were acquired from 26 medication-naïve boys with a diagnosis of ADHD (ages 5.9-10.8 years), and 24 age-matched normal controls. RESULTS: Boys with ADHD had smaller total caudate volumes relative to controls, F(1,48)=4.29, p=0.04. Adjustment of caudate volumes with respect to age demonstrated that this group difference was driven solely by participants in the 5.9-7.3 year range, F(1, 46)=5.64, p=0.022, with an effect size of d=0.69. No Group effect was found in older participants, F(1, 46)=0.82, p=0.37. CONCLUSIONS: These novel findings suggest a different pattern of caudate volume abnormalities across narrow age clusters prior to puberty in boys with ADHD. Anatomical differences in brain structures related to ADHD in prepubertal children should be evaluated with respect to the changing developmental trajectory of brain regions within this period of rapid brain growth.

MRI-related anxiety levels change within and between repeated scanning sessions.

Magnetic resonance imaging (MRI) scans frequently trigger state anxiety in individuals being scanned. It is not known, however, whether levels of MRI-related anxiety change over the course of a single scan or across repeated scanning experiences. Since changes in state anxiety are known to affect regional brain activity in healthy volunteers, systematic changes in levels of MRI-related anxiety could confound findings from neuroimaging studies. We assessed anxiety levels in eleven healthy male volunteers during a control period and during two MRI scanning sessions. Anxiety levels were highest during the first MRI scan, dropping to control levels or below by the second scan. In addition, anxiety fluctuated within scanning sessions, particularly during the first scan, with levels high at the beginning of the session, decreasing during mid-scan and then increasing again toward the end of the session. These results suggest that habituation in an MRI simulator before participating in a neuroimaging study could help to decrease fluctuations in MRI-related anxiety. Moreover, in studies that address several experimental questions within a single scanning session, experimental designs could be adapted to avoid potential confounds from within-scan variation in scanner-related anxiety.

Effects of overnight sleep restriction on brain chemistry and mood in women with unipolar depression and healthy controls.

BACKGROUND: Partial or total overnight sleep deprivation produces immediate mood improvement in about 50% of patients with depression, but not in healthy controls. Our objectives were to compare the neurochemical changes that accompanied partial overnight sleep deprivation in healthy and depressed participants, and to compare baseline neurochemical profiles and overnight neurochemical changes between those depressed participants who did and did not respond to sleep loss with mood improvement. METHODS: We studied 2 brain regions (left dorsal prefrontal area and pons) in 12 women with unipolar depression and in 15 healthy women using proton magnetic resonance spectroscopy acquired at 1.5 T. The scans took place at baseline and 24 hours later after a night with sleep restricted to a maximum of 2.5 hours (22:30-01:00). We assessed 3 neurochemical signals (referenced to internal water): N-acetylaspartate (NAA), choline compounds (Cho) and creatine-plus-phosphocreatine (tCr). RESULTS: In both groups combined, sleep restriction caused a 20.1% decrease in pontine tCr (F(1-16) = 5.07, p = 0.039, Cohen's d = 0.54) and an 11.3% increase in prefrontal Cho (F(1-21) = 5.24, p = 0.033, Cohen's d = 0.46). Follow-up tests revealed that prefrontal Cho increases were significant only among depressed participants (17.9% increase, t(9) = -3.35, p = 0.008, Cohen's d = 1.06). Five depressed patients showed at least 30% improvement in mood, whereas 6 showed no change or worsening in mood after sleep restriction. Baseline pontine Cho levels distinguished subsequent responders from nonresponders to sleep restriction among depressed participants (z = 2.61, p = 0.008). LIMITATIONS: A limitation of this study is the relatively small sample size. CONCLUSION: Sleep restriction altered levels of pontine tCr and prefrontal Cho in both groups combined, suggesting effects on phospholipid and creatine metabolism. Baseline levels of pontine Cho were linked to subsequent mood responses to sleep loss, suggesting a role for pontine phospholipid metabolism in mood effects of sleep restriction.

A comparison of affected and unaffected relatives of patients with bipolar disorder using proton magnetic resonance spectroscopy.

OBJECTIVE: Bipolar disorders have a strong genetic underpinning. Little is known about biological predispositions that convey vulnerability for the illness. We searched for biological vulnerability markers using proton magnetic resonance spectroscopy (MRS) in both affected and unaffected participants at high genetic risk for bipolar disorder. METHODS: We recruited high-risk participants aged 15-30 years from families in which multiple members were affected with bipolar disorder. Our primary sample included 14 affected and 15 unaffected relatives of probands with bipolar I disorder. Our extended sample comprised 19 affected and 21 unaffected participants with a family history of either bipolar I or bipolar II disorders. We matched both samples by age and sex with 31 control participants without a personal or family history of psychiatric disorders. We performed single voxel proton MRS at 1.5 T in bilateral dorsal and ventral medial prefrontal cortices with correction for grey matter proportion. RESULTS: We found comparable levels of choline, creatine, myo-inositol and N-acetylaspartate among the groups in both samples. There were no differences between regions of the medial prefrontal cortex or between hemispheres for any of the metabolites in any of the samples. The exclusion of 5 participants taking medication did not change our results. CONCLUSION: Neurochemical changes in the medial prefrontal cortex that are measurable using proton MRS do not appear to be antecedent to the onset of mood disorders in genetically susceptible individuals.

Pituitary volumes in relatives of bipolar patients: high-risk study.

BACKGROUND: Increased, decreased, as well as unchanged pituitary volumes have been reported in bipolar disorders (BD). It is unclear, whether abnormal pituitary volumes increase vulnerability for BD (primary vulnerability marker), or are secondary to burden of illness. To address this question, we performed the first high-risk study of pituitary volumes in affected and unaffected relatives of bipolar subjects. METHOD: High-risk participants (age range 15-30 years) were recruited from families multiply affected with BD and included 24 unaffected, 19 affected subjects with first or second degree bipolar I or II relative, matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. Pituitary volumes were measured on 1.5 T 3D anatomical MRI images using standard methods. RESULTS: We found comparable pituitary volumes among unaffected, affected relatives of bipolar patients and controls. There were no differences in pituitary volumes between male and female subjects nor was there any sex by group interaction. Analyzing 26 participants with bipolar I parent or excluding 5 medicated subjects did not change the results. There were no differences between subjects from families containing bipolar I versus families containing only bipolar II subjects. CONCLUSIONS: The lack of abnormalities in unaffected and also affected subjects early in the course of illness in our study, as well as previous investigations of bipolar and familial unipolar children and adolescents, suggest that pituitary volume abnormalities are unlikely to be a primary risk factor for mood disorders.