Co-occurring manic symptomatology influences HPA axis alterations in depression

Although dysfunctioning of the HPA axis is considered to be a core pathophysiological process in mood disorders, the evidence with regard to depression remains conflicting. This could partly be due to the large heterogeneity within mood disorders, since HPA axis abnormalities may also be associated with the extent of co-occurring manic symptomatology as is seen in bipolar disorder. In this study, patients with depressive disorder and bipolar spectrum disorders were studied with regard to their HPA axis functioning. In 304 healthy controls, 1134 patients with pure unipolar depressive disorder (UP), and 133 bipolar spectrum disorder patients (BD spectrum), cortisol was measured in 7 saliva samples to determine the 1 h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5 mg dexamethasone suppression test. Both patient groups had overall higher CAR levels compared to controls, but only UP patients showed a higher increase over time in the CAR. A linear association was found between increasing bipolarity and cortisol diurnal slope: BD spectrum patients had a significantly higher diurnal slope than UP patients. Dexamethasone suppression did not differ between mood disorder diagnoses. The heterogeneity in HPA axis functioning in patients with depression can partially be explained by co-existing manic symptomatology, since an increase in the CAR appears to be more specific for pure depression whereas the presence of bipolarity is associated with an increase in the diurnal slope of cortisol.     

Brain‐derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions

Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), are the most prevalent psychiatric conditions, and are also among the most severe and debilitating. However, the precise neurobiology underlying these disorders is currently unknown. One way to combat these disorders is to discover novel biomarkers for them. The development of such biomarkers will aid both in the diagnosis of mood disorders and in the development of effective psychiatric medications to treat them. A number of preclinical studies have suggested that the brain‐derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of MDD. In 2003, we reported that serum levels of BDNF in antidepressant‐naive patients with MDD were significantly lower than those of patients medicated with antidepressants and normal controls, and that serum BDNF levels were negatively correlated with the severity of depression. Additionally, we found that decreased serum levels of BDNF in antidepressant‐naive patients recovered to normal levels associated with the recovery of depression after treatment with antidepressant medication. This review article will provide an historical overview of the role played by BDNF in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Particular focus will be given to the potential use of BDNF as a biomarker for mood disorders. BDNF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. Finally, future perspectives on the use of proBDNF as a novel biomarker for mood disorders will be discussed.     

Is the association of alcohol use disorders with major depressive disorder a consequence of undiagnosed bipolar-II disorder?

BACKGROUND: There is emerging evidence that there is a spectrum of expression of bipolar disorder. This paper uses the well-established patterns of comorbidity of mood and alcohol use disorder to test the hypothesis that application of an expanded concept of bipolar-II (BP-II) disorder might largely explain the association of alcohol use disorders (AUD) with major depressive disorder (MDD). METHOD: Data from the Zurich study, a community cohort assessed over 6 waves from ages 20/21 to 40/41, were used to investigate the comorbidity between mood disorders and AUD. Systematic diagnostic criteria were used for alcohol abuse, alcohol dependence, MDD, and BP-II. In addition to DSM criteria, two increasingly broad definitions of BP-II were employed. RESULTS: There was substantially greater comorbidity for the BP-II compared to major depression and for alcohol dependence compared to alcohol abuse. The broadest concept of BP-II explained two thirds of all cases of comorbidity of AUD with major depressive episodes (MDE). In fact, the broader the definition of BP-II applied, the smaller was the association of AUD with MDD, up to non-significance. In the majority of cases, the onset of bipolar manifestations preceded that of drinking problems by at least 5 years. CONCLUSIONS: The findings that the comorbidity of mood disorders with AUD was primarily attributable to BP-II rather than MDD and that bipolar symptoms usually preceded alcohol problems may encourage new approaches to prevention and treatment of AUD.     

Comparing anxiety disorders and anxiety-related traits in bipolar disorder and unipolar depression

The frequent comorbidity of anxiety disorders and mood disorders has been documented in previous studies. However, it remains unclear whether specific anxiety traits or disorders are more closely associated with unipolar major depression (MDD) or bipolar disorder (BPD). We sought to examine whether MDD and BPD can be distinguished by their association with specific types of anxiety comorbidity. Individuals with a primary lifetime diagnosis of either bipolar disorder (N=122) or major depressive disorder (N=114) received diagnostic assessments of anxiety disorder comorbidity, and completed questionnaires assessing anxiety sensitivity and neuroticism. The differential association of these anxiety phenotypes with MDD versus BPD was examined with multivariate modeling. Panic disorder and generalized anxiety disorder (GAD) specifically emerged amongst all the anxiety disorders as significantly more common in patients with BPD than MDD. After controlling for current mood state, anxiety sensitivity and neuroticism did not differ by mood disorder type. This study supports prior research suggesting a specific panic disorder-bipolar disorder connection, and suggests GAD may also be differentially associated with BPD. Further research is needed to clarify the etiologic basis of anxiety disorder/BPD comorbidity and to optimize treatment strategies for patients with these co-occurring disorders.     

A continuity between bipolar II depression and major depressive disorder?

BACKGROUND: A recent series of studies has questioned the current categorical split of mood disorders into bipolar and depressive disorders. Mixed states, especially mixed depression (i.e., depression plus co-occurring, noneuphoric, hypomanic symptoms) might support a continuity between bipolar II (BP-II) depression and major depressive disorder (MDD). The aim of the study was to assess the distribution of intradepressive hypomanic symptoms rating between BP-II and MDD depressions. A bi-modal distribution would support a categorical distinction, and no bi-modality would support continuity. METHODS: Consecutive 389 BP-II and 261 MDD major depressive episode (MDE) outpatients were interviewed (off psychoactive drugs) with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide (HIG, to assess intradepressive hypomanic symptoms), and the Family History Screen, by a mood specialist psychiatrist in a private practice. Mixed depression was defined as MDE plus 3 or more intradepressive, noneuphoric hypomanic symptoms, a definition validated by Akiskal and Benazzi. The distribution of intradepressive hypomanic symptoms rating was studied by Kernel density estimate and by histogram. RESULTS: BP-II depression, versus MDD depression, had significantly lower age at onset, was significantly more likely to be atypical and mixed, had more depression recurrences, and a higher bipolar family history loading. BP-II depression, versus MDD depression, had significantly more irritability, racing/crowded thoughts, distractibility, psychomotor agitation, talkativeness, increased goal-directed activity, and excessive risky activities. HIG scores were significantly higher in BP-II. The distribution of intradepressive hypomanic symptoms rating showed no bi-modality in the entire depression sample. CONCLUSIONS: Interpretation of study findings relies on the method used to define a categorical disorder. By using classic diagnostic validators (such as family history and age at onset), BP-II and MDD depressions would seem to be distinct disorders. Instead, by using the 'bi-modality' approach, a continuity would seem to be supported. Which of these methods for classification is the best has yet to be shown.     

Are mood disorders and obesity related? A review for the mental health professional

OBJECTIVE: We reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap. METHOD: We performed a MEDLINE search of the English-language literature for the years 1966-2003 using the following terms: obesity, overweight, abdominal, central, metabolic syndrome, depression, mania, bipolar disorder, binge eating, morbidity, mortality, cardiovascular, diabetes, cortisol, hypertriglyceridemia, sympathetic, family history, stimulant, sibutramine, antiobesity, antidepressant, topiramate, and zonisamide. We evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. We also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response. RESULTS: The most rigorous clinical studies suggest that (1). children and adolescents with major depressive disorder may be at increased risk for developing overweight; (2). patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity; and (3). obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that (1). depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms; (2). obesity is associated with major depressive disorder in females; and (3). abdominal obesity may be associated with depressive symptoms in females and males; but (4). most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices. CONCLUSION: Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. Clinical and theoretical implications of this overlap are discussed, and further research is called for.     

Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.     

Critical role of brain-derived neurotrophic factor in mood disorders

The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders.     

Mood patterns and classification in bipolar disorder

PURPOSE OF REVIEW: The aim of this review is to highlight recent studies that have questioned the current split of mood disorders into the categories of bipolar and depressive disorders. RECENT FINDINGS: A continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder was supported by several lines of evidence: depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support the splitting between mania/hypomania and depression); family history, major depressive disorder is the most common mood disorder in relatives of bipolar probands; lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; bipolar features in major depressive disorder; major depressive disorder shifting to bipolar disorders; history of manic/hypomanic symptoms in major depressive disorder and correlation between lifetime manic/hypomanic symptoms and depressive symptoms in major depressive disorder; factors of hypomania inside major depressive disorder; recurrent course of major depressive disorder; depression more common than mania and hypomania in bipolar disorders; trait mood lability in major depressive disorder. SUMMARY: This review of the recent findings on the relationship between bipolar disorders (especially bipolar II disorder) and depressive disorders seems to support a continuity among mood disorders, and runs against the current classification of mood disorders dividing them into independent categories. Further research is needed in the area, in part because of its possible treatment impact.     

Family history of mood disorder and characteristics of major depressive disorder: a STAR*D (sequenced treatment alternatives to relieve depression) study

INTRODUCTION: Clinicians routinely ask patients with major depressive disorder (MDD) about their family history. It is unknown, however, if patients who report a positive family history differ from those who do not. This study compared the demographic and clinical features of a large cohort of treatment-seeking outpatients with non-psychotic MDD who reported that they did or did not have at least one first-degree relative who had either MDD or bipolar disorder. METHODS: Subjects were recruited for the STAR( *)D multicenter trial. Differences in demographic and clinical features for patients with and without a family history of mood disorders were assessed after correcting for age, sex, race, and ethnicity. RESULTS: Patients with a family history of mood disorder (n=2265; 56.5%) were more frequently women and had an earlier age of onset of depression, as compared to those without such a history (n=1740; 43.5%). No meaningful differences were found in depressive symptoms, severity, recurrence, depressive subtype, or daily function. CONCLUSIONS: Women were twice as likely as men to report a positive family history of mood disorder, and a positive family history was associated with younger age of onset of MDD in the proband. Consistent with prior research, early age of onset appears to define a familial and, by extension, genetic subtype of major depressive disorder.     

An update on regional brain volume differences associated with mood disorders

PURPOSE OF REVIEW: Structural brain changes are apparent in some magnetic resonance imaging studies of patients with mood disorders, but results are inconsistent. The focus of this review is to examine whether there are demographic or clinical characteristics of people with mood disorders that are associated with regional brain volume changes. A systematic search of the literature in English, from January 2004 to July 2005, was performed on MEDLINE. References cited in all reports were searched iteratively to identify missing studies. RECENT FINDINGS: Recent studies have focused on factors that might help to reconcile the divergent reports of regional brain volume changes in major depressive disorder and bipolar disorder. Small hippocampal volumes are apparent in patients with recurrent major depressive disorder, but not generally reported early in the course of adult onset depression. Small hippocampal volumes may be apparent in patients with childhood onset illness. Small hippocampal volumes are infrequently reported in bipolar disorder, but studies to date have not accounted for illness history or treatment status. Changes in amygdala volumes are inconsistently reported in patients with major depressive disorder or bipolar disorder. There are relatively fewer reports of other brain regions, including the areas of the frontal cortex and striatum. An extensive preclinical literature suggests that various psychotropic medications may have neurotrophic and neuroprotective effects, making documentation of treatment history essential. SUMMARY: Patients' age, sex, age at onset of disease, course of illness and treatment status may affect the detection of regional brain volume changes in people with mood disorders.     

The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review

BACKGROUND: Current treatment guidelines recommend discontinuation of an antidepressant within 3 to 6 months after remission of depression in patients with bipolar illness. Yet few studies directly compare the impact of antidepressant discontinuation versus antidepressant continuation on the risk for depressive relapse in patients with bipolar disorder who have been successfully treated for a depressive episode. METHOD: In a retrospective chart review, patients with DSM-IV bipolar disorder who were treated for an index episode of depression by adding antidepressant medication to ongoing mood stabilizer medications were identified. The risk of depressive relapse in 25 subjects who stopped antidepressant medications after improvement was compared with the risk of depressive relapse in 19 subjects who continued antidepressants after improvement. RESULTS: Termination of antidepressant medication significantly increased the risk of a depressive relapse. Antidepressant continuation was not significantly associated with an increased risk of mania. CONCLUSION: While this study may have been limited by the retrospective nature of the chart review, nonrandomized assignment of treatment, and reliance on unstructured progress notes, it suggests that antidepressant discontinuation may increase the risk of depressive relapse in some patients with bipolar disorder. Further research is needed to clarify whether maintenance antidepressant treatment may be warranted in some patients with bipolar disorder, especially in those with frequent recurrent depressive episodes.     

Challenging the unipolar–bipolar division: Does mixed depression bridge the gap?

BACKGROUND: Mixed states, i.e., opposite polarity symptoms in the same mood episode, question the categorical splitting of mood disorders in bipolar disorders and unipolar depressive disorders, and may support a continuum between these disorders. Study aim was to find if there were a continuum between hypomania (defining BP-II) and depression (defining MDD), by testing mixed depression as a 'bridge' linking these two disorders. A correlation between intradepressive hypomanic symptoms and depressive symptoms could support such a continuum, but other explanations of a correlation are possible. METHODS: Consecutive 389 BP-II and 261 MDD major depressive episode (MDE) outpatients were interviewed, cross-sectionally, with the Structured Clinical Interview for DSM-IV, the Hypomania Interview Guide (to assess intradepressive hypomanic symptoms) and the Family History Screen, by a mood disorders specialist psychiatrist in a private practice. Patients presented voluntarily for treatment of depression when interviewed drug-free and had many subsequent follow-ups after treatment start. Mixed depression (depressive mixed state) was defined as the combination of MDE (depression) and three or more DSM-IV intradepressive hypomanic symptoms (elevated mood and increased self-esteem were always absent by definition), a definition validated by Akiskal and Benazzi. RESULTS: BP-II, versus MDD, had significantly lower age at onset, more recurrences, atypical and mixed depressions, bipolar family history, MDE symptoms and intradepressive hypomanic symptoms. Mixed depression was present in 64.5% of BP-II and in 32.1% of MDD (p=0.000). There was a significant correlation between number of MDE symptoms and number of intradepressive hypomanic symptoms. A dose-response relationship between frequency of mixed depression and number of MDE symptoms was also found. CONCLUSIONS: Differences on classic diagnostic validators could support a division between BP-II and MDD. Presence of intradepressive hypomanic symptoms by itself, and correlation between intradepressive hypomanic symptoms and depressive symptoms could instead support a continuum. Other explanations of such a correlation are possible. Depending on the method used, a BP-II-MDD continuum could be supported or not.     

Diagnosing major depressive disorder IV: relationship between number of symptoms and the diagnosis of disorder

The symptom inclusion criteria for DSM-IV major depressive disorder (MDD) consist of a list of nine characteristic features of depression, at least five of which must be present. Two of the criteria for MDD, low mood and loss of interest or pleasure, are accorded greater importance than the remaining seven criteria in that one of these two features is required for the diagnosis. The implicit assumption underlying this organization of the criteria is that some individuals might meet five of the nine criteria without experiencing low mood or loss of interest or pleasure and thus be inappropriately diagnosed with major depression. We are not aware of any studies that have examined this assumption. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined how many psychiatric outpatients meet five of the nine DSM-IV criteria for MDD without simultaneously experiencing either low mood or loss of interest or pleasure. If this pattern is rare or does not exist, then the method of counting criteria to diagnose major depression could be simplified to a straightforward five out of nine. Twenty-seven (1.5%) patients reported five or more criteria in the absence of low mood or loss of interest or pleasure. More than half (N = 16) of these 27 patients were diagnosed with MDD or bipolar disorder, depressed type, in partial remission (N = 14), bipolar disorder mixed type (N = 1), or bipolar disorder not otherwise specified (N = 1). Six of the remaining 11 patients were diagnosed with depressive disorder not otherwise specified. Thus, few patients who met five or more of the MDD criteria were not diagnosed with a depressive disorder. This suggests that the diagnostic criteria for MDD can be simplified to a straightforward symptom count without reference to the necessity of low mood or loss of interest or pleasure.     

A review of empirically supported psychological therapies for mood disorders in adults

Background: The mood disorders are prevalent and problematic. We review randomized controlled psychotherapy trials to find those that are empirically supported with respect to acute symptom reduction and the prevention of subsequent relapse and recurrence. Methods: We searched the PsycINFO and PubMed databases and the reference sections of chapters and journal articles to identify appropriate articles. Results: One hundred twenty‐five studies were found evaluating treatment efficacy for the various mood disorders. With respect to the treatment of major depressive disorder (MDD), interpersonal psychotherapy (IPT), cognitive behavior therapy (CBT), and behavior therapy (BT) are efficacious and specific and brief dynamic therapy (BDT) and emotion‐focused therapy (EFT) are possibly efficacious. CBT is efficacious and specific, mindfulness‐based cognitive therapy (MBCT) efficacious, and BDT and EFT possibly efficacious in the prevention of relapse/recurrence following treatment termination and IPT and CBT are each possibly efficacious in the prevention of relapse/recurrence if continued or maintained. IPT is possibly efficacious in the treatment of dysthymic disorder. With respect to bipolar disorder (BD), CBT and family‐focused therapy (FFT) are efficacious and interpersonal social rhythm therapy (IPSRT) possibly efficacious as adjuncts to medication in the treatment of depression. Psychoeducation (PE) is efficacious in the prevention of mania/hypomania (and possibly depression) and FFT is efficacious and IPSRT and CBT possibly efficacious in preventing bipolar episodes. Conclusions: The newer psychological interventions are as efficacious as and more enduring than medications in the treatment of MDD and may enhance the efficacy of medications in the treatment of BD. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Mental disorders in offspring of parents with bipolar and major depressive disorders

Vandeleur C, Rothen S, Gholam‐Rezaee M, Castelao E, Vidal S, Favre S, Ferrero F, Halfon O, Fumeaux P, Merikangas KR, Aubry J‐M, Burstein M, Preisig M. Mental disorders in offspring of parents with bipolar and major depressive disorders. Bipolar Disord 2012: 14: 641–653. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. Methods: A total of 376 offspring (aged 6.0–17.9 years; mean = 11.5 years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co‐parents were interviewed by psychologists blind to proband diagnoses, using a semi‐structured diagnostic interview. Results: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). Conclusions: These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence.     

Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+)McN5652.

BACKGROUND: Several lines of studies have suggested the involvement of serotonin transporter (5-HTT) in the pathophysiology of mood disorders. The aim of this study was to examine whether 5-HTT binding was altered in patients with mood disorders using positron emission tomography (PET). METHODS: Thirteen antidepressant-naive or -free patients with mood disorders and 21 age-matched healthy control subjects participated in this study. The patients consisted of 7 with major depressive disorder (MDD) and 6 with bipolar disorder (BD). Positron emission tomography scans were performed using a selective ligand for 5-HTT, [11C](+)McN5652. The uptake was quantified in the thalamus and midbrain by graphical method with reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. RESULTS: Binding potential in the thalamus was significantly increased in patients with mood disorders as compared to control subjects, whereas BP in the midbrain did not differ between the groups. Subgroup comparison showed that MDD patients had significantly higher BP in the thalamus compared to control subjects. Binding potential of the thalamus was higher by approximately 22% in the combined patients and 23% in MDD patients relative to control subjects. CONCLUSIONS: These findings may suggest the possibility of altered 5-HTT in patients with mood disorders. Functional abnormality in the thalamus may be involved in the pathophysiology of mood disorders.     

Possible Association of Prokineticin 2 Receptor Gene (PROKR2) with Mood Disorders in the Japanese Population

Several investigations have suggested that disruption of circadian rhythms may provide the foundation for the development of mood disorders such as bipolar disorder (BP) and major depressive disorder (MDD). Recent animal studies reported that prokineticin 2 or prokineticin 2 receptor gene deficient mice showed disruptions in circadian and homeostatic regulation of sleep. This evidence indicates that prokineticin 2 gene (PROK2) and prokineticin 2 receptor gene (PROKR2) are good candidate genes for the pathogenesis of mood disorders. To evaluate the association between PROK2, PROKR2, and mood disorders, we conducted a case-control study of Japanese samples (151 bipolar patients, 319 major depressive disorder patients, and 340 controls) with four and five tagging SNPs in PROK2 or PROKR2, respectively, selected by HapMap database. We detected a significant association between PROKR2 and major depressive disorder and bipolar disorder in the Japanese population. In conclusion, our findings suggest that PROKR2 may play a role in the pathophysiology of mood disorders in the Japanese population. However, because our samples were small, it will be important to replicate and confirm these findings in other independent studies using larger samples. Taro Kishi and Tsuyoshi Kitajima participated equally in this work.