Abstract: OBJECTIVE: Converging evidence suggests that the subgenual cingulate (SGC) is implicated in regulation of mood and in the pathophysiology of mood disorders. Our objective was to carry out the first meta-analysis of SGC volumes in patients with mood disorders. METHODS: We reviewed 10 volumetric magnetic resonance imaging studies of SGC volumes in patients with unipolar depression and bipolar disorders. For meta-analysis, we used standardized differences between means (SDMs) and random effects models. In the search for sources of heterogeneity, we subdivided the studies on the basis of diagnosis and presence of family history. RESULTS: The volumes of left and right SGC in patients with mood disorders were significantly reduced relative to healthy control subjects (SDM -0.38, 95% confidence interval [CI] -0.67 to -0.1 and SDM -0.2, 95% CI -0.4 to -0.007, respectively). There were significant SGC volume reductions in patients with unipolar (left SGC SDM -0.5, 95% CI -0.92 to -0.07; right SGC SDM -0.33, 95% CI -0.64 to -0.02,), but not bipolar, disorder. Patients with a positive family history of mood disorders showed significant left SGC volume decrease (SDM -0.52, 95% CI -0.96 to -0.07), which was not present among subjects without family history of mood disorders. There was no association between age and SGC volumes. CONCLUSION: The available evidence suggests the existence of left and less robust right SGC volumetric reductions in patients with mood disorders, predominantly in those with unipolar depression. The effect size of this difference was moderate and increased in more homogeneous subgroups of patients with a positive family history. The clustering of SGC abnormalities in patients with a family history, their presence early in the illness course and their lack of progression with age make SGC a candidate for a primary vulnerability marker, although studies in unaffected high-risk subjects are missing.
Abstract: BACKGROUND: Bipolar disorders (BD) have a strong genetic underpinning, yet no biological vulnerability markers for BD have been identified. Decreased volumes of subgenual cingulate (SGC) were replicated in familial bipolar patients. Presence of abnormality in unaffected subjects at genetic risk for an illness needs to be established before SGC volumes can be used as an endophenotype. This is the first study of SGC volumes in affected and unaffected subjects at familial risk for mood disorders. METHOD: High-risk participants were recruited from families multiply affected with BD. The high-risk sample included 13 affected and 13 unaffected offspring of bipolar I parents, who were matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. The expanded sample consisted of 24 unaffected, 19 affected subjects all with a first or second degree relative suffering from BD I or II. The age range for all subjects was 15-30 years. Subgenual cingulate volumes were measured on 1.5 T 3D anatomical MRI images using standard methods. RESULTS: We found comparable SGC volumes among unaffected, affected offspring of BD I parents and controls. Likewise no SGC abnormalities were found in the expanded sample of subjects with BD I or II relatives. Left SGC volumes in all groups were smaller than right SGC volumes without laterality by group interaction. The exclusion of 5 medicated subjects did not change the results. LIMITATIONS: Cross sectional design, inclusion of both bipolar I and bipolar II probands. CONCLUSIONS: Subgenual cingulate volume abnormalities were absent in unaffected or affected relatives of bipolar patients and thus did not meet criteria for endophenotype.
Abstract: OBJECTIVE: To identify specific treatment-emergent symptoms in response to antidepressant therapy in depression preceding bipolar disorder. METHODS: Retrospective chart review of response to antidepressants in "pre-bipolar" depression, compared to a matched unipolar sample. RESULTS: Family history of completed suicide (p=0.0003) and bipolar disorder (p=0.004) were more common in the pre-bipolar subgroup. Earlier age of onset of diagnosed depression (p=0.005) as well as even earlier episodes of untreated retrospectively diagnosed major depression (p<0.0001) were associated with a future bipolar course. The pre-bipolar group was less likely to respond to antidepressant treatment (p=0.009). Treatment-emergent "mixed" symptoms (two or more symptoms of DSM IV mania, mood lability, irritability/rage with co-existing depression) and in particular, "serious symptoms" (treatment emergent or increased agitation, rage or suicidality) occurred more commonly in the bipolar group. The two variables that best accounted for the between-group differences in logistic regression, were early age at first symptoms of depression and treatment-emergent agitation. CONCLUSIONS: Family history of completed suicide and/or bipolar disorder, early onset of depressive symptoms as well as treatment-emergent "mixed" symptoms are common in depression preceding the diagnosis of bipolar disorder.
Abstract: 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.
Abstract: OBJECTIVE: Rapid cycling (RC) affects 13-30% of bipolar patients. Most of the data regarding RC have been obtained in tertiary care research centers. Generalizability of these findings to primary care populations is thus questionable. We examined clinical and demographic factors associated with RC in both primary and tertiary care treated populations. METHOD: Clinical data were obtained by interview from 240 bipolar I disorder (BDI) or bipolar II disorder (BDII) community-treated patients and by chart reviews from 119 bipolar patients treated at an outpatient clinic of a teaching hospital. RESULTS: Lifetime history of rapid cycling was present in 33.3% and 26.9% of patients from the primary and tertiary care samples, respectively. Among community-treated patients, lifetime history of RC was significantly associated with history of suicidal behavior and higher body mass index. There was a trend for association between RC and BDII, psychiatric comorbidity, diabetes mellitus, as well as lower age of onset of mania/hypomania. In the tertiary care treated sample there was a trend for association between lifetime history of RC and suicidal behavior. Tertiary versus primary care treated subjects with lifetime history of RC demonstrated markedly lower response to mood stabilizers. CONCLUSIONS: Lifetime history of RC is highly prevalent in both primary and tertiary settings. Even primary care treated subjects with lifetime history of RC seem to suffer from a more complicated and less treatment-responsive variant of bipolar disorder. Our findings further suggest relatively good generalizability of data from tertiary to primary care settings.
Abstract: 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.
Abstract: BACKGROUND: The amygdala plays an important role in the regulation of emotions and has been implicated in the pathophysiology of mood disorders. Studies of amygdala volumes in mood disorders have been conflicting, with findings of increased, decreased and unchanged amygdala volumes in patients relative to controls. We present the largest meta-analysis of amygdala volumes in mood disorders and the first one to investigate modifying effects of clinical, demographic and methodological variables. METHODS: We reviewed 40 magnetic resonance imaging studies investigating amygdala volumes in patients with unipolar or bipolar disorders. For meta-analysis we used standardized differences in means (SDM) and random effect models. In the search for sources of heterogeneity, we subdivided the studies based on diagnosis, setting, age, medication status, sex, duration of illness, slice thickness, interrater reliability of tracing and anatomical definitions used. RESULTS: The volumes of the left and right amygdala in bipolar (N=215) or unipolar (N=409) patients were comparable to controls. Bipolar children and adolescents had significantly smaller left amygdala volumes relative to controls (SDM=-0.34, 95%CI=-0.65; -0.04, z=-2.20, p=0.03), whereas bipolar adults showed a trend for left amygdala volume increases (SDM=0.46, 95%CI=-0.03; 0.96, z=1.83, p=0.07). Unipolar inpatients had significantly larger left (SDM=0.35, 95%CI=0.03; 0.67, z=-2.17, p=0.03) amygdala volumes than controls, with no significant amygdala volume changes in unipolar outpatients. LIMITATIONS: Heterogeneity of included studies. CONCLUSIONS: The absence of overall differences in amygdala volumes, in the presence of significant and sometimes mirror changes in patient subgroups, demonstrates marked heterogeneity among mood disorders. Amygdala volume abnormalities may not be associated with mood disorders per se, but rather may underlie only some dimensions of illness or represent artifacts of medication or comorbid conditions.
Abstract: Treatment of bipolar disorder (BD) has traditionally focused on alleviation of acute symptoms and prevention of future recurrences. Current treatment guide-lines advocate more or less similar treatment algorithms for all patients. Such approach largely ignores the clinical, genetic, and pathophysiological heterogeneity of BD, which makes certain patients more (or less) likely to respond to specific treatments. Variables such as family history, comorbidity, course of illness, quality and duration of previous remissions, physical and medical comorbidity, and side-effects may help in selecting the most effective treatment for an individual patient, yet their value is not recognized by current algorithms. As well, polymorphisms of specific genes may prove useful in predicting treatment outcome and/or understanding the pharmacological mechanisms of mood stabilization. Novel molecular targets have recently emerged from studies of mechanisms of action of available mood stabilizers. They include inhibitors of protein kinase C, inhibitors of glycogen synthase kinase, or medications modulating glutamatergic neurotransmission. As well, treatment targets are moving beyond acute symptoms and prevention of mood episodes. Cognitive deficits, persistence of residual symptoms, and increased mortality of BD are recognized as important for outcome of BD, yet are not always adequately addressed by traditional treatments.
Abstract: OBJECTIVE: In accordance with the definition of health by the World Health Organization, outcome measures beyond mere syndromic recovery, such as quality of life ratings, would aid psychiatric practice and research. This is the first study of psychiatric diagnosis and illness stage specific profiles of subjective quality of life (SQOL) impairment. METHOD: Patients (n = 150) hospitalized at the Prague Psychiatric Center rated their SQOL using the Schwartz Outcome Scale at admission and discharge. Severity of illness and clinical improvement were measured by the Clinical Global Impression Scale. RESULTS: The highest and lowest SQOL at admission were reported by patients with psychosis and mood disorders respectively (F = 7.3, df = 2,147, P < 0.001). SQOL improved significantly during hospitalization in all diagnostic categories (F = 90.0, df = 1,147, P < 0.001), with the smallest and largest improvement in patients with psychosis and mood disorders, respectively (F = 5.6, df = 2,147, P = 0.005). There was a trend for differences in ratings of clinical improvement by patients, compared with psychiatrists, across diagnostic categories (F = 2.9, df = 2,147, P = 0.06), with significant differences only in patients with anxiety disorders. These patients also reported the lowest SQOL at discharge (F = 3.0, df = 2,147, P = 0.05). Global improvement correlated with improvement in SQOL only in patients with mood disorders (r = -0.4, P = 0.005). CONCLUSIONS: Main psychiatric diagnostic categories differ in SQOL and in association between SQOL and treatment. These differences may reflect illness-specific mechanisms, such as depressive symptoms in mood disorders, low insight in psychotic patients, aggravation of anxiety before discharge in patients with anxiety disorders, and may aid in planning of specific treatment interventions.
Abstract: AIM: Previous studies have suggested altered structural and functional asymmetry of the brain in schizophrenia. METHODS: Functional MRI was used to assess differences in cortical activation during a verbal task in Broca's area and its contralateral homologue in four pairs of right-handed monozygotic (MZ) twins discordant and concordant for schizophrenia with low and high familial loading for the illness and four healthy control MZ twin pairs. RESULTS: Pooled data from all subjects with schizophrenia showed increased activation in the right homologue of Broca's area in contrast to healthy individuals. Concordant twins (i.e. high familial loading group) showed prominent between co-twin differences in lateralization index within given region of interest. Intra-pair differences in lateralization index were significantly higher in concordant twins compared to the controls (0.69+/-0.4 vs. 0.13+/-0.13, P<0.03), albeit no significant differences in the variable were shown between the discordant and control groups. CONCLUSION: This study provides evidence of reduced cerebral dominance for language processing in patients with schizophrenia. The findings further suggest the need for additional research on relative proportion of genetic and environmental factors underlying deviations of functional asymmetry in schizophrenia.
Abstract: OBJECTIVES: The risk of suicidal behavior is substantially elevated in major affective disorders (AD). In bipolar disorder (BD), as many as 15% of patients may commit suicide and family history of suicide is recognized as one of the most important risk factors. Lithium reduces the rates of suicidal behavior in BD, especially in patients who achieve full mood stabilization. Yet even patients who continue experiencing mood episodes do benefit from anti-suicidal properties of lithium. These observations raise questions about the nature of the relationship between the neurobiological mechanisms of BD and suicide, namely whether they are shared or independent. METHODS: We studied the distribution of suicides and suicide attempts in 539 subjects from 78 families of probands with major AD, all responders to lithium prophylaxis. A Cox proportional hazard regression model was used to assess the contribution of several independent variables to the risks of AD, BD, and suicidal behavior. RESULTS: The lifetime prevalence of BD was significantly greater among first-degree relatives of suicide than non-suicide probands (22% versus 11%) and the prevalence of BD in families was associated with an increased risk of developing mood disorder and subsequently committing or attempting suicide (p = 0.003). Families fell into 1 of 3 groups, corresponding to a low (<0.1%), intermediate (17.8%), and high (87.8%) risk for suicide in affectively ill subjects. CONCLUSIONS: Suicidal behavior is distributed unevenly in families of probands with BD, aggregating in a subset of families. Our results also suggest that partially overlapping sets of genetic factors may underlie BD and suicide.
Abstract: PURPOSE: Borrelia burgdorferi (Bb) infection can affect the central nervous system and possibly lead to psychiatric disorders. We compared clinical and demographic variables in Bb seropositive and seronegative psychiatric patients and healthy controls. METHOD: Nine hundred and twenty-six consecutive psychiatric patients were screened for antibodies to Bb and compared with 884 simultaneously recruited healthy subjects. RESULTS: Contrary to healthy controls, seropositive psychiatric patients were significantly younger than seronegative ones. None of the studied psychiatric diagnostic categories exhibited stronger association with seropositivity. There were no differences between seropositive and seronegative psychiatric patients in hospitalization length, proportion of previously hospitalized patients and proportion of subjects with family history of psychiatric disorders. CONCLUSION: These findings elaborate on potential association between Bb infection and psychiatric morbidity, but fail to identify any specific clinical 'signature' of Bb infection.
Abstract: PURPOSE: Decreased hippocampal volume reported in neuropsychiatric and endocrine disorders is considered a result of putative neuronal damage mediated by corticosteroids. This is the first prospective study of hippocampal volume and function in patients treated with corticosteroids. METHODS: 14 subjects treated systemically with prednisone or betamethasone for dermatological or rheumatic disorders underwent prospective neurocognitive testing (Auditory Verbal Learning Test-AVLT, Trail Making Test-TMT, Digit Span-DS) and nine of them also repeated magnetic resonance volumetry. RESULTS: The mean duration of treatment between the first and the second assessment was 73+/- 38 days with mean daily dose of 37+/- 17 mg prednisone and 193+/- 29 days, with mean daily dose of 24+/- 15 mg prednisone between the first and the third assessment. There was a trend towards decreases in total AVLT scores and an improvement in the TMT and DS, but no significant changes in the volumes of the right or the left hippocampi between the assessments. Prednisone dose did not correlate with the hippocampal volume change. CONCLUSION: We observed a trend for decline in verbal memory despite improvement in psychomotor speed, attention/working memory and no macroscopic hippocampal volume changes during 36-238 days of treatment with therapeutic doses of corticosteroids.
Abstract: OBJECTIVES: In this study we examined general assessment of functioning (GAF), and its relation to clinical and demographic factors in bipolar patients. A number of studies, mostly from specialized programs, show that bipolar disorder often leads to occupational and social impairment. Here we report data from patients in a primary care setting. METHODS: A total of 252 patients from the Maritime Bipolar Registry with DSM-IV diagnoses of bipolar I or bipolar II disorder participated in the study. GAF ratings during maintenance treatment were compared across clinical and demographic variables. RESULTS: The mean GAF score in this sample was 67 +/- 17 (range 10-100). The GAF scores followed bimodal distribution with mean values of 50.5 +/- 10.3 and 79.0 +/- 10.3. Decreased functioning was found in patients with chronic illness course, history of rapid cycling, suicidal behaviour, psychiatric comorbidity, hypothyroidism, and diabetes mellitus, regardless of treatment of these conditions. There were no differences in the level of functioning between men and women, bipolar I and II patients, those with and without psychotic episodes, hypertension, treatment with antidepressants or antipsychotics. CONCLUSIONS: Functioning in primary care-treated bipolar patients in maintenance phase of treatment is decreased not only due to specific disorder-related variables, but also due to frequent comorbidity with other psychiatric and medical conditions.
Abstract: T1 and T2 relaxation times were examined in four pairs of monozygotic (MZ) twins discordant and concordant for schizophrenia with low and high genetic loading for the illness and five healthy control MZ twin pairs. Patients with schizophrenia (n = 11) showed significant prolongation in T1 relaxation times in the globus pallidus (GP) bilaterally (P < 0.005, Bonferroni corrected) when compared to 14 healthy MZ twins.
Abstract: OBJECTIVE: Neuroimaging studies show structural brain abnormalities in bipolar patients. Some of the abnormalities may represent biological risk factors conveying vulnerability for the disease. This paper aims to identify neuroanatomical risk factors for bipolar disorder (BD). METHODS: We reviewed magnetic resonance imaging (MRI) findings in populations in which the effects of the disease or treatment are minimal or where the chances of finding genetically coded risk factors shared within the families are increased. Such populations include unaffected relatives of bipolar patients, first-episode patients, children or adolescents with BD and patients with familial BD. RESULTS: MEDLINE search revealed 30 relevant scientific papers. Abnormalities in the volume of the striatum, left hemispheric white matter, thalamus and anterior cingulate as well as quantitative MRI signal hyperintensities were identified already in unaffected relatives of bipolar patients. Subjects in the early stages of the disease showed volume changes of the ventricles, white matter, caudate, putamen, amygdala, hippocampus and the subgenual prefrontal cortex. Reduction in the subgenual prefrontal cortex volume was replicated in three of four studies in patients with familial BD. CONCLUSIONS: Possible candidates for neuroanatomical risk factors for BD are volumetric abnormalities of the subgenual prefrontal cortex, striatum, white matter, and probably also the hippocampus and amygdala. Qualitative finding of white matter hyperintensities was already utilized as an endophenotype.
Abstract: The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness.
Abstract: OBJECTIVE: This paper presents functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) findings in a monozygotic twin pair discordant for schizophrenia. METHOD: Functional magnetic resonance imaging was used to determine hemispheric lateralization for speech and proton MRS (1H-MRS) was employed to assess the extent of putative insult to anterior hippocampus. RESULTS: Despite concordant right handedness, subject with schizophrenia displayed bilateral activation in areas subserving speech with greater extent of the total activated area compared with the healthy twin. The affected twin displayed relative bilateral decrease in N-acetylaspartate/creatin concentration in the anterior hippocampus compared with the healthy one. CONCLUSION: This is an evidence for non-genetic impairment of cerebral lateralization in monozygotic twin with schizophrenia.
Abstract: OBJECTIVE: Borrelia burgdorferi infection can affect the CNS and mimic psychiatric disorders. It is not known whether Borrelia burgdorferi contributes to overall psychiatric morbidity. The authors compared the prevalence of antibodies to Borrelia burgdorferi in groups of psychiatric patients and healthy subjects to find out whether there is an association between this infection and psychiatric morbidity. METHOD: Between 1995 and 1999 the authors screened for antibodies to Borrelia burgdorferi in 926 psychiatric patients consecutively admitted to Prague Psychiatric Center. They compared the results of this screening with findings from 884 consecutive healthy subjects who took part in an epidemiological survey of antibodies to Borrelia burgdorferi in the general population of the Czech Republic. Sera were tested by means of enzyme-linked immunosorbent assay. Circulating immune complexes were isolated by polyethylene glycol precipitation. To control for potential confounders, the two groups of patients and healthy subjects were matched according to gender and age. Results were obtained in a sample of 499 matched pairs. RESULTS: Among the matched pairs, 166 (33%) of the psychiatric patients and 94 (19%) of the healthy comparison subjects were seropositive in at least one of the four assays. CONCLUSIONS: These findings support the hypothesis that there is an association between Borrelia burgdorferi infection and psychiatric morbidity. In countries where this infection is endemic, a proportion of psychiatric inpatients may be suffering from neuropathogenic effects of Borrelia burgdorferi.
Abstract: There is an increasing evidence that corticosteroids damage the hippocampus in rodents and in primates. Hippocampal atrophy induced by corticosteroids may play an important role in the pathogenesis of a range of neuropsychiatric disorders. Hippocampus is necessary for short-term memory consolidation and HPA axis regulation. Signs of hippocampal damage (HPA dysregulation in combination with memory impairment) are found in affective disorders, Alzheimer's disease and in posttraumatic stress disorder. MRI volumetry reveals reduced hippocampal volume in these diseases. Evidence supporting the "glucocorticoid hypothesis" of psychiatric disorders is reviewed in the first part of the paper. Unresolved questions concerning temporary aspects of neurodegeneration, causality, reversibility, type of damage, factors increasing hippocampal vulnerability, and both pharmacological (CRH antagonists, antiglucocorticoid drugs, GABA-ergic, serotonergic, glutamatergic agents) and non-pharmacological (psychotherapy) treatment approaches are discussed in the second part.
