Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Cognitive dysfunction associated with metabolic syndrome.

Metabolic syndrome which includes visceral obesity, elevated triglycerides, elevated fasting blood sugar, high blood pressure and a decrease in high-density lipoprotein cholesterol levels comprises the most common chronic physical illnesses in modern society. Components of the metabolic syndrome play a role in the pathogenesis of a plethora of medical illnesses. Evidence has emerged highlighting the detrimental effects of metabolic syndrome and its constituent features on the cognitive aspects of neurological function. The precise mechanisms underlying this association are not known but a combination of neuroanatomical changes and neuroendocrine consequences of somatic dysregulation may be relevant. As the population ages and the prevalence of metabolic syndrome increases, it is important that this clinically relevant association be recognized.

One-year outcome with antidepressant--treatment of bipolar depression.

OBJECTIVE: To examine the risk of relapse into mania or depression with varying duration of antidepressant treatment in a cohort of 59 patients with bipolar disorder. METHOD: An open naturalistic evaluation using life charting methods of patients with 1 year follow-up, who responded to antidepressant treatment and who then less or more than 6 months of antidepressant treatment. RESULTS: Patients who received more than 6 months of antidepressant treatment were less likely to relapse into depression at follow-up of 1 year. There was no difference in relapse rates for mania in the different antidepressant treatment duration groups. Gender and bipolar subtype did not significantly affect relapse rates for depression or mania. CONCLUSION: Our data, taken with other studies, suggest that the duration of optimal antidepressant treatment in bipolar disorder must be further evaluated.

The phenotypes of bipolar disorder: relevance for genetic investigations.

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.

Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial.

Some hypothyroid patients receiving levothyroxine replacement therapy complain of depressive symptoms despite normal TSH measurements. It is not known whether adding T(3) can reverse such symptoms. We randomized 40 individuals with depressive symptoms who were taking a stable dose of levothyroxine for treatment of hypothyroidism (excluding those who underwent thyroidectomy or radioactive iodine ablation of the thyroid) to receive T(4) plus placebo or the combination of T(4) plus T(3) in a double-blind manner for 15 wk. Participants receiving combination therapy had their prestudy dose of T(4) dropped by 50%, and T(3) was started at a dose of 12.5 micro g, twice daily. T(4) and T(3) doses were adjusted to keep goal TSH concentrations within the normal range. Compared with the group taking T(4) alone, the group taking both T(4) plus T(3) did not report any improvement in self-rated mood and well-being scores that included all subscales of the Symptom Check-List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study (P > 0.05 for all indexes). In conclusion, the current data do not support the routine use of combined T(3) and T(4) therapy in hypothyroid patients with depressive symptoms.

Impaired distractor inhibition in patients with schizophrenia on a negative priming task.

BACKGROUND: Numerous studies have suggested, via the interpretation of negative priming effects, that subjects with schizophrenia are less able than controls to inhibit irrelevant distracting information. Further issues concerning impairment in inhibitory processes are investigated here. First, recent research has revealed that negative priming (NP) effects can be caused by different processes, distractor inhibition or perceptual review. Therefore, conclusions concerning reduced inhibition in patients with schizophrenia are not possible from previous NP research. Secondly, previous NP studies have required subjects to identify some feature of the target. This is the first study to examine NP that uses a spatial task in patients with schizophrenia. METHOD: Twenty-eight subjects with schizophrenia and 28 age and sex matched non-psychiatric control subjects completed a computerized NP task that eliminated the possible contribution of perceptual review. RESULTS: Subjects with schizophrenia had reduced levels of NP compared to control subjects on this spatial NP task (t = 2.46, P < 0.02). Current age, positive, negative or total PANNS scores did not correlate with negative priming scores, but post hoc analyses revealed that clozapine-treated patients had significantly greater levels of negative priming than patients receiving typical antipsychotic medications. CONCLUSIONS: The present experiment eliminated the contribution of perceptual review to negative priming and demonstrated that when a pure measure of inhibition is taken on a localization task, patients with schizophrenia were less able to inhibit irrelevant distracting stimuli. The fact that NP was reduced in a spatial task suggested a more diffuse reduction in inhibition than previous studies that examined only identification-based responses.

Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant.

OBJECTIVE: To assess the effect of different antidepressants on induction of mania and cycle acceleration, commonly accepted unwanted effects of antidepressant treatment for acute bipolar depression. There is, however, the suggestion that certain classes of antidepressants may be less likely than others to cause these unwanted effects. METHOD: We conducted a prospective, open, naturalistic, life charting study to assess the occurrence of onset of mania and cycle acceleration attributable to two antidepressant classes: selective serotonin reuptake inhibitors (SSRIs) and bupropion. RESULTS: No difference was found between the two drug classes for either antidepressant-induced mania or cycle acceleration. Antidepressant-induced mania was much more likely to occur in bipolar I rather than bipolar II patients. The overall occurrence of induction of mania and cycle acceleration was low across antidepressant classes. CONCLUSION: These findings suggest that there is probably no difference in the risk of antidepressant-induced mania or cycle acceleration across commonly used classes of antidepressants for the treatment of bipolar depression.

Recollection memory deficits in patients with major depressive disorder predicted by past depressions but not current mood state or treatment status.

BACKGROUND: Neuropsychological studies have suggested that memory systems reliant on medial temporal lobe structures are impaired in patients with depression. There is less data regarding whether this impairment is specific to recollection memory systems, and whether clinical features predict impairment. This study sought to address these issues. METHOD: A computerized process-dissociation memory task was utilized to dissociate recollection and habit memory in 40 patients with past or current major depression and 40 age, sex and IQ matched non-psychiatric control subjects. The Cognitive Failures Questionnaire was used to assess patients' perceptions of day-to-day memory failures. RESULTS: Patients had impaired recollection memory (t = 4.7, P < 0.001), but no impairment in habit memory when compared to controls. Recollection memory performance was not predicted by indices of current mood state, but was predicted by self-assessments of impairment (beta = -0.33; P = 0.008) and past number of depressions (beta = -0.41; P = 0.001). There was no evidence that standard therapy with antidepressant medication either improved or worsened memory performance. CONCLUSIONS: The results confirm that patients with multiple past depressions have reduced function on recollection memory tasks, but not on habit memory performance. The memory deficits were independent of current mood state but related to past course of illness and significant enough that patients detected impairment in day-to-day memory function.

Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression.

Evidence suggests that brain-derived neurotrophic factor (BDNF) may be important in the pathophysiology of depression, in addition to its role as a neurotrophic factor for sensory neurons. The authors conducted a series of experiments examining the behavioral profile of BDNF heterozygous knockout and wild-type mice. The heterozygous and wild-type mice did not differ on measures of activity, exploration, or hedonic sensitivity, or in the forced swim test. When assessed in the learned helplessness paradigm, heterozygous mice were slower to escape after training than were wild-type mice (p = .02). This effect may be accounted for by the fact that these mice demonstrate a reduced sensitivity to centrally mediated pain, apparent on the hot plate and Formalin injection tests of nociception. Overall, heterozygous mice were not more likely to display anxious or depressive-like behaviors and, consequently, may not constitute a murine model of genetic vulnerability to mood and anxiety disorders.

Backward masking task performance in stable, euthymic out-patients with bipolar disorder.

BACKGROUND: Several studies have suggested that visual backward masking (VBM) impairment is present in patients with bipolar disorder, but the clinical features, such as current symptoms, treatment status and past burden of illness that may contribute to the impairment have not been well described. This study examined well-characterized euthymic patients on two VBM tasks to ascertain the extent of VBM impairment in this group and the clinical correlates of this impairment. METHOD: Twenty-eight euthymic patients with a DSM-IV diagnosis of bipolar disorder were matched by age, sex and IQ with 28 non-psychiatric control subjects. Both groups completed two VBM tasks; one required subjects to locate the target stimulus, one required identification of the target stimulus. Reaction times and error rates across a range of target-mask inter-stimulus intervals were assessed. RESULTS: Patients were significantly slower and had more errors on both VBM tasks. There was a significant relation between reaction times on the identification task and past burden of illness, particularly past number of depressions. There was no discernible impact of treatment status on reaction time or performance, including no difference in lithium-treated versus not treated subjects. CONCLUSIONS: These results are consistent with previous reports of neuropsychological deficits in euthymic bipolar disorder patients. The potential benefit to employing tasks such as VBM is that it may provide a method for relating clinical variables such as illness burden with known neural pathways in order to elucidate better the pathophysiology leading to impaired cognitive performance in patients with bipolar disorder.

Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium.

There is an established relationship between the monoaminergic neurotransmitter system and mood disorders. In an attempt to define further the pathophysiology of mood disorders, research is focussing on intracellular second messenger systems, including cyclic adenosine 3',5'-monophosphate (cAMP) and the polyphosphoinositol generated second messengers. The availability of tissue from the Stanley Foundation Neuropathology Consortium has offered us the opportunity to make a number of observations with respect to these second messenger systems in tissue from patients with major depressive disorder and bipolar affective disorder. There is evidence that antidepressants stimulate components of the cAMP pathway in patients with depression while mood stabilizers blunt the same pathway in patients with bipolar disorder. Furthermore, downstream targets of this pathway appear to be altered in patients with mood disorders. The relations between changes in second messenger systems, gene transcription, and clinical effects of current therapeutic regimens has implications for development of novel treatments of mood disorders.

Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.

BACKGROUND: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. METHODS: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. CONCLUSIONS: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.

Bipolar II disorder: symptoms, course, and response to treatment.

The authors provide an overview of the diagnosis, course, and treatment of bipolar II disorder, a distinct subtype that is often misdiagnosed as unipolar depression or bipolar I disorder. They discuss research suggesting that underdiagnosis of bipolar II disorder reflects a failure to identify subthreshold expression of mania (hypomania). The course of bipolar II disorder is different from that of bipolar I disorder or unipolar depression, with distinct differences in rates of recovery, clinical features, and number of episodes. The risk of suicide appears to be particularly elevated. High rates of comorbid disorders have been reported, including substance abuse or dependence, anxiety disorders, and personality disorders. Few definitive studies exist on which to base conclusions about the differential efficacy of various treatment strategies in bipolar II disorder and bipolar I disorder. Preliminary studies suggest that the newer anticonvulsants may be of benefit for patients with bipolar II disorder, while other data suggest that there may be a greater role for antidepressant medications.

A review of psychosocial outcome in patients with bipolar disorder.

OBJECTIVE: The aim of this paper is to review outcome in patients with bipolar disorder as assessed by interepisode level of functioning, as until recently this dimension of outcome has been relatively under-emphasized. METHOD: Studies that examined psychosocial outcome in bipolar disorder were reviewed on the basis of rating measurements employed, length of follow-up, number of subjects followed and degree of impairment reported. Studies were included only if results from patients with bipolar and unipolar disorder were reported in such a way that the groups could be distinguished. RESULTS: When studies of psychosocial outcome in bipolar disorder are examined in aggregate, it appears that 30-60% of individuals with this disorder fail to regain full functioning in occupational and social domains. CONCLUSION: This review highlights the fact that inter-episode functional recovery is incomplete in some patients, suggesting that comprehensive rehabilitative assessment and intervention may be essential to reduce the morbidity associated with this disorder.

Impaired distractor inhibition on a selective attention task in unmedicated, depressed subjects.

BACKGROUND: Impaired distractor inhibition may contribute to the selective attention deficits observed in depressed patients, but studies to date have not tested the distractor inhibition theory against the possibility that processes such as transient memory review processes may account for the observed deficits. A negative priming paradigm can dissociate inhibition from such a potentially confounding process called object review. The negative priming task also isolates features of the distractor such as colour and location for independent examination. METHOD: A computerized negative priming task was used in which colour, identification and location features of a stimulus and distractor were systematically manipulated across successive prime and probe trials. Thirty-two unmedicated subjects with DSM-IV diagnoses of non-psychotic unipolar depression were compared with 32 age, sex and IQ matched controls. RESULTS: Depressed subjects had reduced levels of negative priming for conditions where the colour feature of the stimulus was repeated across prime and probe trials but not when identity or location was the repeated feature. When both the colour and location feature were the repeated feature across trials, facilitation in response was apparent. CONCLUSIONS: The pattern of results supports studies that found reduced distractor inhibition in depressed subjects, and suggests that object review is intact in these subjects. Greater impairment in negative priming for colour versus location suggests that subjects may have greater impairment in the visual stream associated with processing colour features.

Effect of number of episodes on wellbeing and functioning of patients with bipolar disorder.

OBJECTIVE: To examine the relationship between number of episodes and inter-episode functioning in bipolar disorder. METHOD: Sixty-four euthymic subjects with bipolar affective disorder completed the Medical Outcomes Questionnaire Short Form and the Global Assessment of Functioning Scale. Goodness-of-fit models were used to define the relation between episode number and level of function. RESULTS: Non-linear logarithmic and power relations best described the association between number of episodes and outcome. Number of past depressions was a stronger determinant of outcome than past manias. CONCLUSION: Strategies to minimize the number of episodes experienced by patients with bipolar illness must be pursued aggressively if function is to be maintained, with particular attention given to minimizing episodes of depression.

Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression.

OBJECTIVE: This study's purpose was to clarify the appropriate treatment of bipolar depression by comparing the addition of an antidepressant versus a second mood stabilizer for inpatients being treated with lithium carbonate or divalproex sodium. METHOD: Twenty-seven patients were randomly assigned to groups that received double-blind treatment with paroxetine or a second mood stabilizer (lithium carbonate or divalproex sodium) for 6 weeks. RESULTS: Both groups showed significant improvement in depressive symptoms during the 6-week trial. There were significantly more noncompleters in the group being treated with the two mood stabilizers than in the group being treated with a mood stabilizer and paroxetine. CONCLUSIONS: Both treatments appeared to be effective; however, the addition of an antidepressant may have greater clinical utility in the treatment of bipolar depression.

Gabapentin as an adjunctive treatment in bipolar disorder.

OBJECTIVE: To evaluate the efficacy of gabapentin as an adjunctive treatment for bipolar disorder in both depressed and manic phases. METHOD: Thirty seven patients with bipolar type I or II with or without a rapid cycling course were openly treated with gabapentin added to current treatment for up to six months. Mood symptoms were rated weekly for 12 weeks then monthly for 3 months utilizing the HamD and YMS. RESULTS: Participants experienced a significant reduction in both depressive and manic symptoms. CONCLUSIONS: These findings are consistent with others in establishing the efficacy of gabapentin in both phases of bipolar disorder. LIMITATIONS: Small sample size and the use of an open uncontrolled design limit interpretation of results.