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.

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.

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.

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.

Late-onset Tay-Sachs disease presenting as catatonic schizophrenia: diagnostic and treatment issues.

BACKGROUND: It is not commonly appreciated that patients with hexosaminidase A deficiency (Tay-Sachs disease) can first present in adulthood with psychiatric illness. METHOD: A 17-year-old non-Jewish male patient was referred with a history of treatment-resistant catatonic schizophrenia. We uncovered coexistent neurologic abnormalities and evidence of cognitive decline. Metabolic screening revealed a severe deficiency of beta-hexosaminidase A. We reviewed the literature on late-onset gangliosidosis with attention to (1) the nature of the associated psychiatric and neurologic abnormalities and (2) the treatment of psychosis in these patients. RESULTS: The patient's catatonia responded promptly to benzodiazepine therapy. Treatment with neuroleptic medication resulted in the rapid development of neuroleptic malignant syndrome. The patient was thereafter maintained on lorazepam with resolution of his acute psychiatric disturbances and unexpected improvement in his neurologic status. CONCLUSION: Patients with hexosaminidase deficiency may first present in adolescence or adulthood with psychiatric illness, particularly schizophrenic-like psychosis. The presence of speech disturbance, gait abnormalities, movement disorders, and cognitive decline may indicate an underlying metabolic disorder. The use of traditional neuroleptics to treat the psychosis in such individuals may produce an unacceptably high risk/benefit ratio. Benzodiazepines may ameliorate the psychiatric and neurologic abnormalities in these patients.

Conditional immunomodulation following training with cyclophosphamide.

In 5 experiments, paired-group rats received a conditional stimulus (CS) paired with the immunosuppressive drug cyclophosphamide (CY). In Experiments 1-3, the CS was saccharin (SAC). Consistent with previous reports, these rats acquired a SAC aversion. However, there was no evidence of conditional immunosuppression. Rather, when reexposed to SAC in conjunction with an antigenic challenge, paired-group rats evidenced hemagglutination antibody titers similar to those seen in rats that never received the immunosuppressant. That is, the usual effect of CY in compromising immunological functioning was attenuated or eliminated by the CY-paired flavor. The findings of Experiments 1-3 were confirmed in Experiments 4-5, which used nongustatory CSs. Both audiovisual (noise and flashing-light) and pharmacological (pentobarbital) cues were also effective signals for CY injection. Following pairing with CY, these cues protected animals from the immunosuppressive effects of the drug.

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.

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.

Levels of functioning and well-being in recovered psychotic versus nonpsychotic mania.

The aim of the study was to compare psychotic and nonpsychotic bipolar patients on demographic and outcome measures. Sixty two patients with bipolar disorder were divided into groups on the basis of psychosis during an index episode of mania. Groups were compared on demographic, clinical and outcome measures. Psychotic patients were more symptomatic during the index episode, but they did not differ from nonpsychotic patients on ratings of function and well being when euthymic. Psychosis occurring within the context of an exacerbation of mania does not seem to predict a poorer outcome when patients return to the euthymic state. A limitation of the present study is that it involves short-term outcome, but the data can be used to inform patients and family about the possibility of full recovery even in the psychotic form of mania.

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.

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.

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.

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.

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.

Neuropsychiatric aspects of the adult variant of Tay-Sachs disease.

Tay-Sachs disease (a GM2 gangliosidosis) is an inherited neuronal storage disease that can affect individuals across the age spectrum. Psychosis is reported in 30% to 50% of adult-onset patients, and many are misdiagnosed with schizophrenia. Mood disorders are present in more than 25% and cognitive impairment in more than 20%. Treatment of psychosis with neuroleptics may not have a favorable risk/benefit ratio, but treatment with benzodiazepines or electroconvulsive therapy may be efficacious. Metabolic diseases such as gangliosidosis are probably under-recognized as causes of neuropsychiatric illness. Increased awareness of these disorders will lead to accurate diagnosis, appropriate treatment selection, and genetic counseling.

A two-illness model of bipolar disorder.

The current approach to mood disorders is that bipolar disorder, comprising both mania and depression, is a discreet illness distinct from unipolar depression. This formulation has profoundly influenced the approach to understanding the biology and etiology of these disorders, as well as the manner in which the various phases of bipolar disorder are treated. Our new model suggests that bipolar disorder comprises two distinct illnesses, mania and depression, and that bipolar depression is no different from unipolar depression. Studies of clinical syndromes, course of illness, family history and genetics, biological factors, and treatment response data directly or indirectly support this new model.

Color aftereffect contingent on text.

During adaptation, two different letter strings (each five or six letters) were presented to subjects alternately, one in green and the other in magenta. The extent to which these letter strings subsequently elicited a color aftereffect was assessed. In different experiments, the chromatic letter strings consisted of words and nonwords. The results indicated that letter strings that form English words can contingently elicit a color aftereffect. This was the case even when the words were anagrams. There was no evidence that nonword letter strings could contingently elicit such an aftereffect, even when the nonwords conformed to English orthography. The results are relevant to understanding other contingent color aftereffects (McCollough effects), illusory color noted by computer operators who work at monochrome (green or amber) displays, and the processing of text.

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.

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.