Bipolar disorder (BPD) is one of the most severe psychiatric disorders and ranks in the top 10 causes of medical disability worldwide. The lifetime prevalence is approximately 4% in the United States,¹ with depressive symptomatology dominating the longitudinal course of the illness.² Currently approved treatments for bipolar depression include lithium, quetiapine, and the combination olanzapine and fluoxetine. Other treatments used during the depressive phase of the illness include lamotrigine, antidepressants, and atypical antipsychotics. However, many patients with bipolar depression do not respond adequately to these medications despite adequate trials.^2-4 Another limitation of existing therapeutics is that they are associated with a considerable lag of onset; only a fraction of patients meet response criteria by the end of the first week of treatment.^5-7 This delayed onset of antidepressant effects can result in considerable morbidity, including increased suicide risk.^8,9 Therefore, rapid-onset pharmacological strategies with pronounced and sustained effects would have an enormous impact on public health; this is particularly true because BPD is perhaps the psychiatric disorder with the highest mortality rate.¹⁰

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen’s d=−0.293; P=1.71 × 10⁻²¹), left fusiform gyrus (d=−0.288; P=8.25 × 10⁻²¹) and left rostral middle frontal cortex (d=−0.276; P=2.99 × 10⁻¹⁹). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. clinicaltrials.gov Identifier: NCT00088699.

Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function—mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity—were regulated by long-term corticosterone (CORT) treatment in an inverted “U”-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d = 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.