Insights and Advances Into Treatments for Major Depression

Visontay et al. (4) use a large longitudinal database along with a statistical approach that allows for making assumptions related to causality to understand the association between different amounts of alcohol consumption and depressive symptoms. Data drawn from the National Longitudinal Survey of Youth 1979 came from 5,667 participants beginning at ages 29–37. Longitudinal data up until age 41–49 were available from 3,593 of the participants. At different time points, participants’ alcohol use was assessed and characterized as abstinent (no drinking), occasional consumption (less than 1 day/week; no heavy episodic drinking), moderate consumption (greater than or equal to 1 day/week with no more than seven drinks/week for women and no more than 14 drinks/week for men; no heavy episodic drinking), and consumption above guidelines (greater than or equal to 1 day/week and more than seven drinks/week for women and 14 drinks/week or more for men; and/or heavy episodic drinking). Depression symptoms were derived from the Centre for Epidemiological Studies-Depression Scale short form. Using analytic methods that incorporate marginal structural models, significant protective effects were observed for the consistent occasional and consistent moderate alcohol drinkers such that, compared with abstainers, they were likely to have lower depression scores at 50 years of age. In contrast, when compared with abstainers the consistent above-guideline drinkers were found to have nonsignificantly higher depression symptoms. Similar findings were observed when categorical analyses were performed in relation to the likelihood of individuals having syndromal depression. The authors point out that these findings are consistent with previous reports and with the statistical method used they assert that the results may provide support for a statistically based causal relation between different amounts of alcohol use and depression. Dr. Edward Nunes from Columbia University contributes an editorial (5) that further discusses the intertwined relation between depression and alcohol use and more specifically addresses the clinical relevance of the findings from this paper.

Both antidepressants and cognitive behavioral therapy (CBT) are effective treatments for major depression and evidence supports that they are most effective when combined. While the specific mechanisms underlying the efficacy of these treatments are not understood, they are hypothesized to, in part, be due to the modification of different neural pathways. In this regard, Dunlop and colleagues (6) use resting-state functional MRI to assess brain changes associated with remission from major depression. A primary goal of the study was to compare changes in brain activity between psychotherapeutic and psychopharmacologic interventions. The study used resting-state functional connectivity (RSFC) data from 131 individuals collected at the beginning and end of a randomized clinical trial in which treatment-naive depressed patients received either 16 weeks of CBT, duloxetine 30–60 mg/day, or escitalopram 10–20 mg/day. Seed-based analyses were performed to assess RSFC using a posterior cingulate cortex seed for the default mode network, dorsolateral prefrontal cortex seed for the executive control network, anterior insular cortex seed for the salience network, and subgenual cingulate cortex seed for the affective network. Data from the two antidepressant medication treatment groups were combined in the analysis. First, shared brain changes in remitters were assessed across all treatment groups (N=64 of 131), and next data from antidepressant remitters (N=45 of 91) were compared with data from CBT remitters (N=19 of 40). Across both treatments, remitters (Hamilton Depression Score [HAM-D] ≤ 7), and nonresponders (≥50% reduction HAM-D) demonstrated significantly decreased RSFC between the subgenual anterior cingulate and motor cortices. Numerous differential changes in RSFC were detected when comparing CBT with antidepressant medication remitters involving connectivity patterns of the executive control network, the affective network, and the salience network. For example, when using the dorsolateral prefrontal cortex as a seed, its connectivity with the left inferior parietal lobule increased in CBT remitters and decreased in antidepressant remitters. Likewise, when using the subgenual cingulate cortex seed, increased connectivity with the posterior insula was observed in the CBT responders, whereas decreased connectivity occurred in the antidepressant responders. In the discussion section, the authors emphasize the finding that CBT remitters, and not antidepressant remitters, showed increased connectivity between the executive control network and attention-related regions. In an editorial (7), Dr. Stephen Strakowski from Indiana University discusses the difficulties in replicating findings in studies of this nature and cautions the reader to consider the findings as preliminary. He also highlights the potential importance and veracity of the findings defining the functional brain changes that are associated with successful CBT treatment.

The subgenual anterior cingulate cortex (sgACC) serves as an integrative hub between regulatory prefrontal cortical regions and emotion-related limbic structures, such as the amygdala, and altered sgACC function has often been associated with depression. Furthermore, this region has also been used as a deep brain stimulation target for the treatment of refractory depression. In relation to repetitive transcranial magnetic stimulation (rTMS), a number of studies, yielding somewhat mixed results, have assessed the value of using negative functional connectivity measures between the left dorsolateral prefrontal cortex (dlPFC) stimulation site and sgACC as a means to improve rTMS targeting. Elbau et al. (8) present data from a large sample, 295 participants, with the goal of further understanding the extent to which individualized functional connectivity measures between the left dlPFC stimulation site and sgACC predict treatment outcomes. The resting functional MRI data used for the analyses came from a sample of individuals with treatment-resistant depression that previously participated in a noninferiority clinical trial designed to compare 10Hz rTMS to theta burst TMS (9). It is important to note that the same neuroanatomical coordinates for the left dlPFC TMS stimulation site were used across all the subjects, and this was based on neuroanatomical coordinates from an earlier study that linked functional connectivity measures to optimal outcomes. In other treatment studies, individualized dlPFC stimulation sites are selected based on the dlPFC region that is most negatively functionally coupled to sgACC (10). The current study is distinguished by its large sample, and the thorough analytic approach that was used, which included electric field modeling to estimate the actual subregions of dlPFC in which electrical changes were induced. The authors found that pretreatment individual differences in negative functional coupling between the dlPFC stimulation site and sgACC accounted for 3% of the variance in treatment outcomes. While this is a considerably smaller effect than previously reported, it is important to consider that the method used here did not prospectively select the dlPFC site that was most functionally connected with sgACC. It is interesting that the strongest effects for the predictive value of the functional coupling between the stimulation site and sgACC were found to be in a subgroup of patients that had a distinct breathing pattern characterized as “burst breathing.” Burst breathing, which is associated with a pattern of BOLD signal fluctuations across the brain, also has distinct impacts on resting connectivity that differ from individuals that typically engage in other forms of breathing such as deep breathing (11). In their editorial (12), Dr. Noah Phillips from Brown University and Dr. Shan Siddiqi from Harvard Medical School discuss this finding in relation to earlier work and comment on important methodological issues as they relate to the small but significant predictive effect that was observed.

Sachs and colleagues (13) report data from a Phase III study that is aimed at assessing the extent to which cariprazine is an effective add-on treatment for individuals with major depression that have not responded to their current treatment. This study builds on earlier studies with cariprazine and on studies demonstrating the efficacy of other atypical antipsychotic medications as adjunctive treatments for major depressive disorder, some of which have received FDA approval (i.e., aripiprazole, quetiapine, and brexpiprazole). Cariprazine was also recently approved by the FDA as an adjunctive treatment for major depression and is also approved for treating schizophrenia and bipolar disorder (mania, depression, and mixed). Cariprazine has multiple neurochemical effects, including acting as a partial agonist at the D₃, D₂, and 5-HT1_A receptors with highest selectivity for D₃. It also acts as a 5-HT_2B and 5-HT_2A partial antagonist. In this 6-week, double-blind study, patients with major depression remained on their antidepressant treatment and also received either placebo, cariprazine 1.5 mg/day, or cariprazine 1.5 mg for 2 weeks and then increased to 3 mg/day. A total of 751 patients were included in the modified intention-to-treat analysis. In relation to the primary outcome measure, change in Montgomery-Asberg Depression Rating Scale (MADRS), cariprazine 1.5mg/d resulted in significantly greater decreases when compared with placebo; however the effects of the 3.0 mg/day dose were not statistically significant. The effect of the 1.5 mg/day dose was found to be significant after 2 weeks of drug administration. Change in the Clinical Global Inventory scale was used as the secondary outcome measure and while both doses of cariprazine were associated with greater reductions than placebo, neither reached statistical significance. Regarding response and remission rates, the 1.5-mg dose of cariprazine demonstrated significantly greater response rates compared with placebo (≥50% MADRS reduction: cariprazine=44.0%, placebo=34.9%) whereas no significant differences were found for remission rates (MADRS≤10: 25.2% versus 23.3%, respectively. Among the side effects, the cariprazine-treated patients experienced more akathisia (3mg group– 7.9%, 1.5mg group −5.2% compared to placebo group-0.8%). In an editorial (14), Dr. Michael Thase from the University of Pennsylvania discusses the specific findings related to cariprazine as well as the overall utility of second-generation antipsychotics in treating depression.