In contemporary psychiatry, depression and mania are conceived as different entities. They may occur together, as in bipolar disorder, or they may occur separately, as in unipolar depression. This view is partly based on a narrow definition of mania and a rather broad definition of depression. Generally, depression is seen as more prominent, common, and problematic; while mania appears uncommon and treatment-responsive. We suggest a reversal: mania viewed broadly, not as simply episodic euphoria plus hyperactivity, but a wide range of excitatory behaviors; and depression seen more narrowly. Further, using pharmacological and clinical evidence, and in contrast to previous theories of mania interpreted as a flight from depression, we propose the primacy of mania hypothesis (PM): depression is a consequence of the excitatory processes of mania. If correct, current treatment of depressive illness needs revision. Rather than directly lifting mood with antidepressants, the aim would be to suppress manic-like excitation, with depression being secondarily prevented. Potential objections to, and empirical tests of, the PM hypothesis are discussed.

Ethnic differences may significantly influence the outcome of psychopharmacological treatment, in terms of prescription, adherence, clinical response, emergence of side effects, as well as pharmacokinetics and pharmacodynamics. The purpose of this review was to explore the available literature in order to provide general suggestions to help clinicians in choosing the best therapeutic option for patients, taking into account ethnicity. Although findings are sometimes controversial, the overall published studies suggest that ethnicities other than Caucasians tend to show a lower response to antidepressants and a reduced compliance. Africans tend to be more prescribed with antipsychotics, probably due to cultural stereotypes, except with clozapine, probably for their chronic benign neutropenia. Asians usually require less antipsychotic dosages than Caucasians. The differential response and side effect profile of antidepressants and antipsychotics have been related to individual intrinsic factors, to genetic make-up, but also to cultural and contextual variables. Interestingly, albeit limited data suggest ethnic-related genetic heterogeneity at the level of the serotonin transporters, the cytochromes and some neuroreceptors. Taken together, no conclusive findings are available about the role and impact of ethnicity in psychopharmacology. One of the main problems is that the majority of the studies in psychopharmacology have been conducted on Caucasians, so that there is an urgent need to have data in other populations. Furthermore, in the era of precision medicine, the role of ethnicity may be also supported by genetic analysis.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier provides a less restrictive definition of mixed mood states, compared to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), including mood episodes that manifest with subthreshold symptoms of the opposite mood state. A limited number of studies have assessed the efficacy of treatments specifically for DSM-5–defined mixed features in mood disorders. As such, there is currently an inadequate amount of data to appropriately inform evidence-based treatment guidelines of DSM-5 defined mixed features. However, given the high prevalence and morbidity of mixed features, treatment recommendations based on the currently available evidence along with expert opinion may be of benefit. This article serves to provide these interim treatment recommendations while humbly acknowledging the limited amount of evidence currently available. Second-generation antipsychotics (SGAs) appear to have the greatest promise in the treatment of bipolar disorder (BD) with mixed features. Conventional mood stabilizing agents (ie, lithium and divalproex) may also be of benefit; however, they have been inadequately studied. In the treatment of major depressive disorder (MDD) with mixed features, the comparable efficacy of antidepressants versus other treatments, such as SGAs, remains unknown. As such, antidepressants remain first-line treatment of MDD with or without mixed features; however, there are significant safety concerns associated with antidepressant monotherapy when mixed features are present, which merits increased monitoring. Lurasidone is the only SGA monotherapy that has been shown to be efficacious specifically in the treatment of MDD with mixed features. Further research is needed to accurately determine the efficacy, safety, and tolerability of treatments specifically for mood episodes with mixed features to adequately inform future treatment guidelines.

Mood episodes with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)–defined mixed features are highly prevalent in bipolar disorder (BD), affecting ~40% of patients during the course of illness. Mixed states are associated with poorer clinical outcomes, greater treatment resistance, higher rates of comorbidity, more frequent mood episodes, and increased rates of suicide. The objectives of the current review are to identify, summarize, and synthesize studies assessing the efficacy of treatments specifically for BD I and II mood episodes (ie, including manic, hypomanic, and major depressive episodes) with DSM-5–defined mixed features. Two randomized controlled trials (RCTs) and 6 post-hoc analyses were identified, all of which assessed the efficacy of second-generation antipsychotics (SGAs) for the acute treatment of BD mood episodes with mixed features. Results from these studies provide preliminary support for SGAs as efficacious treatments for both mania with mixed features and bipolar depression with mixed features. However, there are inadequate data to definitively support or refute the clinical use of specific agents. Conventional mood stabilizing agents (eg, lithium and divalproex) have yet to have been adequately studied in DSM-5–defined mixed features. Further study is required to assess the efficacy, safety, and tolerability of treatments specifically for BD mood episodes with mixed features.

Pharmacogenetics brought the promise of matching individuals with treatments that would be efficacious while minimizing adverse events. This has been long needed in psychiatry, where treatment options have been empirical and treatment choices have been made largely based on clinical judgment. The efficacy and tolerability of antidepressants, the most common drugs used in mood disorders, have been widely studied in pharmacogenetics. Genetic association studies have been reported for pharmacokinetic genes such as the CYP450 isoenzymes or MDR1, and pharmacodynamic genes such as the serotonin transporter (SLC6A4) or the serotonin 2A receptor (HTR2A). However, despite the large number of reports, clinically useful predictors are still scarce for antidepressant monotherapy. Pharmacogenetic predictors of efficacy for mood stabilizers such as lithium and anticonvulsants have not had a dissimilar fate, and clinically meaningful markers are yet to emerge. The lack of consistent results may be in part due to small samples of heterogeneous populations and lack of consensus on phenotype definitions. Current pharmacogenetic recommendations include testing for HLA-B*1502 when using carbamazepine in Asian ancestry populations to prevent Stevens–Johnson syndrome, CYP2D6 genotypes when using pimozide, and CYP2D6 in polypharmacy to minimize drug interactions. This review, which is aimed at clinicians, lays the basis for understanding strengths and weaknesses of pharmacogenetic studies and outlines current clinical uses of these biomarkers.

In this second of two articles on second messenger/signal transduction cascades in major mood disorders, we will review the evidence in support of intracellular dysfunction and its rectification in the etiopathogenesis and treatment of bipolar disorder (BD). The importance of these cascades is highlighted by lithium's (the gold standard in BD psychopharmacology) ability to inhibit multiple critical loci in second messenger/signal transduction cascades including protein kinase C (involved in the IP3/PIP2 pathway) and GSK-3β (canonically identified in the Wnt/Fz/Dvl/GSK-3β cascade). As a result, and like major depressive disorder (MDD), more recent pathophysiological studies and rational therapeutic targets have been directed at these and other intracellular mediators. Even in the past decade, intracellular dysfunction in numerous neuroprotective/apoptotic cascades appears important in the pathophysiology and may be a future target for pharmacological interventions of BD.

Depressive symptoms and episodes dominate the long-term course of bipolar disorder and are associated with high levels of disability and an increased risk of suicide. However, the treatment of bipolar depression has been poorly investigated in comparison with that of manic episodes and unipolar major depressive disorder. The goal of treatment in bipolar depression is not only to achieve full remission of acute symptoms, but also to avoid long-term mood destabilization and to prevent relapses. A depressive presentation of bipolar disorder may often delay the appropriate management and, thus, worsen the long-term outcome. In these cases, an accurate screening for diagnostic indicators of a possible bipolar course of the illness should guide the therapeutic choices, and lead to prognostic improvement. Antidepressant use is still the most controversial issue in the treatment of bipolar depression. Despite inconclusive evidence of efficacy and tolerability, this class of agents is commonly prescribed in acute and long-term treatment, often in combination with mood stabilizers. In this article, we review available treatment options for bipolar depression, and we shall provide some suggestions for the management of the different presentations of depression in the course of bipolar disorder.

Objective: To review and summarize the currently available data on the use of anticonvulsant mood stabilizers (carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate) in the treatment of behavioral and psychological symptoms of dementia (BPSD); to determine whether these medications can be recommended for routine clinical use.

Methods: Literature search in five databases (PubMed, MEDLINE, EMBASE, PsychINFO and COCHRANE collaboration) and analysis of the randomized controlled double-blinded clinical trials found therein.

Results: A total of seven RCTs were identified (two for carbamazepine and five for valproate). One study showed statistically significant improvement of BPSD in the medication group in comparison to the placebo group; five studies showed no significant differences; one study showed statistically significant worsening of the symptoms in the medication group vs. placebo. The majority of the studies reported significantly more frequent adverse effects in the medication group.

Conclusion: Although clearly beneficial in some patients, anticonvulsant mood stabilizers cannot be recommended for routine use in the treatment of BPSD at the present time.