A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

The Committee for Treatment Guidelines of Mood Disorders, Japanese Society of Mood Disorders, published a Japanese guideline for the treatment of late‐life depression in 2020. Based on that guideline, the present guideline was developed and revised to incorporate the suggestions of global experts and the latest published evidence. In the diagnosis of late‐life depression, it is important to carefully differentiate it from bipolar disorders, depressive states caused by physical and organic brain disease, drug effects, and dementia, and to determine the comorbidity between late‐life depression and dementia. It is necessary to fully understand the clinical characteristics and psychosocial background of late‐life depression, evaluate the patient's condition, and provide basic interventions based on these factors. Problem‐solving therapy, reminiscence therapy/life review therapy, and behavioral activation therapy, and other forms of psychotherapy can reduce depressive symptoms. In terms of pharmacotherapy, newer antidepressants or non‐tricyclic antidepressants are recommended for late‐life depression, and it is recommended that the efficacy of least the minimal effective dosage should first be determined. Switching antidepressants and aripiprazole augmentation can be used to treatment‐resistant therapy. Electroconvulsive therapy and repetitive transcranial magnetic stimulation have demonstrated usefulness for late‐life depression. Exercise therapy, high‐intensity light therapy, and diet therapy also show some effectiveness and are useful for late‐life depression. Continuation therapy should be maintained for at least 1 year after remission.

Aims: Irritability, psychomotor agitation, and distractibility in a major depressive episode (MDE) should not be counted as manic/hypomanic symptoms of DSM-5-defined mixed features; however, this remains controversial. The practical usefulness of this definition in discriminating bipolar disorder (BP) from major depressive disorder (MDD) in patients with depression was compared with that of Benazzi's mixed depression, which includes these symptoms. Methods:The prevalence of both definitions of mixed depression in 217 patients with MDE (57 bipolar II disorder, 35 BP not otherwise specified, and 125 MDD cases), and their operating characteristics regarding BP diagnosis were compared.Results: The prevalence of both Benazzi's mixed depression and DSM-5-defined mixed features was significantly higher in patients with BP than it was in patients with MDD, with the latter being quite low (62.0% vs 12.8% [P < 0.0001], and 7.6% vs 0% [P < 0.0021], respectively). The area under the receiver operating curve for BP diagnosis according to the number of all manic/hypomanic symptoms was numerically larger than that according to the number of manic/hypomanic symptoms excluding the abovementioned three symptoms (0.798; 95% confidence interval, 0.736-0.859 vs 0.722; 95% confidence interval, 0.654-0.790). The sensitivity/specificity of DSM-5-defined mixed features and Benazzi's mixed depression for BP diagnosis were 5.1%/100% and 55.1%/87.2%, respectively.Conclusions: DSM-5-defined mixed features were too restrictive to discriminate BP from MDD in patients with depression compared with Benazzi's definition. To confirm this finding, studies that include patients with BP-I and using tools to assess manic/hypomanic symptoms during MDE are necessary.

Anthracyclines are effective antineoplastic drugs, but they frequently cause dose-related cardiotoxicity. The cardiotoxicity of conventional anthracycline therapy highlights a need to search for methods that are highly sensitive and capable of predicting cardiac dysfunction. We measured the plasma level of brain natriuretic peptide (BNP) to determine whether BNP might serve as a simple diagnostic indicator of anthracycline-induced cardiotoxicity in patients with acute leukemia treated with a daunorubicin (DNR)-containing regimen. Thirteen patients with acute leukemia were treated with a DNR-containing regimen. Cardiac functions were evaluated with radionuclide angiography before chemotherapies. The plasma levels of atrial natriuretic peptide (ANP) and BNP were measured at the time of radionuclide angiography. Three patients developed congestive heart failure after the completion of chemotherapy. Five patients were diagnosed as having subclinical heart failure after the completion of chemotherapy. The plasma levels of BNP in all the patients with clinical and subclinical heart failure increased above the normal limit (40 pg/ml) before the detection of clinical or subclinical heart failure by radionuclide angiography. On the other hand, BNP did not increase in the patients without heart failure given DNR, even at more than 700 mg/m². The plasma level of ANP did not always increase in all the patients with clinical and subclinical heart failure. These preliminary results suggest that BNP may be useful as an early and sensitive indicator of anthracycline-induced cardiotoxicity.

The DSM-5 incorporates a broad concept of mixed states and captured ≥3 nonoverlapping symptoms of the opposite polarity using a "with mixed features" specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed.