Clinical Neuropsychopharmacology and Therapeutics Vol. 7(2016)

In the past decade, four main topics have shaped research and clinical practice. 1) In randomized controlled trials, researchers have investigated whether treating prodromal symptoms of schizophrenia helps to reduce the conversion risk to full-blown schizophrenia. Results are ambiguous and the discussion on whether or not an intervention at the stage is justified is ongoing. 2) Following the enhanced understanding of the pathophysiology of schizophrenia, also with respect to specific symptom domains, pharmacological targets beyond D₂ receptor antagonism have been explored. Much work and enthusiasm has revolved around nicotinergic and glutamatergic compounds, so far with mostly discouraging results. 3) Several new-generation antipsychotics have become available as long-acting formulations. All of them have demonstrated a significant positive impact on relapse rates in placebo controlled studies. Whether these compounds also have advantages over first-generation depots and/or oral antipsychotics is still debated. The development of an inhalable antipsychotic has complemented the treatment options for the management of acutely agitated patients. 4) Lastly, attempts from various perspectives, including genetics and neuroimaging, have investigated whether it is possible to predict treatment response and drug safety. Although some look promising, they have not yet reached a stage in which they can be applied to everyday clinical practice. What has become clear, though, is that early non response predicts late non response, leading to the recommendation to switch antipsychotics much earlier than stated in most treatment guidelines.

Lurasidone is a novel atypical antipsychotic approved in the US and elsewhere for the treatment of schizophrenia and bipolar depression. The effect of lurasidone on cognition in patients with schizophrenia has been examined in several different studies, including short and long term studies. Lurasidone has been shown to improve measures of functional capacity as well as cognition and its cognitive enhancing potential has been compared to placebo and to active antipsychotic comparators. In specific, lurasidone has been reported to be superior to placebo and to quetiapine XR for cognitive functioning in a 6-week acute study along with a 6-month blinded extension, conducted in patients with schizophrenia. All doses of lurasidone assessed at study endpoint were superior to quetiapine during the extension study. When analyses of the effect of sleepiness and sedation were performed, only part of the cognitive benefit of lurasidone was attributable to its less sedating properties compared to quetiapine. Later research will need to replicate and expand these results, including examining cognitive benefits in other conditions.

Although the definition of depressive mixed state, more commonly known as mixed depression, is still controversial, about one-third of major depressive episodes are held to contain mixed components. The most frequent manifestations of mixed depression are irritability, distractibility and psychomotor agitation, although these symptoms are not included in the mixed features during a major depressive episode according to the DSM-5 criteria, which is therefore unlikely to cover the full scope of mixed depression in real-world settings. Mixed depression often accompanies risky behavior including impulsive suicide attempts. The early detection and treatment of these unstable conditions is therefore necessary. Also, sufficiently sensitive and specific screening methods for depressive mixed state are needed to avoid both under - and over-diagnosis. Antidepressants should be avoided since these drugs often worsen irritability, agitation and impulsivity, and increase risky behavior. Instead, combination therapy with mood stabilizer (s) to prevent the relapse of the depressive mixed state and atypical antipsychotics for rapid stabilization in the acute phase should be considered. Because there is very little evidence for effective pharmacotherapy in mixed depression, the efficacy of various mood-stabilizing agents, either as monotherapy or in combination therapies, should be extensively examined in the future using quantitative assessments of the psychopathology of mixed depression in patients with confirmed diagnoses of mixed depression.

When initiating treatment for acute-phase schizophrenia, careful consideration needs to be given to which drug will be used in the subsequent maintenance phase. Since blonanserin (BNS) and paliperidone (PAL) are both first-line treatments for acute-phase schizophrenia, our study retrospectively investigated the treatment continuation rate, dose levels, use of concomitant medications, clinical effects, and adverse drug reactions in 93 acute-phase schizophrenia patients receiving either of the monotherapies (BNS: n=40, PAL: n=53) to assess the treatment benefit of these drugs in acute - to maintenance-phase schizophrenia. The efficacy endpoints included the clinical global impression of severity (CGI-S), the clinical global impression of improvement (CGI-I) and the global assessment on function (GAF) scores assessed at Weeks 4, 8, 12, 24, and 52 after treatment initiation. Patients requiring involuntary hospitalization accounted for 75% of the BNS group and 90% of the PAL group and mostly comprised patients who had good social function before onset but relapsed because of poor drug adherence and hence received no residual benefit from their earlier treatment, as well as patients who were experiencing their first episode of schizophrenia. There were differences between the treatment groups in gender, age, and duration of illness. Notably, the BNS group had a higher proportion of females than the PAL group. In both groups, the CGI-S and CGI-I responses were affected by treatment in a majority of the patients who continued treatment, and the GAF score at Week 52 recovered to levels comparable to the pre-onset level in patients continuing treatment. The treatment continuation rate in this study (assessed by the Kaplan-Meier method) was 85% in the BNS group and 77% in the PAL group at Week 8 and 60.9% in the BNS group and 50.9% in the PAL group at Week 52. After Week 24, the number of dropouts in the BNS group decreased while the PAL group still had dropouts due to hyperprolactinemia-related adverse drug reactions. Treatment of schizophrenia requires careful selection of drugs in the acute phase that will ensure a good long-term prognosis and good drug adherence in the maintenance phase, and from this perspective, the results of this study suggest that BNS and PAL could be first-line drugs for the entire duration of treatment, from the acute phase to the maintenance phase.

Japan has the highest rate of triazolam use per capita in the world. A questionnaire-based survey of 820 triazolam users was conducted in order to assess the safety of triazolam therapy in a real-world clinical setting in Japan. The patients who used more than the recommended dose of triazolam (3.8%) were all elderly (65 years of age or older), and were more likely to be dissatisfied with their treatment and to increase the dose by themselves compared with those using an appropriate dose. Adverse symptoms were reported by 4.5% of subjects. The most common symptoms were morning drowsiness (1.7%) and impaired balance and/or falls (1.2%). None of the patients discontinued the use of hypnotics, and 99% of subjects continued triazolam treatment in spite of the unsatisfactory efficacy and/or adverse symptoms. This preliminary study suggests that prescription of triazolam may be associated with addictive behaviors in the elderly.

Selective serotonin reuptake inhibitors (SSRIs) are useful for the treatment of obsessive-compulsive disorder (OCD). Although combination therapies are recommended for treatment-resistant OCD, combination therapies involving the use of two SSRIs are not recommended. Here we report the case of a Japanese female who experienced improvement from combination therapy with escitalopram (ESC) and fluvoxamine (FLV). This patient had previously stopped taking other antidepressants because of tolerability issues. Since ESC had been partially effective, she refused to stop taking ESC. We therefore augmented her ESC therapy with FLV 25 mg/day, which resulted in inhibition of the metabolism of ESC by cytochrome P450 2C19 (CYP2C19). After this augmentation, the patient experienced a remarkable improvement in social functioning. The patient had a CYP2C19*1/*1 polymorphism. The patient's serum levels of ESC in the use of ESC plus FLV combination therapy and in the use of ESC alone were 67.7 ng/mL and 36.0 ng/mL, respectively. ESC and FLV combination therapy may be effective provided patients' CYP2C19 polymorphisms are checked and their serum concentrations of ESC are monitored.