Currently, a major hypothesis for the pathophysiology of schizophrenia proposes that numerous risk factors converge on the N-methyl-D-aspartate (NMDA) receptor for the neurotransmitter glutamate, resulting in neurodevelopmental abnormalities at glutamate synapses and hypofunction of NMDA receptors.This hypothesis was presented in a previous “Trends in Psychopharmacology” column. Novel treatments are now in development that can theoretically boost the function of NMDA receptors by enhancing actions at the glycine co-transmitter site of this receptor complex. Early studies already indicate that this may lead to improvement in negative and cognitive symptoms of schizophrenia, especially when added as augmenting agents to atypical antipsychotics.

There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.

This is a report of a joint World Psychiatric Association/International College of Neuropsychopharmacology (WPA/CINP) workgroup concerning the risk/benefit ratio of antipsychotics in the treatment of schizophrenia. It utilized a selective but, within topic, comprehensive review of the literature, taking into consideration all the recently discussed arguments on the matter and avoiding taking sides when the results in the literature were equivocal. The workgroup’s conclusions suggested that antipsychotics are efficacious both during the acute and the maintenance phase, and that the current data do not support the existence of a supersensitivity rebound psychosis. Long-term treated patients have better overall outcome and lower mortality than those not taking antipsychotics. Longer duration of untreated psychosis and relapses are modestly related to worse outcome. Loss of brain volume is evident already at first episode and concerns loss of neuropil volume rather than cell loss. Progression of volume loss probably happens in a subgroup of patients with worse prognosis. In humans, antipsychotic treatment neither causes nor worsens volume loss, while there are some data in favor for a protective effect. Schizophrenia manifests 2 to 3 times higher mortality vs the general population, and treatment with antipsychotics includes a number of dangers, including tardive dyskinesia and metabolic syndrome; however, antipsychotic treatment is related to lower mortality, including cardiovascular mortality. In conclusion, the literature strongly supports the use of antipsychotics both during the acute and the maintenance phase without suggesting that it is wise to discontinue antipsychotics after a certain period of time. Antipsychotic treatment improves long-term outcomes and lowers overall and specific-cause mortality.

The aim of this study was to examine the pattern of comorbidity among obsessive-compulsive personality disorder (OCPD) and other personality disorders (PDs) in a sample of 400 psychiatric inpatients. PDs were assessed using the Semistructured Clinical Interview for DSM-III-R Personality Disorders (SCID-II). Odds ratios (ORs) were calculated to determine significant comorbidity among OCPD and other axis II disorders. The most elevated odds ratios were found for the cooccurrence of OCPD with cluster A PDs (the “odd” PDs, or paranoid and schizoid PDs). These results are consistent with those of previous studies showing a higher cooccurrence of OCPD with cluster A than with cluster C (“anxious”) PDs. In light of these observations, issues associated with the nosologic status of OCPD within the Diagnostic and Statistical Manual of Mental Disorders clustering system remain unsettled.

Cognitive impairment has emerged as a key treatment priority in neuropsychiatric disorders. However, there is a lack of treatments with solid and lasting efficacy on cognition. A neurocircuitry-based biomarker model of pro-cognitive effects is critically needed to select among new candidate treatments. In a recent review of functional magnetic resonance imaging (fMRI) studies in mood disorders, we found that cognitive impairments are consistently accompanied by aberrant (hypo- and hyper-) activity in the dorsal prefrontal cortex (PFC) and the default mode network (DMN), and that activity change in these regions commonly occurs with cognitive improvements. Here, we (i) review the putative model from our recent review article, which explains the discrepant findings regarding the direction of aberrant dorsal PFC activity and treatment-related activity change in mood disorders. Inspired by the Research Domain Criteria project, we do this in order to (ii) examine whether a similar pattern of activity change occurs across distinct neuropsychiatric disorders and thereby provides a common biomarker for pro-cognitive effects. Lastly, we (iii) discuss whether dorsal PFC and DMN target engagement is a putative transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects, and (iv) outline the necessary next steps to address this question.

The September 11, 2001, attack on New York City was the largest human-made disaster in United States history. In the first few days after the attack, it became clear that the scope of the attacks (including loss of life, property damage, and financial strain) was unprecedented and that the attacks could result in substantial psychological sequelae in the city population. Researchers at the Center for Urban Epidemiologic Studies at the New York Academy of Medicine designed and implemented an assessment of the mental health of New Yorkers 5—8 weeks after the attacks. To implement this research in the immediate postdisaster period, researchers at the center had to develop, in a compressed time interval, new academic collaborations, links with potential funders, and unique safeguards for study respondents who may have been suffering from acute psychological distress. Results of the assessment contributed to a New York state mental health needs assessment that secured Federal Emergency Management Agency funding for mental health programs in New York City. This experience suggests that mechanisms should be in place for rapid implementation of mental health assessments after disasters.

As a result of clinical, epidemiological, neuroimaging, and therapy studies that took place in the late 1980s, obsessive-compulsive disorder (OCD) has been well-characterized in the field of anxiety disorders. Other disorders attracted attention for their similarities to OCD, and were located in the orbit of the disorder. OCD has become known as the “primary domain” of a scientific “metaphor” comprising the putative cluster of OCD-related disorders (OCRDs). It is a “paradigm” with which to explore basal ganglia dysfunction. The OCRDs share common phenomenology, comorbidities, lifetime course, demographics, possible genetics, and frontostriatal dysfunction (particularly caudate hyperactivity.) The adoption of this metaphor analogy has proven useful. However, 15 years since its emergence, the spectrum of obsessive-compulsive disorders remains controversial. Questions under debate include whether OCD is a unitary or split condition, whether it is an anxiety disorder, and whether there exists only one spectrum or several possible spectrums. Further work is needed to clarify obsessive-compulsive symptoms, subtypes, and endophenotypes. There is need to integrate existing databases, better define associated symptom domains, and create a more comprehensive endophenotyping protocol for OCRDs. There is also a need to integrate biological and psychological perspectives, concepts, and data to drive this evolution. By increasing research in this field, the OCD spectrum may evolve from a fragmented level of conceptualization as a “metaphor” to one that is more comprehensive and structured.

The common occurrence and high level of morbidity and burden associated with social anxiety disorder (SAD) are gaining widespread recognition. Interest in understanding and treating the disorder has also grown in response to large-scale investigations that have demonstrated high levels of efficacy with both pharmacologic and nonpharmacologic treatments. Such trials indicate that many patients with generalized SAD (roughly 40% to 60%) respond (eg, Clinical Global Impressions–Improvement rating 1 or 2) after an adequate treatment trial, despite having suffered with disabling symptoms for most of their adult lives. First-line therapy options include the selective serotonin reuptake inhibitors and the dual-acting serotonin-norepinephrine reuptake inhibitor venlafaxine. Second-line options consist of anticonvulsants (gabapentin, pregabalin, valproic acid) and benzodiazepines (clonazepam). Reversible and irreversible monoamine oxidase inhibitors (moclobemide and phenelzine, respectively), while effective, are not widely used. Nonpharmacologic approaches, such as cognitive-behavioral therapy (CBT), are also effective for SAD. Newer treatment strategies such as levetiracetam, atypical antipsychotics, or D-cycloserine in combination with CBT appear promising but require further investigation. Finding a well-tolerated, safe, and effective treatment for each individual patient is crucial as most will require ongoing treatment in order to maintain benefits, prevent SAD relapse, and to experience optimal outcomes in the long term.

Psychiatric genetics, while promising to unravel the mechanisms of psychiatric disorders, has proven to be a challenging field. Psychiatric disorders, like other common genetic traits, are complex and heterogeneous. Psychiatric genetics has also suffered from a lack of quantifiable, biology-based phenotypes. However, the field is currently at an opportune moment. The work of various investigators is on the verge of paying rich dividends. Efforts at positional cloning are being greatly accelerated by the fruits of the Human Genome Project. New tools of functional genomics, such as expression profiling and proteomics, are being applied to animal models. These two methods can complement each other in an approach we have termed convergent functional genomics. Lastly, improvements in the measurement of biologically distinct endophenotypes—or phenomics—will lead to a better understanding of the mapping of genes to phenotypes in both animal and human systems.

Recognizing drug-drug interactions (DDIs) has become increasingly important as the country's demographics have aged, resulting in more complex medication regimens. Budnitz and colleagues highlighted the frequency of adverse drug reactions (ADRs) and the substantial morbidity that results. Their study estimated >700,000 cases of ADRs in emergency rooms (ER) in the United States between 2004 and 2005, and that ADRs accounted for 6.7% of ER visits for unintentional injuries that led to hospitalization. Moreover, medications that require monitoring accounted for 41.5% of all the ADR-related hospitalizations.

These data have tremendous implications for the field of psychiatry because many psychiatric drugs require therapeutic monitoring. The importance of DDIs is particularly relevant for the psychiatric population, where adverse effects not only cause short-term morbidity, but may lead to long-term treatment noncompliance. For many patients taking antipsychotics, adherence is the key to a successful outcome. Minimizing DDIs maximizes the chance that people will avoid unnecessary ADRs while achieving therapeutic drug levels.

Cognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.

To compile the findings of studies assessing emotional and behavioral changes in the survivors of the 2011 Fukushima nuclear disaster, we performed a systematic review in August 2019 using four literature databases (PubMed, PsycINFO, Psychology and Behavioral Sciences Collection, and ICHUSHI). Peer-reviewed manuscripts, either in English or Japanese, were included in the searches. Sixty-one studies were retrieved for the review. Of these, 41 studies (67.2%) assessed emotional consequences, 28 studies (45.9%) evaluated behavioral consequences, and 8 studies (13.1%) evaluated both emotional and behavioral outcomes. The main research topic in emotional change was radiation exposure-associated risk perception, as reported in 15 studies. This risk perception included immediate health effects (eg, acute radiation syndrome) as well as future health effects (eg, future cancer and genetic effects). Lowered subjective well-being was reported in eight studies. Six studies reported perceived discrimination/stigmatization in the disaster survivors. The most critical behavioral change was an increase in suicides compared with residents in the whole of Japan or affected by the earthquake and tsunami, but not by the nuclear disaster. Increased rate of alcohol and tobacco use was reported, although the effect on one’s health was inconsistent. As a conclusion, the Fukushima nuclear disaster survivors suffered issues in risk perception, well-being, stigmatization, and alcohol/tobacco use in the first 8 years after the disaster. The present study is important in order to better understand the emotional and behavioral responses to future nuclear/radiological disasters as well as other “invisible” disasters, such as chemical and biological public health crises.

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.

We appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.