Reviews of Note

Feature |
April 10, 2017

Reviews of Note

  1. Barbara Geller, MD,
  2. Joel Yager, MD,
  3. Jonathan Silver, MD and
  4. Peter Roy-Byrne, MD

Obsessive-compulsive disorder; transition from unipolar to bipolar disorders; neuropsychiatric symptoms in multiple sclerosis; pharmacology for unipolar and bipolar disorders; low-intensity transcranial stimulation; adult ADHD; behavioral therapies added to buprenorphine; alcohol and suicide; inflammation in depression and in schizophrenia; harmless rare mutations

  1. Barbara Geller, MD,
  2. Joel Yager, MD,
  3. Jonathan Silver, MD and
  4. Peter Roy-Byrne, MD

In an occasional column, NEJM Journal Watch Psychiatry editors comment briefly on review articles.

New developments regarding obsessive-compulsive disorder. Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT) have been the core treatments for obsessive-compulsive disorder (OCD) for over two decades. These authors review the evidence supporting these interventions and discuss important elements of efficacy (high dose and long duration for SSRIs; exposure for CBT).1 The article highlights modest developments during the last 5 years in diagnosis (e.g., the diagnosis of hoarding) and in understanding predictors of treatment response (e.g., OCD subtypes involving poor insight or tics). New studies support the efficacy of Internet-based CBT and adjunctive antipsychotic medications. Evidence is still limited for novel agents (riluzole, lamotrigine, N-acetylcysteine, memantine, and ondansetron; see NEJM JW Psychiatry Dec 2016 and J Clin Psychiatry 2016; 77:e1576) Neuromodulatory approaches (NEJM JW Psychiatry May 2017 and J Affect Disord 2017 Mar; 215:187) such as deep brain stimulation have promising evidence and may provide hope to those with treatment-resistant OCD.

Transitions from major depression to bipolar disorder. To study diagnostic changes in depressive and bipolar disorders, these authors conducted a systematic review and meta-analysis of 56 heterogeneous studies with ≥6 months of follow-up and using standardized diagnostic criteria.2 The authors estimate that 22% of patients with major depression followed for 12 to 18 years will develop bipolar disorder, most within the first 5 years of follow-up. Major predictors are family history of bipolar disorder, younger age at onset of depression, and the presence of psychotic symptoms. Patients presenting with these features bear close monitoring, and clinicians should consider prescribing mood stabilizers.

Neuropsychiatric comorbidities in multiple sclerosis. Patients with multiple sclerosis frequently develop neuropsychiatric disorders that impair quality of life and require treatment. These authors comprehensively review the literature on epidemiology, diagnosis, pathology, and treatment for depression, bipolar disorder, psychosis, anxiety disorders, substance misuse, and pseudobulbar affect.3 Missing from this review are fatigue and cognitive problems, both frequent neuropsychiatric symptoms in MS. Detailed tables of studies correlate structural brain imaging results to these disorders. When possible, recommendations, including for therapies, are based on research results. Appropriately, the authors suggest that SSRIs are the treatment of choice for pseudobulbar affect. However, they list phenytoin as an alternative treatment for steroid-induced mania, which is a questionable choice. This article is a valuable current resource for those treating patients with MS.

Pharmacological frontiers for treating depression. The phrase “same-old, same-old” might characterize many antidepressant product launches of the past several decades; however, new psychopharmacological approaches promise exciting times ahead. This review discusses agents thought to modulate glutamatergic (ketamine, and beyond), cholinergic, and opioid systems.4 Other agents that might play therapeutic roles include anti-inflammatory agents, neurogenesis enhancers, neurokinin-1 modulators, and vasopressin antagonists.

Dopaminergic agents for bipolar depression. Successful treatment of bipolar depression remains controversial, complex, and often elusive. This systematic review and meta-analysis of nine randomized, controlled trials and four high-quality observational studies focuses on adjunctive dopaminergic agents (pramipexole, modafinil, and armodafinil, methylphenidate, and amphetamines).5 The four industry-sponsored studies were much larger than the others. No study involved treatment lasting more than 2 months. Additional studies and longer follow-ups are certainly necessary; still, the authors conclude that the available data show some promise for response and remission and, at least in the short run, no evidence for increased mood switches with these agents.

Current status of (transcranial) current stimulation. With the rise of clinical neurostimulation (encompassing electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and deep brain stimulation), transcranial neurostimulation using low-intensity electric currents has become increasingly popular. These largely unregulated techniques have been increasingly advocated, especially by do-it-yourselfers and direct-to-consumer advertisers, for various psychiatric conditions (and nonclinical conditions, such as mood and cognitive enhancement and general well-being). A timely review examines randomized, controlled trials of transcranial direct current stimulation, cranial electrical stimulation, and vagus nerve stimulation for depressive episodes, schizophrenia, cognitive difficulties, and substance use disorders.6 The authors discuss basic electrophysiology, neurophysiology, and risks of these approaches. The studies, which generally have low-quality evidence, report positive therapeutic effects only for depressive disorders. Although better-quality evidence might be produced by the 450 studies on this topic found by the authors at, many questions remain unanswered regarding efficacy and harms.

Persistence of childhood attention-deficit/hyperactivity disorder into adulthood. Because there is burgeoning interest in adult attention-deficit/hyperactivity disorder (ADHD), evaluating the persistence of childhood-onset ADHD is especially timely. To avoid problems with recall and inadequate assessment, investigators analyzed data from all 12 longitudinal studies between 1992 and 2016 that used prospective ADHD diagnoses in childhood (ages, <18 years) and DSM-III or later criteria.7 Study participants were largely white, male, and middle class. Studies used a wide array of diagnostic methods; overall, rates of ADHD persisting into adulthood were 4% to 77%. However, the authors estimate that rates would rise to 40% to 50% if studies included both self-reports and second informants for adult assessments, impairment criteria, and age-specific thresholds for number of symptoms. These data emphasize the need for monitoring children with ADHD for continuing psychopathology.

Adding behavioral interventions to buprenorphine treatment. In the U.S., outpatient, office-based buprenorphine treatment, an approach rapidly gaining in popularity, involves medical management. How helpful is medical management, and what is the value of adding behavioral interventions? Examining eight studies, these authors find 6-month retention rates of about 50% (lower than in facility-based methadone maintenance programs) and high relapse after dropout.8 Four studies showed greater effectiveness for additional treatment, especially contingency-based management for retention. Although adding counseling or other behavioral interventions to buprenorphine has yielded mixed results, contingency-management approaches appear to be more effective for retaining patients in treatment. In practice, results are likely to reflect the quality of contingency-based management and medical management as well as other aspects of stepped-care programs.

Public health, alcohol use, and suicide. Suicide is known to be associated with alcohol intoxication. Using a public-health perspective, these authors review 17 cross-sectional and longitudinal studies offering “natural experiments” that compare various public policies regarding alcohol use or blood alcohol levels and associated suicide mortality in different states and countries.9 Many factors affect suicide rates. Overall, however, lower suicide rates, particularly among younger individuals, have been associated with higher alcohol prices and taxation, higher minimum drinking ages, lower densities of alcohol sales outlets (both on- and off-premises sales), the presence of zero tolerance laws (prohibiting any blood alcohol levels among young drivers), and lower per-capita alcohol consumption. Given the general concern about increasing suicide rates, public-health approaches to uncovering contributing causes and suggesting interventions are welcome.

Neuroinflammation and depression. Inflammatory processes may have roles in depressive disorders. These authors elegantly review these possible associations from a histopathological perspective and examine postmortem inflammatory findings in microglia, astrocytes, oligodendroglia, and neurons (including NMDA receptor complexes, vesicular glutamate transporters, and GABAergic interneurons).10 Studies have variably reported a large number of deficits involving multiple inflammatory mediators and biochemical pathways. The authors are keen to point out that causal relationships are not established and that many studies have been as likely to find inflammatory processes to be consequences of depression as contributors to the disorder. The review also richly underscores the considerable heterogeneity in both pathogenesis and phenomenology subsumed under the rubric of “depressive disorders.”

Inflammation, microglia, and schizophrenia. These authors posit that microglia, prominent cells in the central nervous system that may be involved in cortical pruning and which are activated by stress and immunological stimuli, may play a previously unappreciated role in the pathogenesis of schizophrenia and other psychotic illnesses.11 Reductions in microglial activity have been associated with reduced synaptic pruning and deficits in connectivity; in contrast, overactivity in later life has been associated with synaptic loss and cognitive deficits. The “two-hit” model offered here includes perinatal and early childhood stress and immune activation that result in “primed” microglia which, after stresses in adolescence, can become overactivated, involving genetically mediated processes. The authors discuss possible clinical implications, e.g., the development of agents capable of modifying glial function, particularly during prodromal periods.

Rare mutations may not be harmful. Genetic literature is replete with examples of people with rare mutations that were believed to be causative of their illness. The Exome Aggregation Consortium, using its growing database of 60,000 exomes (Nature 2016; 536:285), has shown that many of these rare mutations occur too frequently among unaffected individuals to be invariably causative. In a clearly written essay, this author explains that this finding is especially important for family members who carry the same rare mutation as the sick relative and believe that they too are at risk.12 Researchers are planning to use the database to identify people with severely mutated, apparently nonfunctional genes — the human equivalent of laboratory knockouts of genes in animals. These people could then be examined for any effects of the “absent” gene on health.

Editor Disclosures at Time of Publication

  • Disclosures for Barbara Geller, MD at time of publication Nothing to disclose

  • Disclosures for Joel Yager, MD at time of publication Editorial boards Bulletin of the Menninger Clinic; Eating Disorders Review (Editor-in-Chief Emeritus); International Journal of Eating Disorders; UpToDate; FOCUS: The Journal of Lifelong Learning in Psychiatry

  • Disclosures for Jonathan Silver, MD at time of publication Royalties Textbook of Traumatic Brain Injury, 2nd edition (less than $1,000) Editorial boards UpToDate Leadership positions in professional societies North American Brain Injury Association (Board Member); Chair of Data Monitoring Safety Board for National Institute on Disability, Independent Living, and Rehabilitation Research study of donepezil on cognition after traumatic brain injury

  • Disclosures for Peter Roy-Byrne, MD at time of publication Equity Valant Medical Solutions Grant / Research support NIH–National Institute of Mental Health Editorial boards Depression and Anxiety; UpToDate Leadership positions in professional societies Anxiety Disorders Association of America (Ex-Officio Board Member); Washington State Psychiatric Society (Immediate Past-President)


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