Reviews of Note

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

Keep meditation in mind. These authors analyze a systematic review (funded by the Agency for Healthcare Research and Quality) of controlled studies on the impact of meditation programs on a large assortment of problems in adults.1 The authors conclude that meditation produces small-to-moderate improvements in anxiety, depression, and pain. For the other issues examined — stress/distress, positive mood, mental-health quality of life, attention, substance use, sleep, and weight — either the evidence was low-grade or data were insufficient to determine any conclusions. Given the few harms involved, clinicians might be mindful about recommending meditation to patients presenting with a wide variety of issues.

Update on chronic traumatic encephalopathy. The frequent reports in the media of chronic traumatic encephalopathy (CTE) from repetitive mild traumatic brain injuries (mTBIs), research suggesting a pathological connection (NEJM JW Psychiatry Sep 17 2012 and Jan 14 2013), and the recent lawsuit by National Football League players have heightened public concern. These authors provide a balanced examination of current research into CTE, including the inconsistent gross and histological pathological definitions of CTE, genetic findings, and unaccounted-for comorbidities.2 The authors review the literature on the possible link between a single mTBI and CTE, the expected outcomes from a single uncomplicated mTBI and repetitive mTBIs, and the connection between TBI and dementia. Finally, the writers discuss the clinical consequences and medicolegal implications of misunderstanding mTBI outcomes and urge caution against the premature generalizing of current findings to the general population. Even those of us who are not involved in forensic work will find this an invaluable and balanced review of the state of knowledge of CTE.

Antidepressant-associated liver injury. After an extensive literature review, these authors conclude that although all antidepressant drugs may produce hepatic injury, only 0.5% to 3.0% of patients receiving these medications develop even mild asymptomatic elevations of hepatic enzyme levels.3 Nevertheless, serious drug-induced liver injury does rarely occur, sometimes irreversibly and even fatally. These risks have been reported more frequently in association with monoamine oxidase inhibitors, tricyclics, tetracyclics, and several other classes of atypical antidepressants and less often with selective serotonin reuptake inhibitors.

Antidepressant use in bipolar disorder. A large international task force offers 12 specific recommendations concerning the use of antidepressants in patients with bipolar disorders.4 The task force concludes that antidepressant use cannot be endorsed in patients with bipolar disorders. However, the task force notes that some patients may benefit; patients with bipolar I disorder should not receive antidepressants without concurrent mood stabilizers; and, overall, tricyclics, tetracyclics, and serotonin-norepinephrine reuptake inhibitors may be associated with greater risk for manic switch than selective serotonin reuptake inhibitors or bupropion. However, evidence on many important issues is limited, and additional study is sorely needed.

How lithium works. In this elegant review of basic mechanisms,5 the authors postulate that lithium helps to restore plasticity to the hippocampus, amygdala, and other key brain systems that are compromised by environmental stresses. Specifically, lithium's neuroprotective effects stem from its neurotrophic effects on cells, modulation of synaptic plasticity via the glutamate system, effects on cytoskeletal processes to alter neuronal morphology, and other still-to-be-determined actions. However, as the authors point out, even with lithium's benefits, concurrent behavioral interventions are required to direct the revitalized neuroplasticity into healthy avenues.

Pharmacologically preventing and managing delirium. Because delirium greatly increases the risk for subsequent dementia, preventing and treating delirium matter considerably. According to this review,6 prospective trials on pharmacological prevention and management of non–substance-induced delirium show that efforts to prevent delirium are more effective than efforts to treat it. In perioperative, post-operative, and intensive care settings, delirium has been successfully prevented with haloperidol, several atypical antipsychotics, iliac fascia block, gabapentin, melatonin, less intensive intraoperative sedation with propofol, and single-dose ketamine during anesthetic induction. In patients on mechanical ventilators, dexmedetomidine has been more effective than other sedative agents. However, once delirium occurs, antipsychotics show inconsistent effects on episode duration and severity, with haloperidol showing more consistent effects than other antipsychotics. Some benefits have been also associated with olanzapine and quetiapine. Prolongation of QTc intervals does not appear to be a frequent or serious problem.

Adjunctive anti-inflammatory medications for psychiatric disorders? These authors systematically review studies on four types of anti-inflammatory agents as adjunctive treatments for major depression, schizophrenia, and bipolar disorders — omega-3 polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, tumor necrosis factor α (TNFα) inhibitors, and minocycline.7 Evidence is offered for some effectiveness of PUFAs in major depression. A COX-2 specific inhibitor had moderate effectiveness in schizophrenia. One study showed the TNFα inhibitor infliximab to be moderately effective as an add-on to antidepressants but only in the 23% of patients who showed elevated high-sensitivity C-reactive protein (>5 mg/L). Minocycline may show promise for schizophrenia, but reports of significant adverse effects caution against its routine use.

The short allele on 5-HTTLPR and PTSD risk after high trauma exposure. Previous research suggests that under adverse environmental stressors, individuals homozygous for the short allele in the gene for the promoter region of the serotonin transporter (5-HTTLPR) are at greater risk for major depression and anxiety disorders. These authors have conducted a meta-analysis of 12 studies; three studies sampled only individuals exposed to high trauma (combat veterans, Rwandan genocide refugees, and post-9/11 veterans).8 Under conditions of high trauma exposure (but not lesser degrees of exposure), homozygosity for the short allele represents a risk factor for post-traumatic stress disorder (odds ratio, 3.80). No associations have been found for people with at least one long allele. Further gene × environment interaction studies are required to better elucidate how the polymorphism contributes to risk for this disorder.

Potential involvement of microRNAs in psychiatric disorders. MicroRNAs are small, noncoding RNA molecules that regulate the expression of genes, including those involved in the development of the central nervous system. These authors review studies that link miRNA to several psychiatric disorders, most notably schizophrenia and affective disorders, but they note that there has been little research into links to anxiety disorders, addictions, or other psychiatric disorders.9 The significance in psychiatry of altered miRNA levels is still unclear, as these might contribute to — or might have been altered by — psychiatrically pertinent processes. A focus on miRNA mechanisms may offer targets for pharmacological interventions.

Reprogrammed cells produce brain organoids. Both embryonic stem cells and reprogrammed adult cells are pluripotent (i.e., they can differentiate into multiple cell types). Now, investigators have extended this work to produce brain organoids in pluripotent cells that are aggregated in culture.10 An essayist clearly describes how the investigators induced these structures from pluripotent states to developing morphological features of cortical layers and the choroid plexus (the lattice-like structure that produces cerebral spinal fluid).11 Similar to human brains, the organoids have periventricular glial progenitors of neurons but, unlike human brains, have no blood supply. This research has already suggested the pathway for microcephaly, in which neurons appear to develop prematurely, and should enhance future research on neuropsychiatric disorders.

Testing for autism, and another immunology theory. Significantly more mothers of autistic offspring have antibodies to fetal brain tissue than other mothers, and animal fetuses exposed to maternal antibrain antibodies have impaired social behaviors. Thus, researchers are trying to establish whether a test for these antibodies would be useful for women of childbearing age, especially those at greater risk for having an affected child (e.g., a woman who already has an autistic child). According to this author, one group with patented screening techniques for antibrain antibodies is now publicizing its development of a test for autism intended for women planning to get pregnant.12 Critics note that this possible test has generated inordinate interest among parents of autistic children, but that it has a positive predictive value of only 16%, way below the >80% that would be clinically useful.