Reviews of Note

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

Current status of transcranial direct current stimulation. In both lay and professional circles, interest in this technology has been increasing as a potentially effective, low-cost, easy-to-implement intervention for a variety of neuropsychiatric conditions (including major depression, schizophrenia, obsessive-compulsive disorder, and substance use disorders) and for cognitive enhancement. These authors review current evidence concerning the various applications of the technology.1 Findings are mixed: Although some are promising, none have been conclusive. Both further research into the technological aspects and larger, more convincing clinical studies are needed.

Olfactory mucosa in the study of neuropsychiatric disorders. Lack of access to patients' living brain tissue constitutes a formidable challenge in the study of intracellular and synaptic processes in neuropsychiatric disorders. Although investigators have used pluripotent stem cells, neural stem cells, and peripheral blood cells as stand-ins for brain cells, each model carries significant limitations. More recently, investigators in both ex vivo and in vitro studies have employed cells derived from biopsies of adult human olfactory mucosa, a regenerative neural tissue. These authors review studies of a wide range of psychiatric, neurodegenerative, and neurodevelopmental diseases, including effects of drugs and pharmacological agents, gene expression, protein localization, epigenetics, and intracellular signaling.2 This model might yield insights into pathogenetic processes and better pharmacological approaches.

Pathophysiology of traumatic brain injury. Study of traumatic brain injury (TBI) has often focused on changes in metabolism, release of neurotransmitters, and calcium. These authors review research into the multiple possible inflammatory mechanisms.3 Some may be beneficial and promote neuroprotection, whereas others may cause secondary injury reactions. Knowledge of inflammatory mechanisms may lead to new therapeutic interventions, including management of excitotoxicity and manipulation of purinergic receptor signaling. Still, inflammatory responses are seen in other disorders, such as depression. Overall, regarding long-term recovery after TBI, we need to determine whether inflammation is a direct result of the brain trauma or is the brain's response to stress.

Free, valid, and reliable mental health screening and assessment measures. With the increasing promotion of measurement-based care, clinicians are on the lookout for suitable tools for screening and monitoring psychiatric symptoms. After a systematic review, these authors identified 264 potential instruments4; of these, they deemed 29 adult- and 20 youth-focused instruments worthy for consideration as “free, brief, and validated.” Although the authors do not specify the time burden that these instruments impose on patients and clinicians, all have fewer than 50 items, and most take no more than 10 to 15 minutes of patients' time to complete.

Contrary to prior thinking, expressive and receptive language areas overlap. It was conventionally thought — based largely on observations of people with accidental brain damage — that speech reception and speech expression were assigned to different brain regions. This view is challenged by recent data that support the existence of overlapping areas for both language comprehension and production.5 As explained by two essayists,6 in one experiment using simultaneous functional magnetic resonance imaging of two participants, one person read a narrative and the second one listened. Regardless of participants' roles, overlapping areas in both brains were activated at precisely the same time. Furthermore, regions outside traditional language sites were also activated, including those associated with mentalization (the ability to realize that other people have their own points of view). These findings are consistent with symptoms of patients with autism spectrum disorders who have impairments both in conversational, communicative language and in mentalizing.

Is there a role for cutting-edge imaging techniques in TBI diagnosis? The many research advances in neuroimaging after TBI have been of particular interest in mild TBI, especially concussions, which currently lack objective “markers” of injury. Outside clinical care, in litigation to “prove” TBI, these modalities are frequently used but with much controversy. This white paper from the American College of Radiology Head Injury Institute was reviewed and approved by prominent researchers in TBI.7 Their conclusion: These techniques (including diffusion tensor imaging, functional magnetic resonance imaging, and magnetic resonance spectroscopy) are for research only. The paper concludes that at this time “there is insufficient evidence supporting the routine clinical use of advanced neuroimaging for diagnosis and/or prognostication at the individual patient level.” The bottom line: This valuable research tool requires much more work before it is clinically (or legally) applicable to a specific patient.

Neuro-ophthalmologic findings in TBI. Abnormal eye movements may be a sensitive indicator of concussion (NEJM JW Psychiatry Oct 2014 and J Head Trauma Rehabil 2015; 30:21). These authors focus on the possible neuro-ophthalmologic findings in patients with all severities of TBI and detail the clinical findings, methods of assessment, and neuroanatomic basis of these abnormalities, including saccades, smooth pursuit, vergence, and accommodation.8

Why exercise after mild TBI? Aerobic exercise may be an effective treatment for uncomplicated concussion (NEJM JW Psychiatry May 2013and J Head Trauma Rehabil 2013; 28:241). The authors of the current review provide data supporting the hypothesis that exercise may modulate cerebrovascular processes to improve recovery.9 The authors review the effects of concussion on cerebrovascular regulation and explain how concussion alters cerebral vasoreactivity, autoregulation, and coupling.

Artificial sweeteners and glucose intolerance. Weight gain is one of the main challenges in treating patients with atypical antipsychotics and other psychotropics, and weight management often includes use of noncaloric artificial sweeteners (NASs). New research, however, in both human and animal models, shows that NASs increase blood glucose and decrease insulin resistance.10 As commenters explain,11 NASs concurrently alter gut microbiota so that Bacteroidetes decrease and Firmicutes increase — the pattern seen in obesity. The Bacteroidetes effects do not occur with ingestion of a fat- or carbohydrate-restricted diet.

More on biological mechanisms of schizophrenic psychopathology. Patients with schizophrenia have long been known to demonstrate sensory processing dysfunctions involving impaired sensory gating and mismatches between expected and actual sensory inputs in auditory and visual systems. These authors review such dysfunctions, tie them to underlying genetic, molecular, and neuropathological causes, and then link them to the misperceptions and hallucinations experienced by patients.12 New therapeutic targets may emerge from identification of the precise deficits in nicotinic, cholinergic, and NMDA-type glutamate receptor mechanisms (and related candidate genes) contributing to these phenomena.

What to do about treatment-resistant schizophrenia? About 20% to 30% of patients with schizophrenia have treatment-resistant problems, and 40% to 70% of these patients don't respond adequately even to clozapine. Where does that leave the prescribing clinician?

Miyamoto and colleagues thoughtfully review evidence for augmenting adequately dosed clozapine with a second antipsychotic, other medications, and nonpharmacologic treatments.13 A summary table lists the current strategies supported with positive, although limited, evidence — transdermal estradiol for women; transcranial direct current stimulation; and clozapine with the addition of a second antipsychotic, lamotrigine, citalopram, or electroconvulsive therapy.

Beck and colleagues show the practical value of having patients with treatment-resistant illness managed in a specialty clinic that employs specific treatment protocols.14 In such a setting, proper diagnosis may lead to better treatment choices and improved adherence.