What’s New in Our Understanding of Schizophrenia

February 22, 2017

During the past 5 years, new insights into the pathophysiological processes that underlie schizophrenia have been revealed. Here's a quick update.

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Specialized treatment programs for first-episode psychosis have demonstrated both therapeutic and cost-effectiveness, and incremental progress has occurred in our arsenal of antipsychotic medications and delivery systems. Changes in health care delivery systems are gradually coming to the long-term management of schizophrenia, including the use of evidence-based algorithms and specialized treatment programs that involve multidisciplinary teams.

Research on prevention

For some time, it has been known that the strongest genetic associations with schizophrenia, at a population level, are at a site in the major histocompatibility complex. Recent research has demonstrated that variants at this site code for differing expression of complement component C4, which is involved in pruning of excessive synapses during adolescent and early adult development.1,2 Errant, excessive pruning may underlie the loss of brain volume and the impairments in cognitive, emotional, and motor function that predate psychosis and ultimately contribute to the loss of control of dopamine release that drives psychosis.

Sensory gating deficits (eg, reduced amplitude of the P50 component of the cerebral evoked response to the second of paired sounds) are seen in many individuals with schizophrenia (and other psychiatric disorders) and their first-degree relatives. The capacity for cerebral inhibition develops in the perinatal period; it is dependent on the maturation of alpha-7 nicotine acetylcholine receptors. Choline can stimulate these receptors in utero and support their maturation.

In a randomized, placebo-controlled trial, supplementation with choline was studied in 100 healthy pregnant women. Significantly more infants exposed in utero to increased dietary choline (76% versus 43% of those not exposed) demonstrated cerebral inhibition at the 5th postnatal week.3 Parent ratings at 40 months comparing the infants exposed versus those not exposed to dietary choline in utero revealed significantly fewer problems with attention and less social withdrawal.4

The promotion of diets rich in choline-containing foods (eg, meat, soybeans, eggs) could potentially support normal brain development and reduce the risk of subsequent mental illness.5

Early intervention

The 2-year Recovery After an Initial Schizophrenia Episode (RAISE) Early Treatment Program for individuals experiencing a first psychotic episode resulted in improved functioning and satisfaction among the individuals who received the comprehensive, multi-disciplinary, team-based approach (NAVIGATE), relative to standard care.6 A subsequent analysis has shown the NAVIGATE approach to be cost-effective.7 The clinicians in the NAVIGATE sites were trained on a preferred medication algorithm for treatment and largely followed the algorithm.8

Two concerning findings from the RAISE program were that the median duration of untreated psychosis in the participating patients was more than 1 year,6 and that the rates of overweight/obesity (48%), smoking (51%), dyslipidemia (57%), pre- hypertension (40%), and hypertension (10%) were high.9


New treatments

Two new oral antipsychotic medications have been approved by the FDA. Cariprazine is for the treatment of schizophrenia and for the treatment of acute manic or mixed episodes associated with bipolar disorder. Brexpiprazole is for the treatment of schizophrenia and adjunctive treatment of MDD. Both medications can be given once daily without attention to food. Both are partial agonists at central dopamine D2 and serotonin 5HT1A receptors, and antagonists at serotonin 5HT2A receptors.

Two long-acting injected preparations of aripiprazole are currently available. Injectable aripiprazole particles of varying size are absorbed slowly over 4 weeks because of their low solubility. The long chain fatty acid moiety of aripiprazole lauroxil is removed at a steady rate over 4 to 6 weeks. Both preparations require co-prescription of an oral antipsychotic for the initial 2 weeks of treatment to provide therapeutic blood levels.

A new 3-month formulation of paliperidone uses NanoCrystal technology, much like the paliperidone 1-month injection. In the case of the former, an increased particle size allows for an extended sustained release.

Tardive dyskinesia

Although second-generation antipsychotics pose less risk of tardive dyskinesia (TD), the risk is not zero. TD is still a concern with higher dosages, especially in patients who have previously taken first-generation antipsychotics. The indications for antipsychotic medications have expanded to childhood conduct disorders and adjunct therapy for depression as well as off-label use to manage behavioral problems associated with cognitive decline, which places many more individuals at risk.10

The Abnormal Involuntary Movement Scale (AIMS) is a well-established, well-designed tool to assess TD movements. However, busy clinicians may want to use the following briefer (2-minute versus 10-minute) screen that includes activation techniques:

Ask the patient to extend his arms in front, allowing the hands to hang limply at the wrists. Then ask him to say 5 words beginning with the letter “T” (watch the hands). Next, ask the patient to touch 4 fingers to his thumb sequentially while holding her/his mouth wide open (watch the tongue and lips and jaw).

Activation may bring out early manifestations of TD when it may be most responsive to treatment, and may show the severity of the TD when the patient is in important, “stressful” social situations, such as meeting new people. Any evidence of TD on the brief screen should lead to the performance of a formal AIMS examination.

The pathophysiology of TD may reflect supersensitive dopaminergic D2 (DAD2) receptors that respond to any passing dopamine molecule in the synapse, thereby initiating an involuntary abnormal movement. Dopamine is packaged into vesicles in presynaptic neurons by vesicular monoamine transporter 2 (VMAT2).11 Inhibitors of VMAT2 have been shown to be highly effective at reducing TD as measured on the AIMS by central raters, probably by leaving vesicles empty of dopamine (firing “blanks”).

Tetrabenazine is a VMAT2 inhibitor with a short half-life, important drug-drug interactions, and metabolites that block DAD2 receptors. Unfortunately, frequent dosing is required, and the drug has been plagued by adverse effects, such as depression and extrapyramidal symptoms. Two new molecules in development are:

• Deuterated tetrabenazine. Deuterium is “heavy” hydrogen; it is non-radioactive and replaces several of the hydrogens on tetrabenazine, which results in slower metabolism, much less peak-trough variability, twice-daily dosing, and an improved adverse-effect profile.

• Valbenazine. This pro-drug is metabolized at a slow rate into only the therapeutically effective and non–DAD2-blocking metabolites of tetrabenazine. This results in much less peak-trough variability, once-daily dosing, and an improved adverse- effect profile.

Social issues

There is growing evidence that cannabis use increases the likelihood of transition into schizophrenia among those at risk.12 As more states move to legalize cannabis, the likelihood of relapse among those recovering from an initial psychotic episode grows stronger. We must certainly caution family members of individuals with schizophrenia about this risk.

To deal with the complexities of schizophrenia, it may be desirable to train schizophrenia “specialists” who are involved early in the diagnosis and treatment planning with patients who experience a first psychotic episode; these specialists are called on for crises or for individuals who do not respond to standard care. Standard care is likely to be guided by evidence-based treatment algorithms and checklists to support decision-making and can be undertaken by generalist providers. The care of patients with schizophrenia and multiple comorbidities (eg, substance use disorders or complex medical problems) will be best served by multidisciplinary practice teams.


Editor’s note: For this article, Dr. McEvoy summarized his presentation “Schizophrenia 2.0: What’s New in the Past 5 Years” at the US Psychiatric & Mental Health Congress on October 24, 2016, in San Antonio, TX.


Dr. McEvoy is Professor of Psychiatry and Health Behavior and the I. Clark Case Distinguished Chair in Psychotic Disorders at the Medical College of Georgia in Augusta, GA. Dr. McEvoy reports that he has served on the Advisory Boards for Teva and Neurocrine. He has received grants from Teva, Otsuka, Alkermes, Avanir, and Boehringer Ingelheim.


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2. Dhindsa RS, Goldstein DB. Schizophrenia: from genetics to physiology at last. Nature. 2016;530:162-163.

3. Ross RG, Hunter SK, McCarthy L, et al. Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. Am J Psychiatry. 2013; 170:290-298.

4. Ross RG, Hunter SK, Hoffman MC, et al. Perinatal phosphatidylcholine supplementation and early childhood behavior problems: evidence for CHRNA7 moderation. Am J Psychiatry. 2016;173:509-516.

5. Freedman R, Ross RG. Prenatal choline and the development of schizophrenia. Shanghai Arch Psychiatry. 2015;27:90-102.

6. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program. Am J Psychiatry. 2016;173:362-372.

7. Rosenheck R, Leslie D, Sint K, et al. Cost-effectiveness of comprehensive, integrated care for first episode psychosis in the NIMH RAISE Early Treatment Program. Schizophr Bull. 2016;42:896-906.

8. Robinson DG, Schooler NR, John M, et al. Prescription practices in the treatment of first-episode schizophrenia spectrum disorders: data from the national RAISE-ETP study. Am J Psychiatry. 2015; 172:237-248

9. Kane JM, Schooler NR, Marcy P, et al. The RAISE early treatment program for first-episode psychosis: background, rationale, and study design. J Clin Psychiatry. 2015;76:240-246.

10. Ryu S, Yoo JH, Kim JH, et al. Tardive dyskinesia and tardive dystonia with second-generation antipsychotics in non-elderly schizophrenic patients unexposed to first-generation antipsychotics: a cross-sectional and retrospective study. J Clin Psychopharmacol. 2015;35:13-21.

11. Eiden LE, Weihe E. VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci. 2011;1216:86-98.

12. Kelley ME, Wan CR, Broussard B, et al. Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders. Schizophr Res. 2016;171:62-67.