GME Logo

User login

User menu

GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


Issue 23, February 2014—Guest Commentator: Joseph P. McEvoy, MD, Georgia Regents University, Augusta, Georgia



Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events

Gibbons RD, Mann JJ.
Am J Psychiatry. 2013;170(12):1460-1467.

Objective: In 2009, the U.S. Food and Drug Administration issued a black box warning for varenicline regarding neuropsychiatric events. The authors used data from randomized controlled trials and from a large Department of Defense (DOD) observational study to assess the efficacy and safety of varenicline.

• The authors reanalyzed data from the 17 placebo-controlled trials (N=8,027) of varenicline conducted by Pfizer.
• Complete intent-to-treat person-level longitudinal data were used to assess smoking abstinence and reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea and to compare effects in patients with (N=1,004) and without (N=7,023) psychiatric disorders.
• The authors also analyzed a large DOD data set to compare acute (30-day and 60-day) rates of neuropsychiatric adverse events in patients receiving varenicline or nicotine replacement therapy (N=35,800) and to assess reports of anxiety, mood, and psychotic symptoms and disorders, other mental disorders, and suicide attempt.

Results: In the randomized controlled trials, varenicline increased the risk of nausea (odds ratio=3.69, 95% CI=3.03-4.48) but not rates of suicidal events, depression, or aggression/agitation. It significantly increased the abstinence rate, by 124% compared with placebo and 22% compared with bupropion. Having a current or past psychiatric illness increased the risk of neuropsychiatric events equally in treated and placebo patients. In the DOD study, after propensity score matching, the overall rate of neuropsychiatric disorders was significantly lower for varenicline than for nicotine replacement therapy (2.28% compared with 3.16%).

Conclusions: This analysis revealed no evidence that varenicline is associated with adverse neuropsychiatric events. The evidence supports the superior efficacy of varenicline relative to both placebo and bupropion, indicating considerable benefit without evidence of risk of serious neuropsychiatric adverse events, in individuals with and without a recent history of a psychiatric disorder.

Clinical Commentary
Cigarette smoking is one of the principal factors contributing to accelerated morbidity and mortality from cardiovascular disease and cancer among individuals with severe and persistent mental illness (SPMI). Varenicline is effective in assisting cigarette smokers with or without SPMI to quit. Gibbons and Mann document that varenicline is not associated with any greater risk for producing neuropsychiatric adverse effects than placebo or other smoking cessation aides (eg, nicotine patch) in individuals with SPMI.  Individuals with SPMI comprise a large percentage of the entire population who currently smoke cigarettes. It is now clear that clinicians can safely use varenicline to assist those individuals with SPMI who wish to quit. In an accompanying editorial, A. Edin Evins, MD, MPH, notes that “Too many of our patients who smoke have not had a single aided cessation attempt”, and that “…the average smoker makes five cessation attempts before attaining sustained abstinence, so multiple cessation attempts following relapses to smoking should be expected and encouraged.” Clinicians who care for individuals with SPMI should receive more training and support in the pharmacological and psychosocial interventions currently available to assist their patients to quit cigarette smoking. Peer support counselors who have successfully quit smoking may offer valuable assistance.



Decision-Making Capacity for Treatment in Psychiatric and Medical In-patients: Cross-Sectional, Comparative Study

Owen GS, Szmukler G, Richardson G, et al.
Br J Psychiatry. 2013;203:461-467.


Objective: To compare the abilities relevant to decision-making capacity (DMC) for treatment in medical and psychiatric patients who are able to communicate a treatment choice.

• A secondary analysis of two cross-sectional studies of consecutive admissions: 125 to a psychiatric hospital and 164 to a medical hospital.
• The MacArthur Competence Assessment Tool-Treatment and a clinical interview were used to assess decision-making abilities (understanding, appreciating, and reasoning) and judgments of DMC.
• We limited analysis to patients able to express a choice about treatment and stratified the analysis by low and high understanding ability.

Results: Most people scoring low on understanding were judged to lack DMC and there was no difference by hospital (P=.14). In both hospitals there were patients who were able to understand yet lacked DMC (39% psychiatric v. 13% medical in-patients, P<.001). Appreciation was a better “test” of DMC in the psychiatric hospital (where psychotic and severe affective disorders predominated) (P<.001), whereas reasoning was a better test of DMC in the medical hospital (where cognitive impairment was common) (P=.02).

Conclusions: Among those with good understanding, the appreciation ability had more salience to DMC for treatment in a psychiatric setting and the reasoning ability had more salience in a medical setting

Clinical Commentary
The MacArthur Assessment Tool-Treatment is a semi-structured interview that probes each individual’s (a) understanding of relevant information pertinent to the treatment decision; (b) appreciation that the information is relevant to the individual’s predicament; and, (c) reasoning, ie, logical manipulation of the information necessary in the process of arriving at a decision.

Approximately equal percentages of individuals hospitalized with medical illnesses and individuals hospitalized with psychiatric illnesses agreed to participate in the study (53% and 57%, respectively). Approximately equal percentages of the two participant groups (25% and 24%, respectively) had poor understanding of their situation and the issues involved in the treatment decisions; the poor understanding was explained by diagnoses of delirium and dementia in the group hospitalized with medical illnesses, and by cognitive impairment associated with severe and persistent mental illnesses in the individuals hospitalized with psychiatric illnesses, and the majority of these individuals were judged to not have decision-making capacity. 

Among those with adequate understanding, significantly more of those hospitalized with psychiatric illnesses than those hospitalized with medical illnesses were judged to have impaired decision making capacity (39% versus 13%). This was largely explained by the individuals’ with psychiatric illnesses denial/unawareness that they had psychiatric illnesses that might benefit from treatment. This lack of insight is difficult to remedy and contributes to non-adherence and poor outcomes after discharge



Obstetric Complications as Risk Factors for Schizophrenia Spectrum Psychoses in Offspring of Mothers with Psychotic Disorder

Suvisaari JM, Taxell-Lassas V,
Pankakoski M, et al. Schizophr Bull. 2013;39(5):1056-1066.


Objective: Obstetric complications have predicted future development of schizophrenia in previous studies, but they are also more common in mothers with schizophrenia. The aims of this study were to compare the occurrence of obstetric complications in children of mothers with schizophrenia spectrum psychoses and control children, and to investigate whether obstetric complications predicted children's psychiatric morbidity.

• The Helsinki High-Risk (HR) Study monitors females born between 1916 and 1948 and treated for schizophrenia spectrum disorders in Helsinki psychiatric hospitals, their offspring born between 1941 and 1977, and controls.
• We examined information on obstetric complications and neonatal health of 271 HR and 242 control offspring.
• We compared the frequency of obstetric complications and neonatal health problems in the HR group vs controls and in HR children who later developed psychotic disorders vs healthy HR children.
• A Cox regression model was used to assess whether problems in pregnancy or delivery predicted psychiatric morbidity within the HR group.

Results: Few differences between HR and control offspring were found in obstetric complications. Within the HR group, infections (hazard rate ratio [HRR] 3.73, 95% CI 1.27-11.01), hypertension during pregnancy (HRR 4.10, 95% CI 1.15-14.58), and placental abnormalities (HRR 4.09, 95% CI 1.59-10.49) were associated with elevated risk of schizophrenia spectrum psychoses.

Conclusions: Common medical problems during pregnancy were associated with increased risk of schizophrenia spectrum psychoses in offspring of mothers with schizophrenia spectrum psychoses. These results underline the role of the prenatal period in the development of schizophrenia and the importance of careful monitoring of pregnancies of mothers with psychotic disorder.

Clinical Commentary
The first priority among the issues of pregnancy and childbirth in women with schizophrenia should be a planned pregnancy, because a planned pregnancy is associated with a higher likelihood of adequate nutrition during gestation, including potential supplementation with choline, folate, and long-chain, poly-unsaturated, omega-3 fatty acids. When planning for a pregnancy, medications that have high risk for teratogenicity, e.g. valproate, can be discontinued unless absolutely needed. Efforts at smoking cessation can be considered prior to pregnancy, and efforts can be made to avoid maternal infections (eg, immunization for influenza, condom use to prevent sexually-transmitted diseases, and avoidance of exposure to soil or uncooked meats to limit risk for toxoplasmosis). All too often women with schizophrenia present already pregnant, in which case best efforts to “catch up” the interventions listed above should be undertaken.  Extended hospitalization through delivery may be justifiable in women without stability or support outside the hospital in order to optimize the infant’s chances of avoiding phenotypic expression of psychosis. Quality obstetrical care will minimize the risk for hypoxia and other complications during delivery that are associated with a variety of abnormalities of brain function in the offspring of mothers with schizophrenia. The incidence of schizophrenia has been falling in the developed world, perhaps largely because of increasing implementation of the interventions listed above



Neuroprotective Effect of Lithium on Hippocampal Volumes in Bipolar Disorder Independent of Long-Term Treatment Response

Hajek T, Bauer M, Simhandl C, et al.
Psychol Med. 2014;44(3):507-517.


Objective: Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD).

• To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. • All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes.
• We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts.

Results: The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102=4.97, P=.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t 51=2.00, P=.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t 43 = 2.62, corrected P=.02).

Conclusions: Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

Clinical Commentary
Lithium has been available as an inexpensive generic medication for decades with no pharmaceutical company to sing its praises to the multitude. Its clinical value is under-appreciated. It is robustly effective in the management of bipolar disorder and useful in other diagnoses. It prevents suicide better than any other psychotropic except perhaps clozapine. It preserves brain volume and may decrease risk for cognitive decline across a wide range of brain disorders. Lithium is underutilized as well because its use requires that its prescribers are confident in their medical knowledge, that they understand, for example, the relationships between fluid intake and renal clearance and the potential to impair iodine uptake by the thyroid gland; this does not seem too much to ask. Patients may balk at using it because blood draws are required or previous prescribers caused unnecessary discomforting side effects through excessive dosing. 

Lithium should be considered a foundation medication in the treatment of bipolar disorder the way metformin is considered in diabetes mellitus. Attention should be given to tolerable dosing so that long-term compliance is assured. Other valuable medications can be added to lithium as needed, but none of these can fully replace its benefits.


Identification of Primary Polydipsia in a Severe and Persistent Mental llness Outpatient Population: A Prospective Observational Study

Iftene F, Bowie C, Milev R, et al.
Psychiatry Res. 2013;210(3):679-683.


Objective: Studies to date have only investigated primary polydipsia in hospitalized psychiatric patient populations, where rates range from 3% to 25%. The objective of the present study was to determine the occurrence of primary polydipsia in a psychiatric outpatient population, and to determine the perceptions of outpatients with self-induced water intoxication regarding reasons for drinking excess fluids, health risks, and insight into their behavior.


• All 115 psychiatric outpatients from a Community Outreach Program in Kingston, Ontario, were invited to participate in this study. Of these, 89 (77.4%) were enrolled.
• Data collection included chart reviews, structured interviews, weight measurements, and urine collection.

Results: The incidence of primary polydipsia was found to be 15.7%. One-half of the polydipsic people presenting with medical complications suggestive for water intoxication had cigarette smoking as a strong correlate. There were interesting answers to the self-induced water intoxication questionnaire. These showed a lack of knowledge related to the normal quantity of fluids necessary daily and about healthy behaviors.

Conclusion: Excessive drinking occurs in psychiatric patient populations outside of institutional/hospital settings. Patients have limited awareness of the severity and possible complications from their problem. Given the prevalence of polydipsia, more effort should be put into identifying and treating this problem.

Clinical Commentary
When these investigators took the trouble to ask about excessive water drinking, many of their patients readily acknowledged doing this, although they did not consistently view it as a problem. Changes in their weight from the morning to the afternoon may offer a useful method for confirming excessive water drinking; those with excessive water drinking had daily weight variation of 8–11 pounds in contrast to the 2–3 pound variation in individuals without excessive water drinking. Urine specific gravity over the course of the day is another usual indicator. This large variation suggests much larger fluid intake than the 4–5 liters the patient acknowledged. it is worth knowing which patients have excessive water drinking; anything that will increase the release of antidiuretic hormone in these individuals (eg, high nicotine intake, carbamazepine) may lead to hyponatremia, seizures, and death. In addition, if the excessive fluid intake consists largely of sugar-containing and/or caffeinated beverages, the caloric implications, impairments in sleep, and potential for exacerbation of psychopathology are noteworthy. The only effective treatment for excessive water drinking is clozapine. if a patient has treatment-resistant psychopathology, heavy cigarette smoking, and evidence of excessive water drinking, s/he is a wonderful candidate for clozapine.

To contact GME, email us at [email protected]

GME does not provide medical advice. The website and articles are intended for informational purposes only. They are not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the GME Website. If you think you may have a medical emergency, immediately call your doctor or dial 911.

Log In

Join GME For Free

Become a GME subscriber and gain full access to our extensive library of 700+ psychiatric medical education videos, free CME webcasts, latest research updates, and more. To sample our content, watch the featured videos below.
Join Today!