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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 6, September 2012 — Guest Commentator: Joseph P. McEvoy, Duke University


Disease-Modifying Properties of Long-Term Lithium Treatment for Amnestic Mild Cognitive Impairment: Randomized Controlled Trial

Forlenza OV, Diniz BS, Radanovic M, et al
Br J Psychiatry. 2011;198(5):351-356.

Objective: Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment.

Aims: To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI).

Methods: Forty-five participants with aMCI were randomized to receive lithium (0.25-0.5 mmol/l) (n=24) or placebo (n=21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ[42]), total tau (T-tau), phosphorylated-tau (P-tau). Trial registration: NCT01055392.

Results: Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P=0.03) and better performance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%.

Conclusions: The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.

Clinical Commentary
This group previously reported a lower prevalence of Alzheimer’s disease (AD) among elderly individuals with bipolar disorder (BD) treated with lithium than among elderly individuals with BD not treated with lithium.(1) Two additional cohort studies reported similar advantages for lithium-treated patients with BD. Lithium inhibits glycogen synthase kinase 3 beta, a tau-kinase in the brain that modulates the cleavage of amyloid precursor protein and contributes to the pathophysiology of AD.(2) However, two prospective studies of lithium in individuals with AD without BD failed to demonstrate any advantage for lithium. The present study, in patients with amnestic mild cognitive impairment, was based on the possibility that earlier intervention with lithium, prior to the presence of diagnosed AD, might be more effective. The investigators targeted lithium levels between 0.2–0.5 mEq/L which were very well tolerated by the participants, and benefits were seen in cognitive performance and on biomarkers for AD. The results offer initial promise that as methods become available to detect individuals at high risk for developing AD, early intervention with lithium may have mitigating potential.


Cortical Thinning in Psychopathy

Ly M, Motzkin JC, Philippi CL, et al
Am j Psychiatry. 2012; May 11. doi: 10.1176/appi.ajp.2012.11111627. [Epub ahead of print]

Objective: Psychopathy is a personality disorder associated with severely antisocial behavior and a host of cognitive and affective deficits. The neuropathological basis of the disorder has not been clearly established. Cortical thickness is a sensitive measure of brain structure that has been used to identify neurobiological abnormalities in a number of psychiatric disorders. The authors assessed cortical thickness and corresponding functional connectivity in psychopathic prison inmates.

Methods: Using T1 MRI data, the authors computed cortical thickness maps in a sample of adult male prison inmates selected on the basis of psychopathy diagnosis (21 psychopathic inmates and 31 nonpsychopathic inmates). Using resting-state functional MRI data from a subset of these inmates (20 psychopathic inmates and 20 nonpsychopathic inmates), the authors then computed functional connectivity within networks exhibiting significant thinning among psychopaths.

Results: Relative to nonpsychopaths, psychopaths had significantly thinner cortex in a number of regions, including the left insula and dorsal anterior cingulate cortex, the left and right precentral gyri, the left and right anterior temporal cortices, and the right inferior frontal gyrus. These neurostructural differences were not due to differences in age, IQ, or substance use. Psychopaths also exhibited a corresponding reduction in functional connectivity between the left insula and the left dorsal anterior cingulate cortex.

Conclusions: Psychopathy is associated with a distinct pattern of cortical thinning and reduced functional connectivity.

Clinical Commentary
Psychopathy is characterized by callous, unemotional traits. Psychopaths fail to resonate with other people’s distress and demonstrate impaired ability to recognize fear stimuli. Only 20% to 50% of individuals with antisocial personality disorder (ASPD) demonstrate psychopathy. However, ASPD with psychopathy is associated with increased likelihood of violence, and the heritability of ASPD with psychopathy is stronger than that for ASPD without psychopathy.(3) Psychopathy (callous unemotional traits) can also be present in children and adults without ASPD. As early as 4–8 years of age, children with callous unemotional traits can be shown to fail to attend to the eyes of attachment figures (e.g. their mothers); this impairment is independent of maternal behaviors but associated with “fearlessness” in their fathers.(4) Children with callous unemotional traits have increased risk for later antisocial behavior, poor peer relationships, and hyperactivity. The present article supports prior work demonstrating anatomical and functional imaging abnormalities in the brains of psychopaths.


Dialectical Behavior Therapy Compared with General Psychiatric Management for Borderline Personality Disorder: Clinical Outcomes and Functioning Over a 2-year Follow-up

McMain SF, Guimond T, Streiner DL, et al
Am J Psychiatry. 2012;169(6):650-661.

Objective: The authors conducted a 2-year prospective naturalistic follow-up study to evaluate posttreatment clinical outcomes in outpatients who were randomly selected to receive 1 year of either dialectical behavior therapy or general psychiatric management for borderline personality disorder.

Methods: Patients were assessed by blind raters 6, 12, 18, and 24 months after treatment. The clinical effectiveness of treatment was assessed on measures of suicidal and nonsuicidal self-injurious behaviors, health care utilization, general symptom distress, depression, anger, quality of life, social adjustment, borderline psychopathology, and diagnostic status. The authors conducted between-group comparisons using generalized estimating equation, mixed-effects models, or chi-square statistics, depending on the distribution and nature of the data.

Results: Both treatment groups showed similar and statistically significant improvements on the majority of outcomes 2 years after discharge. The original effects of treatment did not diminish for any outcome domain, including suicidal and nonsuicidal self-injurious behaviors. Further improvements were seen on measures of depression, interpersonal functioning, and anger. However, even though two-thirds of the participants achieved diagnostic remission and significant increases in quality of life, 53% were neither employed nor in school, and 39% were receiving psychiatric disability support after 36 months.

Conclusions: One year of either dialectical behavior therapy or general psychiatric management was associated with long-lasting positive effects across a broad range of outcomes. Despite the benefits of these specific treatments, one important finding that replicates previous research is that participants continued to exhibit high levels of functional impairment. The effectiveness of adjunctive rehabilitation strategies to improve general functioning deserves additional study.

Clinical Commentary
Exploratory, unstructured treatment for borderline personality disorder (BPD) proved to be of limited use, and counter-productive in some patients. Current general psychiatric treatment for patients with BPD is structured and based on manuals with recommendations for addressing common clinical problems. Clinicians providing treatment for patients with BPD should want and choose to do this. They must demonstrate empathy and engagement while providing coherent explanations linking the subjective experience of BPD to a model of pathology. Patients are expected to be active, to become preemptive, and to accept self-agency, in particular to accept links between actions and feelings.(5) With such treatments, most patients with BPD achieve symptomatic remission over 10 or more years of follow-up, although the majority demonstrates persistent functional impairment.(6)


Nocturnal Enuresis with Antipsychotic Medication

Barnes TR, Drake MJ, Paton C.
Br J Psychiatry. 2012;200(1):7-9.

Nocturnal enuresis can be discomfiting and troublesome. There is increasing evidence that as a side effect of second-generation antipsychotics, particularly clozapine, it may be under-recognized. Direct but sensitive questioning may be required to elicit this side effect. We briefly review possible mechanisms of this problem, and management and treatment options.

Clinical Commentary
Estimates of the incidence of nocturnal enuresis among patients taking clozapine have ranged up to 40%; the incidences on risperidone, olanzapine, or quetiapine appears to be lower (5% to 10%).(7) In many individuals enuresis occurs early during treatment and resolves spontaneously, but in some patients the problem persists. It is clear that many patients are deeply embarrassed by this side effect and it is commonly not discovered unless asked about by a trusted clinician. It is likely that this side effect leads to medication noncompliance in some patients, with loss of the therapeutic benefit of the antipsychotic treatment. Effective treatments for enuresis are available. We most commonly use ephedrine 25 mg at bedtime or twice daily(8) or pseudoephedrine if ephedrine is not available. Patients should be told about the possibility of this side effect and that the side effect can be readily and safely corrected should it occur.


Metformin for Treatment of Antipsychotic-Induced Amenorrhea and Weight Gain in Women With First-Episode Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Study

Wu RR, Jin H, Gao K, et al
Am J Psychiatry. 2012;169(8):813-821.

Objective: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia.

Methods: Eighty-four women (ages 18–40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1,000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis.

Results: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group.

Conclusions: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

Clinical Commentary
Many antipsychotic medications lead to weight gain and insulin resistance, contributing to accelerated cardiovascular risk and the striking disadvantage in mortality that afflicts patients with serious and persistent mental illnesses. The most problematic antipsychotic medications, clozapine and olanzapine, provide additional therapeutic benefit to many patients incompletely responsive to other antipsychotic medications, and they cannot be substituted for. Almost a decade passed after the availability of atypical antipsychotic medications before widespread awareness of these side effects among clinicians occurred, followed by calls to monitor (to what end?). Finally, we have evidence that intervention with metformin is not only effective, but safe, in qualified hands.(9) The value of metformin in diabetes prevention is well established.(10) These authors also call attention to the value of metformin in reducing amenorrhea in antipsychotic-treated women with schizophrenia. We can hope that other potential mitigating agents (e.g. omega-3 fatty acids, statins, aspirin) will be similarly well-studied and ultimately utilized if proven effective and safe.


Comparison of Oral Health Between Inpatients with Schizophrenia and Disabled People or the General Population

Chu KY, Yang NP, Chou P, et al
J Formos Med Assoc. 2012;111(4):214-219.

Objective: There is little comparative research evidence to support the claim that there is disparity in dental care between inpatients with schizophrenia and the disabled people or the general population. This study aimed to investigate whether schizophrenia inpatients had poorer dental care and worse oral health than the disabled people and the general population, respectively.

Methods: An oral health survey was conducted in a specific-psychiatric long-term care institution in Taiwan in 2006. The results of this survey were compared with the findings of oral health investigations of the disabled people or the general population in Taiwan using proportion test and t-test.

Results: This study used decayed, missing, and filled teeth index (DMFT) to describe the condition of dental caries. Compared with the disabled people, schizophrenia inpatients aged 19 to 44 years had a lower subjects' filling rate of DMFT index (FI) and a higher caries experience, but schizophrenia inpatients aged 45 or more had a lower mean number of DMFT. Compared with the general population, schizophrenia inpatients had higher caries experience, mean number of DMFT, percentage edentulous, and community periodontal index and lower FI and number of remaining tooth among various gender or age groups.

Conclusion: In Taiwan, inpatients with schizophrenia have a lower FI than the disabled people and a worse overall oral health status than the general population.

Clinical Commentary
When matched against normal control populations, individuals with schizophrenia are 3–4 times more likely to be edentulous, a condition that affects an individual’s ability to eat comfortably and speak clearly, as well as the individual’s appearance (and contributes to stigma). Among those who have teeth, individuals with schizophrenia have significantly higher rates of dental caries than matched normal control populations.(11) Severe periodontal disease as assessed by plaque index and bleeding on probing is also more prevalent among patients with schizophrenia.(12) Untreated caries and periodontal disease are the leading causes of becoming edentulous. Clinicians certainly should urge patients and their caregivers to support dental hygiene practices (e.g. brushing regularly) and to reduce smoking, but the most important action clinicians can take is to avoid prescribing medications that produce dry mouth. Saliva protects teeth through four mechanisms: diluting and eliminating sugars and other substances, buffer capacity, balancing demineralization/remineralization, and antimicrobial action.(13)

1. Nunez PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007;190:359-360.
2. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer disease. J Neurochem. 2008;104:1433-1439.
3. Rutter M. Psychopathy in childhood: is it a meaningful diagnosis? Br J Psychiatry. 2012;200(3):175-176.
4. Dadds MR, Allen JL, Oliver BR, et al. Love, eye contact and the developmental origins of empathy vs. psychopathy. Br J Psychiatry. 2012;200(3):191-196.
5. Bateman AW. Treating borderline personality disorder in clinical practice. Am J Psychiatry. 2012;169(6):560-563.
6. Paris J. The outcome of borderline personality disorder: good for most but not all patients. Am J Psychiatry. 2012;169:445-446.
7. Harrison-Woolrych M, Skegg K, Ashton J, Herbison P, Skegg DC. Nocturnal enuresis in patients taking clozapine, risperidone, olanzapine and quetiapine: comparative cohort study. Br J Psychiatry. 2011;199(2):140-144.
8. El Hemaly AK. Nocturnal enuresis: pathogenesis and treatment. Int Urogynecol J Pelvic Floor Dysfunct. 1998;9(3):129-131.
9. Smith RC. Metformin as a treatment for Antipsychotic Drug Side Effects: Special focus on Women with schizophrenia. Am J Psychiatry. 2012;169:774-776.
10. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35(4):731-737.
11. Kisely S, Quek LH, Pais J, Lalloo R, Johnson NW, Lawrence D. Advanced dental disease in people with severe mental illness: systematic review and meta-analysis. Br J Psychiatry. 2011;199(3):187-93.
12. Eltas A, Kartalcı S, Eltas S, Dündar S, Uslu M. An assessment of periodontal health in patients with schizophrenia and taking antipsychotic medication. Int J Dent Hyg. 2012 May 15. doi: 10.1111/j.1601-5037.2012.00558.x. [Epub ahead of print]
13. Llena-Puy C. The rôle of saliva in maintaining oral health and as an aid to diagnosis. Med Oral Patol Oral Cir Bucal. 2006;11(5):E449-55.

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