Antipsychotic-Associated Weight Gain and Clinical Improvement Under Clozapine Treatment.

BACKGROUND: Antipsychotic-associated weight gain is a common adverse effect with several negative outcomes in the clinical evolution of patients, which might also affect patients' self-identity from physical appearance and imply treatment discontinuation. However, recent research has drawn attention to an unexpected clinical improvement associated with weight gain, mostly in patients under treatment with clozapine or olanzapine. METHODS: Twenty-three treatment-resistant psychosis patients initiating clozapine were evaluated. Longitudinal psychopathological assessment through the Positive and Negative Syndrome Scale (PANSS) and anthropometric evaluation were performed at baseline, week 8, and 18. RESULTS: Body mass index (BMI) change during clozapine treatment was associated with clinical improvement measured with PANSS total score at week 8 (P = 0.021) while showed a trend at week 18 (P = 0.058). The PANSS general score was also associated with weight gain at week 8 (P = 0.022), whereas negative subscale score showed a trend at week 8 (P = 0.088) and was associated between week 8 and 18 (P = 0.018). Sex differences applied at week 8 for PANSS total score, where clinical improvement was significantly associated with BMI in male subjects (P = 0.024). We also stratified for time to initiate clozapine, finding significant associations in negative symptom at week 8 (P = 0.023) and week 18 (P = 0.003) for subjects, which started clozapine after 3 years of illness. CONCLUSIONS: Our results suggest that in subjects initiating clozapine, clinical improvement is associated with BMI increase, mostly in negative symptom and in patients after 3 years of antipsychotic use. Our findings were already described in the preantipsychotic era, suggesting some pathophysiological mechanism underlying both conditions.

Do FSH/LH ratio and gonadal hormone levels predict clinical improvement in postmenopausal schizophrenia women?

Menopause is a process characterized by a decline in estrogen levels and is therefore a period of biological vulnerability for psychotic relapse in women with schizophrenia. Our goal was to correlate not only gonadal hormone levels but also follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels with improvement in specific clinical symptoms. Thirty-seven acutely ill postmenopausal schizophrenia women with a newly initiated, clinically determined change in antipsychotic medication participated in a 12-week prospective observational outcome study. Scales used were the PANSS scale for psychotic symptoms, the PSP for functioning, and CGI for global clinical impression. Circulating FSH, LH, estradiol, progesterone, and testosterone serum levels were determined by chemiluminescent immunoassay. Partial correlational analyses were performed along with a Bonferroni significance correction (p < 0.0007). After adjustment for confounding factors, the FSH/LH ratio correlated positively with mean changes in PANSS positive scores, and there was a correlation with worsening of CGI total and cognitive scores. Testosterone was also positively associated with improvement in PANSS positive scores. However, after correction for multiple testing, the initial correlations were no longer statistically significant. In summary, while the hormone assays we did in this small sample did not prove to be significantly linked to clinical improvement in any of the schizophrenia symptom domains, we recommend further investigation of pituitary, adrenal, and gonadal hormone ratios as potential markers of clinical improvement in this population.

Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.

BACKGROUND: The loss of estrogens in the menopause may lead to increased vulnerability for psychotic relapse, poor clinical outcome, and a need for increased antipsychotic dose. However, confounders such as cumulative estrogen exposure and time since menopause have been inadequately studied. Our aim was to investigate potential variables capable of influencing antipsychotic response in a sample of postmenopausal women with schizophrenia. METHODS: Sixty-four postmenopausal schizophrenic women were followed in a 12-week prospective treatment-by-clinical requirement study. Duration of reproductive years was considered an indirect measure of lifetime cumulative estrogens exposure. Psychopathological assessment included the following: Positive and Negative Syndrome Scale, Personal and Social Performance, and Clinical Global Impression-Schizophrenia Scale. Response was defined as a reduction of 30% or more of Positive and Negative Syndrome Scale total scores. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Regression analyses were performed to investigate the association between potential confounding factors and antipsychotic response. RESULTS: Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with overall antipsychotic response, explaining almost 42% of the variance of the model used. Smoking and cumulative estrogen exposures were associated with improvement in negative symptoms. Smoking and time since menopause were associated with improvement in excitement symptoms, and smoking was positively associated with improvement in depressive and cognitive symptoms. DISCUSSION: Time since menopause was significantly negatively associated with antipsychotic response in postmenopausal schizophrenic women, suggesting a decline in antipsychotic response after menopause. The neurobiological basis for antipsychotic response may include a role for estrogen and nicotine receptors.