Donna A. Wirshing

Novel antipsychotics and new onset diabetes

BACKGROUND The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non-insulin-dependent diabetes mellitus. METHODS We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases. RESULTS Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics. CONCLUSIONS Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychotic-associated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic beta-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia.

The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone

BACKGROUND Neurocognitive deficits are core features of schizophrenia that are linked to functional outcome for the disorder. Recent studies and reviews have concluded that newer antipsychotic medications are better for neurocognitive deficits than conventional antipsychotic medications; however, one difficulty in interpreting this literature is that the comparisons have mainly been with high doses of conventional medications. This study examined the neurocognitive effects of low-dose haloperidol compared with risperidone over a 2-year period. METHODS Sixty-two patients were randomly assigned to medication (starting at 6 mg of each medication) and administered neurocognitive batteries six times over the course of follow-up. At 6 months, the mean dose of haloperidol was 5.0 mg, and the mean dose of risperidone was 6.0 mg. Neurocognitive data were reduced into cluster scores and a global summary score. RESULTS We found no significant overall differences in treatment effects on the cluster scores or the global score. The global score revealed a significant group by time interaction, reflecting the fact that the haloperidol group tended to improve initially and then stay stable, whereas the risperidone group improved more gradually over the follow-up period. CONCLUSIONS This study did not provide support for neurocognitive advantages of a newer antipsychotic medication over a low-dose conventional medication. We speculate that conventional medications may have neurocognitive benefits at low doses that are neutralized or reversed at higher doses.

Lack of insight in schizophrenia: impact on treatment adherence.

People with schizophrenia commonly lack insight, that is, they are unaware of their illness and the consequences thereof. One of the most important consequences of lack of insight is a failure to recognise the need for treatment, leading to treatment nonadherence. With several scales that now enable objective measurement of insight, it is possible to examine correlates of insight change, including course of illness and treatment adherence. Specific interventions, both pharmacological and psychotherapeutic, have been developed to enhance illness insight and treatment adherence. The extent to which second-generation antipsychotic medications, including a recently released long-acting formulation, improve insight and/or enhance treatment adherence remains to be determined.

Risperidone vs. haloperidol on reaction time, manual dexterity, and motor learning in treatment-resistant schizophrenia patients

BACKGROUND The present study compared the effects of risperidone vs. haloperidol on reaction time, manual dexterity, and two types of motor learning in a sample of treatment-resistant schizophrenia patients. METHODS Fifty-six DSM-III-R diagnosed schizophrenia inpatients participated in a randomized, double-blind comparison of risperidone vs. haloperidol. Measures of reaction time, manual dexterity, motor sequence learning, and gross motor learning were administered at baseline, after 4 weeks of fixed-dose medication, and after 4 weeks of flexible-dose medication. RESULTS The results indicated that patients receiving risperidone showed greater improvement in reaction time and manual dexterity than patients receiving haloperidol. After covarying symptom changes and movement disorder ratings, the results remained significant. The two treatment groups did not differ on either measure of motor learning. CONCLUSIONS The differences in performance in reaction time and manual dexterity may be due to a specific beneficial effect of risperidone, as opposed to a general reduction in extrapyramidal symptom liability, compared to haloperidol.

Risperidone-associated new-onset diabetes

BACKGROUND Weight gain, and its associated complications such as the development of diabetes, is becoming increasingly recognized as an important potential side effect of the novel antipsychotic drugs. METHODS Two retrospective cases are described in which patients with schizophrenia developed diabetes while taking the antipsychotic medication risperidone. RESULTS Both patients had preexisting risk factors for diabetes and developed insulin resistance in the context of weight gain. Both cases necessitated medical intervention and one patient requires ongoing treatment with insulin. CONCLUSIONS Although the exact mechanism of antipsychotic induced diabetes remains obscure, weight gain appears to be a significant risk factor. Careful monitoring of weight and fasting glucoses is recommended for any patient taking novel antipsychotic medications.

Sexual side effects of novel antipsychotic medications

BACKGROUND The novel antipsychotic medications offer a more favorable extrapyramidal side effect profile than conventional agents. It is uncertain that the novel antipsychotics have a benefit in terms of sexual side effects. METHODS We prospectively administered a survey of sexual functioning to 25 male patients with DSM-IV schizophrenia, taking conventional and novel antipsychotics. Contrasts were made between three treatment groups: clozapine (CLOZ), risperidone (RIS), and a combined haloperidol/fluphenazine (HAL/FLU) group. RESULTS A decrease in overall sexual functioning was reported in all medication groups (40-71%). The majority of subjects taking RIS or HAL/FLU reported a decline in one or more aspects of sexual functioning. Examining specific aspects of sexual functioning revealed that, a decline in sexual interest was significantly less common on CLOZ compared to RIS (0 vs. 64%; chi(2)=6.1, df=1, p=0.01) or HAL/FLU (0 vs. 67%; chi(2)=5.2, df=1, p=0.02), while a decline in the erectile frequency was significantly more common on RIS compared to CLOZ (40 vs. 93%; chi(2)=6.2, df=1, p=0.01) or HAL/FLU (50 vs. 93%; chi(2)=4.8, df=1, p=0.03) (0%). For enjoyment of orgasm and ejaculatory volume, significantly fewer CLOZ compared to RIS subjects reported a decline (20 vs. 86%; chi(2)=7.4, df=1, p=0.01). CONCLUSIONS Sexual side effects are common clinically pertinent adverse effects associated with both novel and conventional antipsychotic medications. They deserve increased attention in clinical work and future research with emerging antipsychotic drugs.

Prevalence of the metabolic syndrome in veterans with schizophrenia.

The metabolic syndrome has become a focus of clinical attention due to its high prevalence in the United States (23%) and impact on cardiovascular risk, yet limited data exist on the prevalence of this syndrome among U.S. veterans with schizophrenia. Methods: A convenience sample of patients diagnosed with schizophrenia or schizoaffective disorder was obtained from inpatient units and outpatient clinics at Veterans Affairs medical centers in San Diego and Los Angeles. Results: In this predominantly male (92.5%) sample of 80 veterans, with mean age of 49.0 years, the age-adjusted prevalence of the metabolic syndrome was 51.2%, more than twice the age-adjusted prevalence in the general U.S. population. The female cohort was small (n = 6), but had a greater mean body mass index and higher prevalence of metabolic syndrome than the male subjects. Conclusions: The metabolic syndrome is highly prevalent in this sample of patients with schizophrenia and represents an enormous source of cardiovascular disease risk. Clinicians who treat patients with schizophrenia should monitor for the parameters that define the metabolic syndrome as part of the ongoing management of patients treated with antipsychotics.

Antipsychotic and anticholinergic effects on two types of spatial memory in schizophrenia.

Spatial memory is of interest in schizophrenia because of widespread impairments in adaptive functioning, including independent living skills. Short-term spatial memory is impaired in this disease, whereas spatial reference memory, a longer-term spatial memory, has not been evaluated. Animal studies have demonstrated that anticholinergics impair short-term spatial memory but not spatial reference memory. The effects of haloperidol and risperidone on these two types of spatial memory were evaluated in a double-blind randomized comparison in inpatients with schizophrenia. It was predicted that risperidone would have a greater beneficial effect on spatial working memory than haloperidol. Computerized measures of spatial working memory and spatial reference memory were developed based on animal assessment of these functions. Subjects with schizophrenia were assessed during a medication-free period and again following 4 weeks of fixed-dose treatment. Risperidone, compared to haloperidol, improved spatial working memory performance, an effect that became nonsignificant when benztropine co-treatment was controlled. There were no treatment effects on spatial reference memory performance. Consistent with animal studies, benztropine impaired spatial working memory but not spatial reference memory. The relative benefits of risperidone on spatial working memory performance were largely explained by differential benztropine treatment for the haloperidol-treated subjects.

Stress and coping responses to a natural disaster in people with schizophrenia.

Investigations of how individuals with schizophrenia differ from non-patients in their responses to stressful life events are subject to the criticism that any between-group differences might merely reflect differences in the types of stressful events that each group experiences. This report presents new analyses of data collected from schizophrenia patients (n=96), bipolar disorder patients (n=18), and healthy controls (n=18) immediately after the Northridge Earthquake that struck Southern California in 1994, a natural experiment that confronted all groups with the same stressful event. Participants completed the Impact of Events Scale (IES; [Horowitz, M.J., Wilner, N., Alvarez, W., 1979. Impact of Events Scale. A measure of subjective stress. Psychosomatic Medicine 41, 209-218]) at 1 week and 5 weeks post-earthquake. At the 5-week follow-up, measures of coping, social support, and self-esteem were also completed. Both patient groups reported higher IES avoidance symptoms than controls immediately after the earthquake. The schizophrenia group also reported lower approach coping, self-esteem, and social support than controls, with the bipolar group reporting intermediate levels. Within the schizophrenia group, higher levels of avoidance coping predicted higher residual stress symptoms at follow-up. Results support the validity of prior reports of altered responses to stressful life events in schizophrenia and demonstrate the clinical relevance of individual differences in coping among affected individuals.

Failure to confirm association between RGS4 haplotypes and schizophrenia in Caucasians

The regulator of G‐protein signaling (RGS) and RGS‐like proteins are a diverse family of over 30 molecules that function as GTPase activating proteins for Gα subunits of the Gq and Gi families of heterotrimeric guanine nucleotide‐binding proteins (G proteins). By accelerating GTPase activity, RGS proteins drive G proteins into their inactive GDP‐bound forms. G‐protein coupled dopamine, metabotropic glutamate, and other neurotransmitter receptors can be modulated by RGS4, the predominant form in brain. The recent finding of decreased RGS4 mRNA expression in post‐mortem brains from schizophrenic patients, coupled with the map position of RGS4 to a region previously linked to schizophrenia, as well as other biological data, prompted the investigation of the gene as a disease candidate. Multiple family‐based and case‐control association studies have been conducted, with modest and conflicting support for particular single nucleotide polymorphism (SNP) markers and SNP marker haplotypes. The present case‐control analysis of 568 patients and 689 controls, one of the largest single studies to date, failed to confirm support for association of particular RGS4 SNP alleles, or for association of any particular four, three, or two SNP haplotype.