Clozapine Side Effects Risk Gene Identified

Clozapine is a “gold standard” drug for managing treatment-resistant schizophrenia (TRS), who do not respond adequately to first-line antipsychotics.

Schizophrenia is a serious mental disorder affecting up to one percent of the adult population. Antipsychotics are effective at relieving symptoms for most patients, but up to 30% do not respond well to standard treatments and are considered to have treatment-resistant schizophrenia.

Often when one traditional antipsychotic medication does not work, clinicians change to another traditional antipsychotic. Clozapine is often seen as a drug of last resort, although it is the only medication approved by the FDA for treatment-resistant schizophrenia.

Clozapine Side Effects Genome Analysis

Despite its efficacy with treatment-resistant schizophrenia, the use of Clozapine is significantly restricted by severe side effects, such as Clozapine-induced agranulocytosis (CIA) or Clozapine-induced granulocytopenia (CIG), which are rare (CIA: 1% and CIG: 3%) but potentially life-threatening.

Common clozapine side effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, and weight gain.

The risk of developing extrapyramidal symptoms such as tardive dyskinesia is below that of typical antipsychotics; this may be due to clozapine’s anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.

Ryota Hashimoto, an associate professor at Osaka University, Nakao Iwata, a professor at Fujita Health University, and Taisei Mushiroda, a group director at RIKEN conducted a genome-wide pharmacogenomic analysis and detected a significant association of the allele HLA-B*59:01 with CIA/CIG (CIAG).

An allele is one of a number of alternative forms of the same gene. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation. However, most genetic variations result in little or no observable variation.

HLA-B*59:01 is one of the variant forms of HLA-B gene, which is involved in recognition of ‘self’ and ‘non-self’ and induction of immune response.

The allele HLA- B*59:01 may be clinically useful as a marker to prioritize the CIG patients who have low risk to develop CIA, by accumulating scientific grounds through prospective clinical studies based on this group’s research results. The analysis of functions of HLA-B*59:01 is also essential for the clarification of mechanism for CIAG.

Insulin Resistance

Patients treated with clozapine may be at an increased risk for insulin resistance, which is a major risk factor for diabetes mellitus, according to a study in the Archives of General Psychiatry.

“Compared with the general population, life expectancy in patients with schizophrenia is shorter by as much as 20 percent, attributable to higher rates of suicide, accidental deaths, and natural causes such as cardiovascular disease, infectious disease, and endocrine disorders,”

according to background information in the article.

“Recently, the newer ‘atypical’ antipsychotic agents have been linked to several forms of morbidity, including obesity; hyperlipidemia; type 2 diabetes mellitus; and diabetic ketoacidosis [a severe complication of diabetes].”

David C. Henderson, M.D., from Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues, evaluated 36 non-obese outpatients with schizophrenia or schizoaffective disorder who were treated with clozapine, olanzapine, or another medication, risperidone. Participants were given a diet to follow to maintain body weight and were told to fast for 12 hours prior to undergoing a frequently sampled intravenous glucose tolerance test.

“Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects,” the researchers found.

In conclusion, the authors write:

“Psychiatrists and primary care professionals should be aware that patients treated with clozapine and olanzapine may be at increased risk for insulin resistance, even if not obese. Insulin resistance is associated with hyperlipidemia, hypertension, and cardiovascular disease and over time may increase the risk for diabetes mellitus in vulnerable individuals. Patients treated with these agents should be routinely screened, counseled to reduce risk, and provided early interventions.”

Takeo Saito, et al.
Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population
Biological Psychiatry, 2016; DOI: 10.1016/j.biopsych.2015.12.006

T. Scott Stroup, Tobias Gerhard, Stephen Crystal, Cecilia Huang, Mark Olfson
Comparative Effectiveness of Clozapine and Standard Antipsychotic Treatment in Adults With Schizophrenia
American Journal of Psychiatry, 2015; appi.ajp.2015.1 DOI: 10.1176/appi.ajp.2015.15030332

Image: George Alexander Ishida Newman/Flickr

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