Clozapine: a distinct, poorly understood and under-used molecule.

Consensus of opinion is rare in psychiatry. Even in the field of clinical trials, where experimentation is tightly controlled and regulatory bodies scrutinize the proof, controversies are frequent and difficult to resolve. One issue for which there is a widespread consensus is the unique place that clozapine occupies in the treatment of severe mental illnesses, particularly refractory schizophrenia. This molecule is distinct because of its effectiveness, numerous and sometimes mysterious pharmacologic characteristics, serious side effects and under use. Historically, clozapine was distinguished by one of its dangerous and sometimes lethal side effects, agranulocytosis, which almost caused its complete banishment from the psychiatric pharmacopoeia. It was only rescued when its superior therapeutic effects compared with chlorpromazine in patients with refractory schizophrenia were demonstrated. Since its controlled comeback, clozapine has consistently demonstrated advantages in a variety of clinical situations. Its enhanced therapeutic profile in patients with schizophrenia who respond poorly to other antipsychotic medications, both typical and atypical, have been reported in many studies and encompass many dimensions of the schizophrenia syndrome. Positive symptoms are most consistently improved by clozapine, but there are also reports indicating that anxiety, mood and negative symptoms as well as hostile behaviours are better controlled with clozapine than with other neuroleptics, although the data are less consistent. Moreover, it has been reported that patients are more likely to remain compliant with clozapine than with other atypical antipsychotics. Clozapine is also the only antipsychotic medication that has shown an anticraving effect for drugs of abuse, a significant effect in reducing suicide rates in patients with schizophrenia and an efficacy on refractory mood disorders. Every clinician who has prescribed clozapine can recount a few experiences of seeing patients emerge from their chaotic psychotic experience. This is one of the most rewarding experiences that a psychiatrist can have in his or her professional life, and it is among the most important strikes we have made against one of the most devastating diseases affecting mankind. Expiration of the patent on clozapine in 2007 has lessened the burden of economic constraints against the use of clozapine. However, side effects remain a major issue affecting the choice to use the drug. With respect to both the presence and absence of side effects, clozapine again distinguishes itself. Historically, clozapine was the first neuroleptic identified without motor side effects. In this regard, it is the prototypical molecule of a new generation of antipsychotic agents that have limited or no adverse effects on movement while curbing psychotic symptoms. These atypical neuroleptics almost completely replaced the older generation of antipsychotics. Although this major shift in practice was initially hailed as one of the most important and positive changes in the treatment of schizophrenia, recent studies seriously questioned this change in practice, both on the grounds of efficacy and safety. Indeed, while most of the new generation antipsychotics do not distinguish themselves from the older ones with regards to efficacy and effectiveness, there are unquestionable and major problems associated with the use of this new class of molecules: increased food intake, weight gain and dysregulation of glucose and lipid metabolism, all of which are risk factors for cardiovascular morbidity and mortality. Here, sadly, clozapine again came out ahead, further demonstrating the uniqueness of this molecule with respect to both beneficial and adverse effects. Patients taking clozapine can sometimes gain more than 25 kg, posing a real dilemma to clinicians about how to optimize remission while keeping the patient’s physical well-being and safety under control. These effects came under very strong scrutiny in the last decade because of their possible contribution to the major mortality gap (20–25 yr) between patients with schizophrenia and the general population. Although this tension between controlling psychotic symptoms and side effects will always remain an issue for each individual patient, a recent epidemiologic study, the largest of its kind, surprisingly suggested that clozapine is paradoxically associated with decreased overall mortality at the population level. This study, which analyzed mortality between