Schizophrenia: Treatment Resistance and Negative Symptoms

Treatment Resistance and Negative Symptoms

The concept of treatment resistance has undergone significant modification in recent years. The original concept of treatment refractory applied to the use of typical antipsychotic agents. With the advent of the novel agents, which are generally more effective than the traditional ones, the patient should fail at least one novel antipsychotic agent before initiating a trial of clozapine mainly to avoid its side effects. The definition of the duration of a drug trial has also evolved over the years. It is increasingly appreciated that a 4 to 6 weeks duration of treatment with an antipsychotic agent at therapeutic doses can be considered an adequate trial. The recommended dosing has also undergone changes. The orig-inal recommendation considered a trial of 1000 mg equivalent of chlorpromazine as a necessary minimum requirement but this threshold is now reduced to 400 to 600 mg/day equivalent based on the knowledge that these doses block enough dopamine D₂ re-ceptors with higher doses providing no additional benefit. Thus, a 4 to 6 week trial of 400 to 600 mg of chlorpromazine equivalent is accepted as an adequate antipsychotic trial.

In treatment refractory patients, typical antipsychotic use results in less than 5% response rate. Clozapine is the only an-tipsychotic drug proven more efficacious in rigorously defined treatment refractory groups. However, monitoring of blood counts and fear of its side effects makes it one of most underused effective treatment for schizophrenia.

Risperidone clearly appears to be superior to typical an-tipsychotics in treatment refractory patients but does not appear to be as efficacious as clozapine Olanzapine has been reported to have better outcome than haloperidol in the treatment-resistant schizophrenia group. However, when olanzapine was compared with chlorpromazine in a treatment refractory group using a double-blind study design, the outcome with olanzapine was not comparable to what is typically seen with the use of clozapine.

Negative symptoms, such as apathy, amotivational syn-drome, flattened affect and alogia, are often the most problematic for patients with schizophrenia, accounting for much of the mor-bidity associated with this illness. In addition, these symptoms are often the most difficult to treat and do not respond well to traditional neuroleptics. The atypical antipsychotic agents are more effective against the negative symptoms than are the typical agents. However, the magnitude of the effect of these compounds on primary negative symptoms is not clear. Clearly, one of the goals of psychopharmacological research is to develop new antip-sychotic agents with low associated risk, a more effective treat-ment for negative and cognitive symptoms, a further reduction in positive symptoms, and an improvement in long-term relapse rate for patients with chronic schizophrenia.