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Ask the Experts


What is the deficit syndrome of schizophrenia and what is the best pharmacological treatment for the primary negative symptoms for people with this condition?

Answered by: L. Fredrick Jarskog

This is a complex issue with no easy answers.

The symptoms of schizophrenia are often considered in 3 domains: positive (hallucinations and delusions), negative (social withdrawal, poor motivation, absence of emotional expression or feeling), and cognitive deficits. Negative symptoms are thought to represent a core aspect of schizophrenia. Negative symptoms that are enduring and inherent to a patient's range of symptoms are called primary negative symptoms. Negative symptoms can also be caused by factors other than the core disease process. Examples include medication side-effects, concurrent depression, and limited social stimulation - these are called secondary negative symptoms.

Primary negative symptoms are usually enduring, but they may be most noticeable between acute psychotic episodes. Secondary negative symptoms are generally not enduring and are often modifiable, especially if they represent side-effects from a particular antipsychotic medication.

Primary negative symptoms respond poorly to treatment. Many researchers find no credible evidence that antipsychotic medications can treat primary negative symptoms. The few studies that have tested novel non-antipsychotic medications have so far proved disappointing.

It should be noted, though, that many antipsychotic treatment studies report improvement on negative symptoms. However, most studies did not adequately control for the presence of secondary negative symptoms that were present before study entry. Therefore, any improvement could be due to the withdrawal of the offending agent that was producing negative symptoms, often in the form of "Parkinsonian" symptoms, a common side-effect of antipsychotic medications.

Furthermore, whether primary or secondary, any effect on negative symptoms tends to be small. Therefore, at this time the best approach is to focus on reducing secondary negative symptoms which we know can be improved. This means interventions such as lowering the dose of the current antipsychotic, or switching to an antipsychotic less prone to causing Parkinsonian side-effects, or using an anti-Parkinsonian drug, such as the anticholinergic agent benztropine. Diagnosing and treating ongoing depression can also improve secondary negative symptoms. Finally, while clozapine has not been found to have a clear effect on primary negative symptoms, it is the most effective medication for patients that are not responding well to other antipsychotics.

Thus, the overall level of functioning of a patient with prominent negative symptoms as well as enduring positive symptoms may improve with clozapine even if the negative symptoms do not change much. The fundamental problem with trying to treat the deficit syndrome is that we have very little understanding of the underlying neurobiology of negative symptoms. There are ongoing efforts at improving this understanding and once more is understood, we can make better decisions about what types of pharmacological agents might be most likely to improve negative symptoms and these can then be tested in clinical trials.