Practicing 'Rational' Polypharmacy in Psychiatry

January 19, 2012

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Hello. This is Dr. Jeffrey Lieberman of Columbia University in New York City speaking to you for Medscape. Today, I would like to talk about polypharmacy and why I think this will be a treatment strategy of the future for patients with mental illness, and specifically patients with schizophrenia and psychotic disorders.

Now, you might be saying, "What's so new about that?" Polypharmacy has been around for a long time, and it is quite prevalent in current practice when treating people with mental illnesses -- particularly severe mental illnesses, such as schizophrenia. Few patients who are being treated for schizophrenia are receiving monotherapy with an antipsychotic drug.

What I am talking about is rational polypharmacy, in contrast to an improvised or irrational form of polypharmacy. What we practice now involves the use of multiple antipsychotics in combination or an antidepressant, a mood stabilizer, benzodiazepines, or anxiolytics added to antipsychotics. Clinicians do this because the antipsychotic by itself isn't working sufficiently well, and they are trying to improve the level of response. But little evidence supports the use of these additional medications, and virtually no evidence supports the benefits of combining antipsychotic drugs.

When I speak of polypharmacy as a treatment strategy for the future, I am referring to a rational form of polypharmacy with treatments that have been developed to target specific neuroreceptors that are thought to be associated with some of the residual morbidity of schizophrenia beyond psychosis. This would include residual psychotic symptoms that may persist despite an adequate dose of an antipsychotic drug, such as negative symptoms or, perhaps most important, cognitive impairment or cognitive symptoms.

For a number of years, we have tried to identify neurobiological targets for symptoms that are not adequately improved by antipsychotic medication. First and foremost among these has been the effort to develop drugs that produce improvement in cognition (ie, cognitive enhancers). Several targets have been identified as being desirable or attractive for drug development, including some of the glutamate receptors, particularly the NMDA (N-methyl-D-aspartate) receptor, the dopamine-1 receptor, the cholinergic receptors, and specifically those cholinergic receptors stimulated by nicotine (the nicotinic cholinergic receptors).

Cholinergic receptors and nicotinic receptors were thought to be attractive targets because of the propensity of people with schizophrenia to smoke; the inference from this observation was that this might be a form of self-medication, that nicotinic stimulation would ameliorate symptoms of the illness. The effort to develop nicotinic agonists grew out of this. The first of these that attracted a great deal of attention were nicotinic agonists at the alpha-7 receptor. The pioneering work of Bob Freedman, who identified this as a target, proved the association with schizophrenia and the involvement with psychophysiologic measures, such as the P450 wave form and acoustic startle, and demonstrated the efficacy of an experimental drug in alleviating cognitive impairment and negative symptoms. This was seminal and groundbreaking work.

More recently, in addition to the nicotinic alpha-7 receptor, studies have focused on the nicotinic alpha-4 beta-2 receptor. Among the drugs that have been used to test or prove this hypothesis is varenicline, which is marketed as a treatment for smoking cessation. I mention varenicline and alpha-4 beta-2 because in late 2011, 2 articles were published about this drug in relationship to schizophrenia treatment. The first appeared in Archives of General Psychiatry[1] and described the effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia. The second article,[2] "Adjunctive Varenicline Treatment With Antipsychotic Medications for Cognitive Impairments in People With Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial," appeared in Neuropsychopharmacology.

Varenicline is a partial agonist that activates the receptor by 30% to 60% of what the full nicotine agonist would do. The studies found that when added to the antipsychotic medication the patients were receiving, this medication produced a subtle or modest improvement in specific cognitive functions or in the psychophysiologic measures that are associated with cognitive impairment in schizophrenia, such as the P450 wave form or acoustic startle.

The improvements were not huge, but they were statistically significant and clinically encouraging enough to warrant enthusiasm for the potential of developing further drugs to target these nicotinic receptors. This is important because it heralds the stage we are moving toward: a phase of rational development of new drugs that target known biological substrates that are believed to be involved in the pathophysiology of cognitive impairment or negative symptoms, and potentially also residual cognitive symptoms.

Drugs developed to add to antipsychotic medications in this way will enhance the efficacy of treatment and, I think, will justify the use of multiple medications to treat schizophrenia, in a way that is rational and justified.

I encourage you to take a look at these articles and to stay tuned for further developments in the scientific literature.

Thank you for your attention. Good day for now, from Jeffrey Lieberman in New York City, for Medscape.


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