However, a substantial proportion of these individuals do not respond to clozapine,^2,6 and this has prompted clinicians to resort to various augmentation strategies—most, if not all, of which unsubstantiated. Although this is a serious problem that affects thousands of patients, it is not a well-studied area and scientific evidence for the approach to clozapine-resistant patients is lacking. In such situations a clinician generally makes decisions based on his or her past experience. Similarly, most of the reports in the literature with regard to clozapine-resistant patients are from case reports and anecdotal evidence.⁷ There have been several randomized, controlled studies comparing clozapine monotherapy with augmentation strategies, usually with another antipsychotic agent.^8–10 However, it may not be practical to study, in a controlled manner, all possible combinations and compare their benefits and risks. In addition, even such comparison studies may not help a clinician to treat a specific patient who may have multiple factors influencing his or her illness.¹¹

All of these factors add to the complexity a clinician faces in the clinic or hospital setting. Expert consensus such as the Texas Algorithm for the Use of Antipsychotics in Schizophrenia (TMAP),¹² a review of collective wisdom from experienced clinicians, recommends a variety of augmentation strategies, including polypharmacy. Polypharmacy is an anathema in many professional settings, and supervisors are loath to recommend polypharmacy with any level of comfort to their trainees and students.¹⁰ However, polypharmacy is a reality, and in many cases a major problem that increases cost and possibly worsens the situation by adding side effects, with little or no tangible benefit. It is believed that approximately 15% of outpatients with schizophrenia are prescribed two or more antipsychotics,⁶ and a Danish study reported that 35% of patients with clozapine are prescribed concomitant antipsychotics.¹³ Antipsychotic medications, especially the recent second-generation antipsychotics, are not clean drugs that act on a single receptor.¹⁴ These so-called ‘dirty drugs’ act on a range of receptors and, theoretically, each may constitute polypharmacy. However, in practice there are many situations that result in polypharmacy of a patient with schizophrenia. Sometimes patients show good response on two medications during cross-titration and may choose to remain on the combination, or some may be stable on more than one medication for long periods of time and may not warrant a change (status quo). Clozapine partial response may be a true case that warrants an augmentation strategy, at least for lack of a better option. However, in light of poor understanding of the pathophysiology of schizophrenia, any attempt to rationalize the use of combination drugs becomes meaningless.¹⁴ The mechanism of action of antipsychotics is believed to be in the dopamine/serotonin system of the brain, but a clear and specific laboratory model of the illness and response to medication is lacking.^15,16 Considering this, any attempt toward a new pharmacological strategy with an educated guess would need clinical benefit of evidence.

One of the preferred combination methods is to use a second-generation antipsychotic medication that acts on dopaminergic and serotonergic systems (in this case clozapine) with a first-generation antipsychotic medication that primarily acts as a dopamine blocker. The underlying assumption in this strategy is that the combination will augment or increase the degree of dopamine blockage—which is believed to be the primary antipsychotic action—without causing extrapyramidal side effects. Clozapine has an excellent antipsychotic effect with a relatively lower percentage of dopamine receptor (D2) occupation. It is believed that the D2 occupation is related to the antipsychotic effect, as well as to extrapyramidal side effects.¹⁷ Although clozapine achieves its antipsychotic effects with relatively less D2 occupancy, it is safe to assume that, in selected patients, partial response may be due to this suboptimal receptor occupation. For example, D2 occupancy is shown to increase from 55% with clozapine alone to 79% on the addition of 4mg of haloperidol to the clozapine using a positron emission tomography (PET) scanner.¹⁸ From this it can be inferred that the benefits of clozapine are obtained without an optimal D2 blockade—the addition of haloperidol can increase the D2 blockade—possibly resulting in full benefit of D2 blockade, along with the ‘atypical’ effect of clozapine or ‘optimum’ atypical and conventional effects.¹⁹

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