CASE PRESENTED BY: Mohamed A. Aziz, MD, MS, Andrea Pepler, MS, and Connie McNeely, MSN
The use of combinations of antipsychotic medications has been reported to result in increased effectiveness in the treatment of psychotic disorders.1-3 A possible mechanism for this increased effectiveness is that drugs with different specific patterns of receptor coverage and affinity may be more effective when combined. This increase in effectiveness may be due to extended receptor coverage, receptor relief in pathways involved in adverse effects, and increased receptor binding in areas in need of receptor stimulation or blockade.4
The successful treatment of patients with refractory schizophrenia is a challenge and is often complicated by significant adverse effects.5 We report two cases in which the addition of the conventional antipsychotic haloperidol to the second generation (atypical) antipsychotic quetiapine resulted in increased response (reduced positive and negative symptoms) in patients with previously treatment-resistant psychotic disorders, with the added benefit of reduction in extrapyramidal symptoms (EPS).
To date, no reports have been published concerning the efficacy of using a combination of haloperidol and quetiapine to reduce symptoms related to schizophrenia. In achieving relief from psychosis, it is desirable to minimize adverse drug side effects. In animal studies, it has been reported that EPS associated with haloperidol are not aggravated by the addition of quetiapine.6 It is also significant that the addition of haloperidol to quetiapine has been shown not to significantly alter the pharmacokinetics of quetiapine, suggesting that the improvement in symptoms reported here is more likely due to pharmacodynamic alterations rather than changes in pharmacokinetic profiles.7 The mechanism of action resulting in treatment success in the cases described here may be related to the fact that the two medications have different receptor affinities and patterns of receptor coverage. In general, the conventional antipsychotic haloperidol provides robust coverage in areas generating positive symptoms, while the second generation antipsychotic quetiapine also has effects on areas that generate negative symptoms. Therefore, this combination may provide the strong antipsychotic effects of haloperidol with added coverage of negative symptoms. In addition, it should be noted that, consistent with the animal studies mentioned above, EPS in patients taking haloperidol were not worsened in the presence of quetiapine and subjectively appeared to be reduced.5
The first case involved a 37-year-old African-American female with a long history of refractory schizoaffective disorder, bipolar type. The patient had been hospitalized on six occasions, the most recent of which lasted 14 months. This most recent admission resulted from auditory and visual hallucinations and delusions which caused her to enter strangers' homes and to believe that people were harming her. During her mental status examination, the patient displayed retarded psychomotor activity, thought blocking, impoverished speech, and flat affect. She was oriented to place and person, but not time, and had poor judgment. She had fair insight, but did not have insight into the need for medication. Medications on admission included gabapentin 600 mg in the morning and 1,200 mg in the evening, long-acting injectable risperidone (Risperdal Consta) 37.5 mg given 2 weeks before admission, and oral risperidone 3 mg at bedtime.
The patient was continued on long-acting injectable risperidone during the first 2 months of the admission. During the course of this admission, the patient was tried on many antipsychotic medications as monotherapy and in combination with other medications, including mood stabilizers. Olanzapine, ziprasidone, and risperidone (both oral and long-acting) were tried as monotherapy and in combination with oral haloperidol and haloperidol decanoate in an attempt to treat the patient's persistent positive and negative symptoms, but without significant clinical response. Clozapine was not tried during this admission because the patient had a history of consistent noncompliance with the necessary blood work. The patient was started on haloperidol decanoate with the dose increased to 200 mg every 4 weeks. After 2 months, oral haloperidol 5 mg twice a day was started and then increased to 5 mg in the morning and 10 mg at bedtime. Due to lack of response to haloperidol monotherapy, up to 8 mg of oral risperidone was added to the haloperidol for 8 weeks. However, the patient demonstrated minimal improvement in symptoms and continued to have delusions of harm, believing that others were spraying chemicals on her skin and suspecting fellow patients of spitting into and putting blood in her food. She began a ritual of scrubbing her face and eyes with strong cleaners to remove the chemicals, resulting in severe injury to her eyes and skin, which had to be medically treated.
The risperidone was then discontinued and a low dose of quetiapine was started in combination with the haloperidol. The dose of quetiapine was increased to 200 mg in the morning and 400 mg in the evening. At the time of the annual reassessment, the patient had been taking the combination of haloperidol decanoate 150 mg every 3 weeks and quetiapine 200 mg t.i.d. for 3 months; during the interview, she displayed normal psychomotor appearance, good affect, highly improved cognition, and insight into her disease state and medications. These signs indicated that both her negative and positive symptoms had improved. She was able to acknowledge that the thoughts of microbial and chemical contamination came from inside her head. She also stated that she would need medication for "the rest of [her] life," indicating improved insight. The patient reported being happy to be discharged to an outpatient supervised care facility.
At the patient's final interview prior to discharge, she displayed good affect, conversed easily, and reported no delusions. She also demonstrated insight into her illness and had made friends with fellow patients about whom she had previously held paranoid delusions. The patient was therefore able to be discharged. Due to the refractory nature of the patient's illness, it was felt that a trial of quetiapine monotherapy was not justified and the patient was continued on the combination of quetiapine and haloperidol.
The patient was a 31-year-old white male with a history of paranoid schizophrenia and frequent admissions to the hospital. His most recent admission occurred after an increase in paranoid and persecutory delusions and threats of harm to a family member. In addition, the patient displayed significant negative symptoms such as blunted affect, isolation, and anhedonia. While in the hospital, the patient had a recurring belief that the staff was manipulating the unit environment in an attempt to poison him. At times, he would not eat the meals or drink the water because he thought they contained fluphenazine. The delusions of poisoning caused him to attempt to escape from the closed unit on several occasions.
During this hospitalization, all five first-line second generation antipsychotics were tried without success. Clozapine was not tried because the patient had a family history of serious adverse events (cardiac arrhythmia and sudden death) with clozapine. Limited improvement was seen when the patient received a combination of risperidone and aripiprazole. This treatment regimen was initiated with long-acting injectable risperidone (Risperdal Consta) 50 mg IM every 2 weeks, which was supplemented with 1 mg oral risperidone three times a day. Because the patient's psychotic symptoms persisted, aripiprazole 5 mg at bedtime was added, with the dose gradually increased to 15 mg at bedtime. Initially, the patient showed a decrease in paranoid thoughts with the combination of risperidone and aripiprazole. He also began to demonstrate a broader range of affect and was able to engage in meaningful conversation with staff. He was observed laughing more and engaging in group activities. However, after approximately 3 weeks on the combination of risperidone and aripiprazole, the patient began to display inappropriate behaviors, such as sexually pursuing staff members and conversation with increased sexual content. His previous delusions involving death increased.
The patient did not have a history of mania, which suggested that these symptoms had possibly been induced by the addition of aripiprazole to the risperidone. Valproic acid was added in an attempt to treat the aggressive behavior but was not effective. After 6 weeks, the aripiprazole was discontinued, while the risperidone treatment regimen (oral risperidone 1 mg three times a day and long-acting injectable risperidone 50 mg IM every 2 weeks) was continued. The patient's psychotic symptoms, including paranoid thoughts, and prominent negative symptoms returned to the previous level.
At this time, other patients on the unit were showing a positive response to the combination of haloperidol and quetiapine and this patient was therefore switched to this combination. The patient was started on oral haloperidol 5 mg twice a day in combination with a low dose of quetiapine, which was gradually increased to 200 mg three times a day. After several weeks, haloperidol decanoate was added, with the dose adjusted upwards to 200 mg IM every 3 weeks. After a few weeks, the patient's behavior and outlook improved. The content of his interactions with others was appropriate, his delusions did not return, and the patient had good affect and showed interest in daily activities. The patient's only complaint while being treated with this combination of medications was some initial fatigue which gradually decreased; no other adverse effects were observed in this patient while on this combination of medications. The combination of haloperidol and quetiapine provided the first successful treatment for this patient's negative and positive symptoms, with the added benefit of minimal adverse effects.
A systematic review of the literature concerning use of antipsychotic polypharmacy revealed that, while many reports of successful results with various drug combinations have been published, few controlled, randomized trials have been done in this area. Thus the majority of reports of successful treatment of psychotic disorders with antipsychotic polypharmacy are currently in the form of case studies, and additional evidence-based studies are needed. Such research studies of polypharmacy need to include adequate trials of each of the individual drugs as well as an adequate trial of the combination of drugs in the same patients. Another problem with research in this area is the lack of standardized criteria for evaluating symptomatic improvement.3
Until more evidence-based literature is available, the rationale for the efficacy of various drug combinations is speculative, since it is based only on known profiles of individual drugs and clinical experience. With this caveat, we propose a rationale for the efficacy of the combination of haloperidol and quetiapine in the patients reported here based on the receptor-binding profiles of the two agents and the clinical effects of each drug.
Differences in the receptor mediation of haloperidol and quetiapine may explain the response of patients with refractory psychotic disease to this combination as well as the few adverse effects experienced. Quetiapine is the only antipsychotic that has greater affinity for serotonin receptors (especially 5-HT2C) than for the D2 receptor.8 Blockade of serotonin receptors is thought to underlie successful treatment of negative symptoms; it also causes release of dopamine in the nigrastriatal pathway, which combats EPS. Quetiapine binds only loosely at the D2 receptor, in contrast to haloperidol, which binds tightly to the D2 receptor. Haloperidol is very effective at treating positive symptoms because of this strong D2 binding. However, over time, the D2 receptors are upregulated at synapses in response to this strong blockade.9 When the synapses adjust to the drug, it then loses effectiveness. With quetiapine competing for D2 receptors, it is possible that the amount of time each haloperidol molecule spends bound to a particular receptor is decreased, in which case D2 receptor upregulation would not occur to as great an extent as with haloperidol alone. Even if competition at D2 receptors is not significant, when quetiapine is added to haloperidol, the adverse effect of EPS is blocked and negative symptoms are also treated. This was demonstrated by the patients in these case reports who quickly showed marked improvement and also maintained good status while on this combination. Achieving optimal control at D2 and 5-HT2C receptors by using a combination of medications with high affinity for these two receptors produced a good response in the patients described here and appears to be a good option for patients with refractory psychotic disorders. A limiting factor in interpreting the results of these case reports is that the patients did not receive a trial of monotherapy with each of the agents.
Although we have experience with only a few clinical cases, our findings provide hope for patients with treatment-refractory schizophrenia. The use of combinations of conventional and second generation antipsychotics is understudied, and the current lack of antipsychotic treatment regimens for patients with refractory schizophrenia dictates further research in this area of clinical interest. A randomized clinical research study comparing haloperidol monotherapy, quetiapine monotherapy, and combined treatment with haloperidol plus quetiapine in patients with treatment-refractory schizophrenia appears warranted based on our preliminary success with this combination.
COMMENTARY by Jack M. Gorman, MD
Before commenting on the specific combination of medications Aziz and colleagues have found so dramatically helpful for their two patients with previously treatment-refractory schizophrenia, it is worth spending a moment on the whole concept of "polypharmacy." Almost all of us learned to regard "polypharmacy"-loosely defined as prescribing more than one medication to a patient to treat a single illness-as, plain and simply, bad practice. We were warned that drug-drug interactions and adherence problems almost always made polypharmacy a high-risk enterprise and that the skilled clinician should usually be able to boil a patient's drug regimen down to a single medication per ailment.
Of course, in practice, the reverse is generally the case: patients with psychiatric illnesses rarely do well on just one drug. This, of course, does not mean we shouldn't try; sometimes polypharmacy is the result of accretion-like phenomena in which succeeding drugs are added to the patient's regimen with no consideration for the possibility that prior interventions might no longer be necessary or might even be causing problems. Given the modern demands of managed care in which clinicians are pressured to avoid "rocking the boat" and must spend as little time as possible with each patient, it is often not possible for clinicians to undertake valiant attempts to see if drugs prescribed earlier in a patient's history can be stopped. Nevertheless, experienced clinicians know that it is in fact rare that all but the simplest psychiatric illness can be adequately managed with one medication.
This should not be a surprise if we think about the practices of our colleagues in other specialties of medicine. I was recently asked to consult concerning a woman with depression. This patient was using three different eye drops for her chronic glaucoma and no one questioned that each was needed to insure that her intraocular pressure remained low enough to prevent visual loss. Patients with hypertension, an extremely common medical problem, often require more than one antihypertensive agent to control blood pressure; the attitude here is, whatever it takes to maintain blood pressure at a normal level is justified in the battle to reduce the risk of heart attack and stroke. One could go on enumerating such examples, but it is clear that at least two factors tend to make "polypharmacy" seem more acceptable outside psychiatry. First, in situations involving conditions such as glaucoma and hypertension, there are objective markers of a drug's success, making it somewhat simpler to decide if adding medications is warranted. Second, the perception has traditionally been that an antidepressant is an antidepressant and an antipsychotic is an antipsychotic. Indeed, the former almost all block the reuptake of serotonin or norepinephrine, while the latter mostly block the dopamine type 2 receptor. Such considerations can make it seem futile to prescribe more than one psychiatric drug.
In fact-and Aziz and colleagues make this point quite nicely-the mechanisms of action of psychiatric drugs are far more subtle than what I outlined above, making it entirely plausible that combinations of medications may achieve goals that single agents alone cannot. Perhaps more importantly, the illnesses we treat are themselves so complex in etiology, involving the body's most complex organ, that it is perhaps naïve in the first place to assume that a single medication could almost ever be sufficient. This is especially striking when we think of the kinds of cases presented here. A compelling aspect of these two patients is the challenge they present. These three authors, along with I am sure many experienced clinicians, systematically applied multiple medications in attempts to treat two very ill patients, all without success. This reassures us about two concerns. First, the decision to try the combination of haloperidol and quetiapine was not a casual one but rather it was the product of careful clinical decision-making. Second, given all the prior failed attempts, it becomes less likely that the response these two patients had to the specific haloperidol/quetiapine combination was merely coincidence. What we seem to have here is a genuine response that should be of value to other clinicians in similar circumstances.
It is important to remember that haloperidol is a very effective drug on its own. Although its penchant for causing EPS, hyperprolactinemia, and tardive dyskinesia made it fall from grace as the atypical antipsychotics were introduced, very few rigorously controlled studies in which appropriate doses were used have shown that any other antipsychotic drug, including the atypical agents, works much better for positive symptoms. In the recent landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study,10 the conventional antipsychotic perphenazine performed more or less equally to the atypical drugs for positive symptoms. Perhaps clinicians should keep haloperidol in mind more often when confronted with patients with schizophrenia who respond to nothing else and would otherwise be doomed to constant hospitalizations. A bit more mysterious is the nearly complete lack of the adverse events usually associated with haloperidol, which the authors attribute to an increase in dopamine release in the nigrostriatal pathway secondary to quetiapine's blockade of serotonin receptors. This dopamine-enhancing effect of atypical antipsychotic medications has been difficult to prove and it is unclear that, even if true, it could account for patients tolerating doses of haloperidol of 15 mg and 10 mg daily, respectively, without evidence of EPS. Of course, these patients are still at risk for developing tardive dyskinesia at some point and hence abnormal movements should be monitored. The authors also ascribe the improvement in negative symptoms experienced by their two patients to this effect on dopamine neurotransmission. This is, again, a controversial hypothesis, since quetiapine has not to date been shown to have a robust effect on negative symptoms in controlled trials, and dopamine agonists have also been only modestly successful in treating negative symptoms. However, the authors' speculations are worth considering and hopefully will form the basis for further research investigation.
One might ask whether these two patients would be better off taking clozapine, the gold standard for treatment-refractory schizophrenia, rather than the the combination of haloperidol and quetiapine. By using clozapine, the patients would presumably be able to avoid "polypharmacy" as well as any risk of tardive dyskinesia. On the other hand, clozapine therapy would almost inevitably cause substantial weight gain and leave the patients at risk for hypertension, hyperlipidemia, and diabetes. Given how well these two patients seem to be doing, it is not at all clear that clozapine monotherapy would be a superior option. Aziz et al. forcefully call for controlled trials of combination therapies for the treatment of schizophrenia. In reviews of available studies, Freudenreich and Goff11 and Patrick et al.3 found some evidence to support augmentation of one antipsychotic with another when monotherapy was insufficiently successful, but few controlled trials were available. Clearly, the two cases presented here are striking examples of how "polypharmacy" should not be automatically dismissed and Aziz et al are entirely correct in their strong advocacy for controlled, unbiased investigation into this area.
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