ANTIPSYCHOTIC AGENTS     


Treating Schizophrenia

      It is important to understand that while symptom remission is the goal in almost any case, regardless of psychiatric malady, the cost of symptom remission must be carefully balanced against side effects. All symptoms of schizophrenia, depression, or even anxiety can be suppressed, regardless of severity — at the cost of sedation and quality of life associated with high doses necessary to eradicate symptoms. The quest for optimum therapeutic choice has historically, and remains today, a question of how to reduce symptoms to a tolerable level while maintaining side effects at a tolerable level in order to maximize quality of life.
     The antipsychotics are a prime example. Both the “conventional” or “typical” (the older agents) and “atypical” or “novel” antipsychotics (the newer and more expensive products) are clinically equally-effective – no clinical evidence exists to support successful ubiquitous use of one agent or even one class over another in all cases. Each case must be considered on it’s own individual parameters, and this includes pharmacogenetic factors (see the section on pharmacogenetics). Thus, not only must the clinician account for the individuals’ symptoms and their severity, he must also consider genetic and cultural variables based on proven clinical data regarding racial and ethnic considerations. Since the patient presenting with psychiatric symptoms is likely to have comorbid conditions and the antipsychotic agents are particularly predisposed to drug interactions by right of their metabolism, drug interactions must also play a primary role in choice of therapeutic agent.
     Thus, optimum choice of therapeutic agent relies more on side effect profile than on therapeutic efficacy. Bottom-line: The patient experiencing severe side effects is less likely to adhere to prescribed regimens on his own than the patient who perceives side effects a worthwhile tradeoff against primary pathology. Only 58% of outpatients treated for psychoses adhere to prescribed regimens, and the patient who is non-compliant due to side effects is likely to soon be readmitted for further evaluation; which is not only traumatic for the patient, but extremely expensive for the health care system, as a majority of such patients have no access to private health care insurance.
    Strong statistical evidence corroborates the fact that keeping a patient under close observation (institutionalized) for 30 days or more on a STEADY-STATE regimen typically precludes re-institutionalization. While inpatient admission costs upward of $8,000 (accounting for all personnel and their time involved in the admittance process), keeping that same patient institutionalized requires only around $450 per day when properly supervised.
     Steady state requires 5.5 half-lives of the administered medication, and adequate evaluation of the clinical effect of such therapy requires a MINIMUM of 21 days (AFTER steady-state achievement). Evidence suggests that polypharmacy (more than one medication to treat a condition in the case of schizophrenia) is effective in only a small minority of patients, so failure of one medication at optimum dosage is a strong indicator to switch to another medication or class (largely for pharmacokinetic reasons), rather than to add another antipsychotic agent. Thus, institutionalization of a patient for 5 days to establish an effective regimen is a pharmacotherapeutic joke. Such patients tend to be readmitted within only a few days because of side effects or non-compliance (with the attendant $8,000+ bill for each readmission), while the patient stabilized on a conservative regimen of one medication that minimizes side effects for around 30 days typically places the patient back in the community productively for months without relapse. Clearly, side effects are the most accurate predictor of therapeutic efficacy; and side effects cannot be assessed until steady state is maintained for an adequate amount of time.

Antipsychotic Side Effects
     In the absence of clinical evidence that any antipsychotic agents are reliably more efficacious than others, drug development has largely resulted in reduction of the severe side effects that have plagued conventional antipsychotic agents, the most significant of which are movement disorders. While side effects from this class of agents are almost inevitable with the older agents, since long-term therapy is essential, minimizing them increases the likelihood of compliance and thus of successful therapy. The goal of therapy is generally: 1) remission of acute symptoms, and 2) maintenance of remission (prevention of relapse and re-institutionalization) by achieving an optimum balance between symptom management and tolerability of side effects, not total eradication of symptoms. Any psychiatric illness can be symptomatically controlled at the expense of total somnolence. A great deal of overlap and coexistence persist among the following groups of side effects, often making differential diagnosis difficult. Thus, the choice of therapeutic agent for a given psychosis often relies heavily upon the likelihood and severity of such side effects.
     So why are side effects such a critical issue, when psychiatric illness itself can be so devastating both to the patient and to the health care system? The answer to this question is complex. Certainly anticholinergic side effects seen with other types of medication are a concern, where somnolence, dry mouth, visual disturbances, and even urinary retention can be concerns, especially in dosing of the older antipsychotic agents and in older patients affected more dramatically by side effects that might seem trivial in younger patients. When such side effects become intolerable, the patient is unlikely to adhere to prescribed regimens regardless of the consequences. For the psychotic patient with a history of non-compliance, these can be serious on their own; but extrapyramidal symptoms and tardive dyskinesia especially are fairly peculiar to the antipsychotics and severe in their consequences.

Extrapyramidal Side Effects (EPS)
   Cholinergic symptoms affecting the part of the nervous system that regulates muscular reflexes (tremor, slurred speech, akathisia, dystonia, anxiety) and distress, paranoia, and bradyphrenia are primarily associated with long-term use of antipsychotics. Involuntary movements, tremors and rigidity, body restlessness, muscle contractions, and changes in breathing and heart rate have given such side effects the name pseudo-Parkinsonism or drug-induced Parkinsonism, since the presentation is usually indistinguishable from true Parkinsonism, except that they are generally reversible upon discontinuation of the causal medication. They are dose- and duration-related, with at least 60% of patients receiving older conventional agents inevitably experiencing them to some degree, especially with prolonged therapy. By the time efficacy is observed, EPS are often evident as well. As a general rule, effective therapy should be continued for a year after remission of an initial schizophrenic episode and for 3 years after remission of a recurrent episode, so long-term therapy is almost always essential.
     While such symptoms can sometimes be minimized to a degree by anticholinergic therapy (as with true Parkinsonism), it is generally wise to consider switching antipsychotic agents, as side effects tend to worsen with continued therapy in spite of anticholinergic measures, which of course cause their own set of side effects. It is generally better to avoid EPS than to treat them, when possible.
     This brings up the point of simplicity in medication regimens. While an inpatient has little choice in compliance (with the exception of those intent on deceiving caregivers, which is fairly unique to this patient population), the patient required to take multiple medications (some to counter the side effects of others) at multiple times each day on his own (especially a patient who is psychotic) can reliably be expected to fail therapy. This highlights the therapeutic value of taking the time to find a single therapeutic agent that provides maximum control of pathology with the fewest and most benign side effects on the simplest possible regimen. It also highlights the value of the newer atypical antipsychotics, which tend to cause fewer EPS, in spite of greater cost. Fortunately, most of the antipsychotic agents are appropriately dosed only once daily, and the injectable decanoates can be dosed at intervals of up to 30 days. The long-acting dosage forms, though, are typically more prone to EPS and especially tardive dyskinesia, which tends to limit their long-term effectiveness.
     The complexities of the pathophysiology of schizophrenia remain ill-defined; and though early theories (and older typical antipsychotic agents) focused on antagonism of dopamine D2 receptors, it has become clear that interplay among other dopamine receptors (D1, D4, D5, and D7), various serotonin receptors (notably 5HT2, 5HT6, and 5HT7), muscarinic, alpha-adrenergic, and histaminic systems are also involved to variable degrees in individual patients. To complicate this clinical picture, the location of dopamine receptors and the regional anti-dopamine effects of various receptor-antagonist/agonist properties of available agents seem equally important: nigrostriatal (movement disorders), mesolimbic (relief of hallucinations and delusions), mesocortical (relief of psychosis, worsening of negative symptoms) or tuberoinfundibular (prolactin release). The antipsychotics as a group, though, are considered dopamine antagonists. (See the section on Receptor Science below.)
     The older conventional agents are notorious for their extrapyramidal side effects, almost inevitably associated with prolonged therapy and higher doses, especially in older patients. While considered equipotent in equivalent doses, the more-potent agents have a greater tendency to cause extrapyramidal symptoms, and the less-potent agents tend to cause more sedation (and other anticholinergic side effects) at equivalent doses. The atypical agents (risperidone, clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole) are noted for their lesser tendency to cause such symptoms; and risperidone’s EPS potential is clearly dose-related.

Some other common side effects
• Antihistaminic (sedation),
• Antiserotonergic (weight gain),
• Antidopaminergic D2 (EPS, prolactin release),
• Anticholinergic (urinary hesitancy and retention, dry mouth, blurred vision, exacerbation or precipitation of angle-closure glaucoma, constipation, sinus tachycardia, cognition and memory effects), and
• Anti-alpha 1-adrenergic (orthostatic hypotension, reflex tachycardia).

Weight Gain
    Weight gain can seem a trivial matter when considering the seemingly more drastic consequences of schizophrenia, but the weight gain associated with long-term therapy with the newer antipsychotic agents is also associated with significant shortening of lifespan. The benefits of reducing psychosis must thus be weighed against the potential exposure to risks associated with obesity and all-cause mortality associated with antipsychotic use. Health risks of cardiovascular disease, hypertension, diabetes mellitus, dyslipidemia, and even cancer are significantly greater with the atypical agents, which cause weight gain more reliably than the older typical agents, though weight gain was first recognized as a problem with chlorpromazine. The atypical agents also bear a greater tendency to cause diabetes that has been demonstrated as independent of their weight-gain liability. Aripiprazole, FDA-approved 11/2002, promises improvement in this respect, providing the benefits of the atypical agents with a minimum liability of weight gain.
    This side effect seems a function not only of the degree of effect on serotonergic receptors (5-HT2C) and histamine H1 blockade associated with increases in appetite and decreases in metabolic rate, but to the related degree of disruption of normal prolactin levels (see Endocrine and Metabolic Effects below). Clinical studies show that among the atypical agents for which side effects may be minimized, risk of increased serum prolactin levels, serum leptin levels, and consequent weight gain is as follows:

         aripiprazole <clozapine < olanzapine <quetiapine < ziprasidone <risperidone  

    The atypical agents are less likely to elevate prolactin levels than the typical agents, though, a function of the atypicals’ more favorable 5-HT2A : D2 receptor ratios. Elevations in prolactin levels are more significant with the typical agents with more pure D2 blockade. While amenorrhea or galactorrhea have yet to be reported in conjunction with even risperidal use, elevated prolactin levels tend to reduce estrogen levels and increase vulnerability to osteoporosis, more a concern for women than men.
    Prolactin levels are a significant concern in the young woman attempting to become or already pregnant, as reduced gonadal hormone production makes conception difficult. Yet the atypicals have yet to be proven safe during pregnancy, and clozapine seems an unwise choice in this application. Quetiapine might be a viable option, with its minimal prolactin effects, to be discontinued as quickly as possible after detection of pregnancy, but avoiding relapse.       Greatest risk to the fetus is during organogenesis between days 18 through 60 of gestatio n. At this point, prolific estrogen production with D2 modulation is likely to be sufficient to provide a drug-free first trimester without relapse of psychotic symptoms. Should antipsychotic therapy remain essential, haloperidol has the best pregnancy safety record, especially in low doses. Dosage reduction should target delivery to minimize neonatal withdrawal and facilitate delivery.
    Doses will need to be increased postpartum, and breastfeeding will cause drug neonatal exsposure, prompting careful monitoring of the baby’s level of sedation. Women with psychosis who wish to avoid pregnancy or whose postpartum milk production is lacking may benefit by D2 blockade and consequent increase in prolactin levels. All available antipsychotic agents, typical and atypical, are Pregnancy Category C.