Antipsychotic drugs are the treatment of choice for virtually all patients with schizophrenia. There are two broad classes of antipsychotic drugs: The typical (a.k.a., “first-generation” or “conventional”) antipsychotic drugs and the atypical (a.k.a., “second-generation” or “novel”) antipsychotics (Table 16–11). What follows is a description of each of these broad classes, followed by guidelines for choosing antipsychotic medications and for their clinical use in treating schizophrenia during the acute phase and long-term treatment.
Typical Antipsychotic Drugs
The discovery of chlorpromazine in 1950 revolutionized the treatment of schizophrenia. It and the other typical drugs have a simple mechanism of action: They are direct-acting dopamine D2-receptor antagonists. Thus, they occupy D2 receptors in each of the relevant dopamine pathways, including the mesolimbic tract (where excessive dopamine transmission is believed to underlie positive symptoms), mesocortical tract (where deficits in dopamine transmission are thought to cause cognitive dysfunction and negative symptoms), nigrostriatal tract (where D2 blockade results in extrapyramidal adverse effects, as will be discussed shortly), and the tuberoinfundibular tract (where activation of D2 receptors controls pituitary prolactin release). By this one mechanism, typical neuroleptics remedy positive symptoms but coincidentally result in troublesome antidopaminergic adverse effects (EPS, hyperprolactinemia) and either fail to address adequately or even worsen negative symptoms and cognitive dysfunction. This class of agents does not have a useful impact on work capacity and social functioning.
In terms of treatment response, about 70% of patients with schizophrenia who manifest delusions or hallucinations during some phase of their illness will have a good response of those symptoms to these agents. The therapeutic lag time is about 4–6 weeks. For many, an antipsychotic response will be observed sooner, sometimes within the first week of treatment. The other 30% will have moderate to severe positive symptoms despite adequate doses of these agents for at least 6 weeks, which is considered the minimum, adequate therapeutic trial length. Evidence suggests that lower dosages of typical antipsychotics can bring relief to patients as rapidly and effectively as higher doses and with fewer side effects. For instance, daily dosages of 5–10 mg of haloperidol, or its equivalent (Table 16–11), may be adequate for many, if not most, patients with acute psychosis. First-episode and recent-onset patients almost always respond to lower dosages. Ordinarily, higher dosages should not be tried until at least 4–6 weeks of treatment at the starting dose have been tried. Then, if positive symptoms persist, the dosage may be increased. Plasma levels of antipsychotics and their metabolites vary greatly between patients. The only typical agent with a possible therapeutic window is haloperidol. For haloperidol, a steady-state plasma range of 12–17 ng/L has been associated with optimal antipsychotic action.
The term neuroleptic refers to the neurologic side effects of the typical antipsychotics, such as catalepsy in rodents and EPS in humans. These effects occur in the same dosage range as is associated with an antipsychotic effect; therefore, for typical antipsychotics, treatment emergent EPS is a common and significant treatment-limiting factor. The EPS may be divided into acute and delayed effects. The predominant acute effects are parkinsonism (coarse resting tremor, bradykinesia, hypertonia, unstable gait), akathisia (subjective restlessness and psychomotor agitation), and dystonic reactions (sudden-onset, sustained, intense and often painful muscular contraction). The late occurring side effects are tardive dyskinesia and tardive dystonia. The late occurring effects are sometimes irreversible and, rarely, life threatening. No one with tardive dyskinesia should be treated with a typical neuroleptic now that the atypical antipsychotics are readily available.
As mentioned beforehand, the antipsychotic action and motor side effects of neuroleptics are secondary to their ability to decrease dopaminergic activity due to blockade of D2 receptors in the mesolimbic and nigrostriatal pathways of the brain, respectively. The affinities that antipsychotic agents have for D2, 5-HT2A, and muscarinic receptors are key determinants of their liability to cause EPS. These drugs also have variable affinities for other neurotransmitter receptors which have predictable effects on antipsychotic profile (Table 16–12). These receptors include histamine 1 (H1, antagonism of which may result in sedation and weight gain), alpha-1 (α-1) adrenergic (antagonism of which may result in sedation, orthostatic hypotension, and reflex tachycardia), muscarinic-1 (M1) cholinergic (antagonism of which may result in blurring of vision, dry mouth, urinary retention, constipation, and cognitive dulling) receptors. Hematologic effects, jaundice, cardiac effects (e.g., electrocardiographic changes such as QTc interval prolongation, especially for thioridazine, pimozide, and droperidol), photosensitivity, and retinitis pigmentosa (associated especially with the use of higher doses of thioridazine, which may result in blindness) result from toxic effects on specific target tissues.
Table 16–12. Common Causes of Suboptimal Response to Antipsychotic Treatment in Schizophrenia |Favorite Table|Download (.pdf)
Table 16–12. Common Causes of Suboptimal Response to Antipsychotic Treatment in Schizophrenia
Misdiagnosis of schizophrenia
Diagnosis of schizophrenia should be reconfirmed in every instance of suboptimal treatment response
Undiagnosed psychiatric comorbidity
Comorbid substance use disorder(s)
Poor compliance with treatment
Can confirm using plasma levels for haloperidol and clozapine
Inadequate drug dose (see Table 16–10)
400–600 mg/d chlorpromazine equivalents for all typical agents
Target serum level of ≥350 ng/L for clozapine
Inadequate trial length
≥4–6 weeks is usually necessary
Possibly longer for clozapine treatment or history of refractory disease
Possibly longer for any agent where negative symptoms are prominent
Intolerable side effects, especially:
EPS, including akathisia and parkinsonism
Cognitive dulling (with traditional neuroleptics)
Worsening affective symptoms (with traditional neuroleptics)
Intolerable drug–drug interactions
Poor social support
The choice of typical neuroleptic drug is based on a variety of initial considerations, which include the following:
- side-effect profile,
- past response(s) to antipsychotic drugs,
- the availability of long-acting preparations (e.g., fluphenazine and haloperidol decanoate) required for patients who frequently relapse due to poor medication compliance. In chronically noncompliant patients who are unwilling to take oral medication, biweekly or monthly injections of fluphenazine decanoate or haloperidol decanoate (given at clinics or by visiting nurses) often decrease relapse rates significantly.
- the availability of short-acting injectable or intravenous formulations for use in acute situations (to control agitation and combative behavior) where oral dosing is not feasible, or when the oral route is not available.
Other considerations are based on the side-effect profile. Differences in side-effect profile between low- and high-potency typical neuroleptics are predicted to a great degree by their receptor-binding profiles. For instance, low-potency drugs (e.g., chlorpromazine, thioridazine, mesoridzaine), so named because of their relatively lower affinity for D2 receptors and therefore higher dose requirement for antipsychotic potency (300 mg/d or greater), may result in lower EPS or hyperprolactinemic liability compared to high-potency agents (e.g., haloperidol, fluphenazine). However, low-potency drugs result in more sedation, weight gain, orthostasis, and antimuscarinic effects than high-potency agents do because of their higher affinities for H1, α-1 and M1 receptors. The latter agents produce more EPS than do the low-potency agents (see Table 16–11).
If the patient's history of drug response does not indicate an unusual sensitivity to EPS, high-potency agents such as haloperidol and fluphenazine are preferred to low-potency agents. Thioridazine is believed to have more risk of causing a ventricular arrhythmia than other typical antipsychotic drugs. If EPS develop, anticholinergic agents such as benztropine, diphenhydramine, biperiden, or trihexyphenidyl can be used as a pharmacological adjunct, or the patient can be switched from a high-potency agent to a medium-potency drug (e.g., trifluoperazine) or to a low-potency drug (e.g., thioridazine). A more important strategy for the minimization of EPS is to keep the dose as low as possible (e.g., no more than 5–10 mg/d of haloperidol equivalents), assuming there is a reason why an atypical antipsychotic drug could not be substituted. Persistent EPS, especially akathisia, can contribute to noncompliance or lead to increased agitation or even suicide risk. Thus, in cases of apparently increased agitation and disorganized behavior in the face of ongoing treatment especially with typical antipsychotics, screening for akathisia should always be considered.
Atypical Antipsychotic Drugs
The “atypical” antipsychotic drugs were given this name because they were able to produce an antipsychotic effect at doses which produced little or no EPS (and very few cases of tardive dyskinesia). The prototypical atypical is clozapine, a dibenzodiazepine, which was first identified in 1959. After the hypothesis was advanced that its atypicality was due to a weak D2-receptor blockade coupled to potent serotonin (5-HT2A) antagonism (mechanism of action), a number of other atypical antipsychotic drugs were discovered which shared this mechanism: Risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. The latter differs from the others in substituting partial D2-receptor blockade for D2-receptor antagonism. Other atypical antipsychotics including asenapine, Iloperidone, laurisdione, paliperidone, and perospirone are in development, and have mechanisms of action similar to clozapine. Bifeprunox has a mechanism similar to that of aripiprazole (partial dopamine D2-receptor agonism). Besides being a partial D2 agonist, aripiprazole is also a 5-HT2A antagonist (like most other atypicals) and a 5-HT1A-partial agonist (similar to clozapine, quetiapine and ziprasidone). Bifeprunox is a 5-HT1A-partial agonist and has weak 5-HT2A-antagonist properties.
Clozapine was the first antipsychotic drug shown in controlled clinical trials to alleviate both positive and negative symptoms in patients who had failed to respond to adequate trials of typical neuroleptic drugs. In this treatment-resistant group, clozapine treatment results in a clinical response in 30–60% of cases. It produces almost no EPS, akathisia, tardive dyskinesia, or hyperprolactinemia. The onset of a significant response to clozapine in treatment-resistant patients may be delayed for up to 6 months. Primary negative symptoms tend to improve more slowly than do other types of symptoms. The response to clozapine is usually only partial, but for patients whose symptoms have been virtually nonresponsive to all other therapies, the change can be highly significant.
The remarkable advantages of clozapine (described later in this section) must be balanced against its ability to cause agranulocytosis, in 1% of patients. As a result, clozapine has been approved in the United States only for patients with schizophrenia who have failed to respond adequately to typical neuroleptic drugs (treatment-resistant schizophrenia) or who are intolerant of typical neuroleptic drugs because of EPS or tardive dyskinesia, or who are at high risk for suicide. Poor work function or moderate-to-severe residual negative symptoms are considered a poor response, even if only mild positive symptoms are present.
Clozapine has been shown to reduce depression and suicidality. The latter effect leads to a major decrease in the overall mortality rate associated with schizophrenia, despite the slight increase due to agranulocytosis. Numerous studies have reported that clozapine can improve some aspects of cognitive function, especially verbal fluency, attention, and recall memory. This effect appears to be unrelated to the drug's lack of adverse effect on motor function.
About 40% of patients have positive symptoms that fail to respond adequately to clozapine monotherapy. As previously mentioned, it often takes 6 months and sometimes longer for positive symptoms to be controlled in very treatment-resistant patients. Patience is required. Polypharmacy with other antipsychotic drugs should be avoided, if possible. Only ECT has sometimes been found to be effective as an adjunctive treatment. The effectiveness of adding of mood stabilizers and antidepressants when mood instability or depression is inadequately treated with clozapine has not been studied in a controlled manner. On clinical grounds, trials with various mood stabilizers may be attempted. There is some evidence that lamotrigine and valproate are useful.
Agranulocytosis during clozapine treatment generally occurs within 4–18 weeks after treatment begins, but it can occur rarely at later times. In the United States, white blood cell and absolute neutrophil count (ANC) must be monitored weekly for 6 months, then every 2 weeks for months 7–12, followed by monthly monitoring on an indefinite basis. When the white blood cell count falls below 3000 cells per mm3, or the ANC below 1500 cells per mm3, clozapine should be stopped and not restarted. If agranulocytosis has developed, granulocyte colony stimulating factor (G-CSF) or other growth factors can be used to hasten the recovery process. Recovery generally takes 7–14 days. Hospitalization to prevent or treat sepsis is essential. To date, the death rate from clozapine due to agranulocytosis is about 1 per 10,000.
Clozapine can also cause leukocytosis and eosinophilia in the early stages of treatment. The development of these disorders does not predict later development of agranulocytosis. Other side effects of clozapine include sedation, weight gain, type II diabetes, hyperlipidemia and atherosclerotic heart disease, major motor seizures, obsessive–compulsive symptoms or treatment-emergent obsessive–compulsive disorder, hypersalivation, tachycardia, hypotension, hypertension, stuttering, neuroleptic malignant syndrome, urinary incontinence, myocarditis, and constipation. Many of these side effects diminish over time or are responsive to pharmacologic agents and decreased dosage.
The dosage of clozapine ranges from 100 to 900 mg/d for most patients. It must be titrated slowly because of tachycardia and hypotensive side effects, with a starting dosage of 25 mg/d. The average dosage is 400–500 mg/d, usually given twice daily. Plasma levels of 350–400 ng/L are more likely to be associated with clinical response than are lower levels.
Clozapine has a very complex pharmacologic profile. It has a high affinity for serotonergic (5-HT2A,2C,6,7), adrenergic (a1,2), muscarinic, and histaminergic receptors. Clozapine and related drugs are inverse agonists at 5-HT2A and 5-HT2C receptors, meaning they can block the constitutive activity of these receptors, (i.e., activation of the receptor that is independent of 5-HT stimulation). The major metabolite of clozapine, N-desmethylclozapine is a M1 muscarinic agonist. This mechanism may improve cognitive function and reduce psychosis. No other atypical or a metabolite thereof has M1 muscarinic properties.
Other D2 and 5-HT2a Antagonists
This group of drugs includes quetiapine, olanzapine, risperidone, and ziprasidone. As a class, these agents are as effective as the typical antipsychotic drugs with regard to the control of positive symptoms. The recent CATIE study suggested that olanzapine is superior with regard to some outcome measures; however, CATIE permitted olanzapine to be dosed at a higher than the approved dose range which probably enabled it to be more effective in the subset of patients who were treatment resistant. At clinically equivalent doses, there is no reliable evidence that any of these drugs is significantly more efficacious than the others. Anecdotal evidence suggests that ziprasidone causes an activation syndrome earlier and at lower doses than other treatments do. However, controlled clinical trials do not support this. It may be that patients vulnerable to this type of activation are underrepresented in clinical trials.
These drugs differ in side-effect profiles (Table 16–11). Olanzapine, like clozapine, has the greatest likelihood of causing metabolic side effects. Both drugs show relatively high-affinity binding to H1, α-1 and M1 receptors and thus are associated with corresponding adverse effects. Metabolic effects include weight gain and abnormalities in indices of insulin resistance, including increased fasting blood sugar and an atherogenic lipid profile. Some patients develop type II diabetes or diabetic ketoacidosis. In rank order, the other drugs likely to produce these effects are quetiapine and risperidone (moderate risk), and ziprasidone and aripiprazole (lower risk). Both risperidone and ziprasidone are mild, overall, in this regard. Nevertheless, some patients treated with any of these drugs will gain weight or have glucose and lipid changes. Despite the fact that many patients who develop insulin resistance also experience significant weight gain, these two factors are not highly correlated in many patients. Patients who do not gain weight may therefore show other facets of the insulin resistance syndrome and vice versa. Patients should be monitored for increased lipids and fasting blood sugar after the first 3 and 6 months of treatment, and every 6 months thereafter.
Relative to typical neuroleptics, atypical antipsychotic drugs have less treatment-emergent antidopaminergic side effects than typical neuroleptics do. At higher doses (e.g., above 6 mg/d), dose-dependent EPS and hyperprolactinemic effects can be observed with risperidone, however.
The dose of these drugs should be kept as low as possible in non–treatment-resistant patients. First-episode patients and those within the first 5 years of illness usually require the low end of the dose range. All atypical drugs, with the exception of quetiapine, which has a very short half-life, can be given once a day, generally prior to sleep, to minimize daytime sedation, for example, olanzapine, 10–20 mg/d; quetiapine, 200–1000 mg/d; and risperidone, 2–8 mg/d. Polypharmacy with two antipsychotic drugs should be avoided. If control of positive symptoms is inadequate at these dosages after 6 weeks, it might be useful to increase the dose. However, a switch to clozapine, where the dose can be relatively high with minimal EPS, is often a better strategy, especially after the failure of two adequate antipsychotic trials (e.g., 6 or more weeks at an adequate dose). As with clozapine, augmentation with mood stabilizers, antidepressant drugs or ECT can be attempted on clinical grounds.
Currently, only risperidone is available in a long-acting form. It must be given every 2 weeks and takes 6 weeks before steady state plasma levels are achieved. Therefore, oral risperidone must be continued for at least 3 weeks after the first long-acting risperidone injection, or even longer in some cases. The typical dose of long-acting injectable risperidone is between 35–50 mg every 2 weeks.
Aripiprazole is the first partial dopamine agonist which has been approved for the treatment of schizophrenia. The basis of partial dopamine agonism as a block to dopaminergic blockade is that aripiprazole occupies the receptor, but causes significantly less activation of the receptor than the full agonist, dopamine does. The efficacy of aripiprazole is no doubt dependent, in addition, on its serotonergic properties. It is a 5-HT2A antagonist and a 5-HT1A-partial agonist, both of which effects would be expected to minimize EPS. Aripiprazole is generally given once daily, at a dose of 15 mg/d. Sometimes, doses of 20–30 mg are required. Combination with a typical neuroleptic should be avoided as that could interfere with the partial dopamine agonist properties. Aripiprazole produces mild metabolic side effects, comparable to those of risperidone and ziprasidone. It may also be associated with activation when first administered, and can cause nausea.
The management of schizophrenia is often conceived of as occurring in three phases of treatment (acute, continuation, and maintenance).
The acute phase of schizophrenia is characterized by fully expressed psychotic symptoms. The acuity of symptoms is often such that hospitalization is necessary for control of acute, life-threatening agitation and combativeness. In order to avoid use of physical restraints, oral antipsychotic medication may be offered; however, oral medication is often refused or, more commonly, cannot be safely administered in an acute situation. For patients who are acutely agitated or likely to harm themselves or others, short-acting injectable antipsychotics, benzodiazepines, alone or in combination, may be considered. Currently, the only atypical antipsychotics available in an acute injectable form are ziprasidone and olanzapine. Several typical neuroleptics are available in this form (haloperidol, 5 mg IM), and are often administered alone or in combination with an injectable benzodiazepine (e.g., lorazepam) and/or an anticholinergic drug (e.g., benztropine or diphenhydramine). It is necessary to isolate such patients in a quiet room, with as much supervision as possible. Parenteral haloperidol may be repeated, as needed, every 2–4 hours. Rarely, ECT will be needed.
Once agitation has been controlled or if injectable medication is not indicated, treatment with an orally administered antipsychotic may be initiated. Ordinarily, the first antipsychotic administered should be chosen from aripiprazole, quetiapine, risperidone, and ziprasidone in a never-treated or medication-free patient who has a history of response to antipsychotic drug treatment (Figure 16–1). Olanzapine, because of its higher burden of metabolic side effects, might be kept in reserve. However, not all patients treated with olanzapine develop metabolic side effects. For patients on one of these drugs for whom a switch is indicated to another of the same class, there is no accepted preferred way to do this. Stopping the current drug as the new drug is introduced may be as safe and effective as rapid or slow cross-titration.
Algorithm for the pharmacological treatment of patients with schizophrenia or schizoaffective disorder. First-line options include amisulpiride (AMI, not available in the United States), aripiprazole (ARIP), olanzapine (OLZ), quetiapine (QTP), risperidone (RISP), paliperidone (PALI), or ziprasidone (ZIP). An adequate trial of medication is 4–6 weeks at an adequate dosage before trying a different agent. Clozapine should be considered if a patient does not respond to two or more adequate medication trials. Patients should receive 6 months of clozapine treatment before adequacy of treatment response is judged. If response is inadequate, a number of less well-studied options may be considered. At first assessment and at each initial visits, there are a number of clinical considerations and other important areas that should be assessed, as indicated in the box in the upper left hand corner of the figure. Adapted from the International Psychopharmacology Algorithm Project (IPAP) schizophrenia treatment algorithm, available online at www.ipap.org.
In choosing among the various first-line options, no convincing data suggest superior efficacy in target symptom domains for a particular agent. The clinical decision about which agent to use is based on other factors: side-effect profile, past therapeutic response to agent(s), and patient/caregiver preference. The issue of tolerability due to side-effect burden is no small one, since relapse into acute phase illness is often preceded by unilateral discontinuation of medication.
If circumstances are such that a patient requires treatment with a typical neuroleptic (i.e., prior treatment response to typical rather than atypical drugs in absence of significant EPS, limited formularies, cost considerations, or patient/caregiver preference), treatment is best commenced with an oral drug at low dosage (i.e., 10 mg/d haloperidol equivalent). The dose should not be increased for 4–6 weeks unless psychotic or aggressive symptoms or sleeplessness are severe. Rapid dose increases aggravate the risk of EPS and secondary negative symptoms without added antipsychotic benefit. Routine use of short-acting parenteral medication for newly hospitalized patients is to be avoided unless absolutely necessary.
Long-acting (depot) medication should not be given initially except to those patients noncompliant with other forms of treatment. On the other hand, acute-phase symptoms due to illness relapse in the setting of poor compliance call specifically for consideration of long-acting injectable antipsychotic medication. As previously discussed, long-acting risperidone is the only atypical drug available for such use, whereas haloperidol and fluphenazine are available among the typical drugs. Because of its atypical profile, long-acting risperidone should be the first choice.
Continuation Phase Treatment
Psychotic symptoms respond, usually partially, within the first several days of treatment, or even on the first day in some patients. However, most patients do not achieve a full response at a given dose for 2–6 weeks, and remain vulnerable to early relapse. The purpose of continuation-phase treatment is to monitor patient compliance, therapeutic response, and treatment tolerance. In addition, because a significant lag time may be required to full therapeutic effect at a given dose of drug, it is inadvisable to discontinue a drug prematurely and substitute a different class of neuroleptic agent before the optimal 4–6 weeks of therapy has passed, unless significant side effects develop that are not amenable to treatment. After initial stabilization, continuation treatment ranges in duration up to 6–8 weeks, depending upon treatment response.
In general, the same medication dosage that resulted in control of acute phase symptoms is appropriate for the continuation phase, though the dose may be “fine tuned” during this time in order to minimize adverse effects or bring about a more adequate clinical response. Although some evidence supports intermittent dosing of antipsychotic medication, this strategy has been associated with increased rates of relapse. Continuous dosing is preferred.
The use of several neuroleptics at the same time should be avoided. There is no justification for the concomitant use of two classes of typical neuroleptic drugs (e.g., a parenteral and an oral antipsychotic) unless the patient's route of treatment is being converted from intramuscular to oral. In some instances, particularly when a neuroleptic does not adequately control anxiety and agitation, the adjunctive use of benzodiazepines may be helpful.
The primary goals of maintenance treatment are prevention of relapse and optimization of psychosocial functioning. Long-term illness management also calls for monitoring and treating medical comorbidities (including the effects of antipsychotic treatment), addressing comorbid psychiatric and substance use disorders, and addressing the important issue of medication compliance.
As is the case with continuation-phase treatment, the dosage used to achieve clinical response in the acute phase is often continued, but may be subject to “fine tuning” for the reasons specified above. Continuous dosing is preferred. Ongoing monitoring of medication compliance must be paramount, as this is still the most common reason for relapse. Noncompliance stems from a number of factors: Denial of illness (poor insight); intolerable side effects; suboptimal management of clinical symptoms; cognitive deficits; and other reasons. Weight gain, EPS (especially akathisia), and sedation can also be distressing to patients. Because many of the adverse effects of medication are dose dependent, problems with compliance may be managed by lowering the dosage, or switching to agents that result in fewer side effects. Pharmacological adjuncts may be required to counter particular adverse effects if dosage adjustment or switching are not clinically feasible. For most patients, treatment with antipsychotic medications will be of indefinite duration.
In spite of recent advances in antipsychotic treatment, a significant proportion of patients are left with persisting symptoms, especially negative and neurocognitive symptoms. Even under the best of circumstances, however, positive symptoms frequently persist, though in a less acute form. Incompletely treated symptoms are associated with significant psychiatric and physical health-related morbidity, and with an increased risk of relapse and rehospitalization. Thus, management during maintenance phase must endeavor to achieve as optimal a treatment response as possible. If at least a partial response to a well-executed antipsychotic trial has been achieved, remaining options include watchful waiting (since some treatment effects may take longer to appear), upwardly adjusting the drug dosage, using adjunctive medication, or switching to another medication, assuming that other factors that contribute to suboptimal treatment response have been ruled out (Table 16–12). For typical neuroleptics, clinical evidence indicates that the dose–response profiles eventually either plateau, or the side-effect liability begins to outweigh therapeutic benefit as doses are increased. For atypical antipsychotics, the dose–response interactions have been less well studied, though there is some evidence in favor of high-dose strategies for olanzapine and other atypicals.
The evidence for augmenting nonclozapine atypical antipsychotics is generally lacking. Serial trials of antipsychotic monotherapy are preferred. For treatment-refractory patients, a trial of clozapine monotherapy is clearly indicated (discussed later). However, when dosages of antipsychotic medication cannot be raised, when the risk of losing the partial response already achieved outweighs the potential benefit of switching medication, or when no other options are feasible, augmentation may be considered for specific target symptoms or psychiatric comorbidities that antipsychotic monotherapy cannot address. When an adjunct is being considered, great care must be taken to review all medications, in order to anticipate unwanted drug interactions and other risks of combining medications. Specific clinical subgroups for whom adjuncts have at least some support include patients with aggressive behavior (valproate, benzodiazepines), anxiety (benzodiazepines, antidepressants), substance use problems (naltrexone), prominent affective symptoms (valproate, lithium, antidepressants), positive symptoms (benzodiazepines), negative symptoms (antidepressants) and cognitive difficulties (antidepressants, buspirone). These strategies, again, are based on anecdotal reporting and, in cases where the evidence is stronger, clinical responses can be highly variable or even worse, especially in the case of benzodiazepines.
Treatment-resistant schizophrenia is variously defined. Failure of two well-carried-out therapeutic trials of antipsychotic from any pharmacological class is a generally accepted definition. The atypical antipsychotic, clozapine, is the only drug with proven efficacy for treatment-resistant patients. It remains the gold standard in this subgroup. Approximately 30–60% of all schizophrenic patients who fail to respond to typical antipsychotics respond to clozapine. Data concerning the usefulness of other atypical antipsychotics at conventional doses are not convincing, though higher-than-usual doses of other atypical antipsychotics may be of benefit. As was previously discussed in regard to other atypicals, there are several potentially useful adjuncts for addressing a partial antipsychotic response to clozapine, though none have a particularly strong empirical basis. To date, the most evidence is for ECT. While the rationale for the use of augmenting therapies would be the strongest for clozapine, given its status as a treatment of last resort, the potential for dangerous adverse effects with certain drug combinations is considerable. Thus, the need for caution may be even greater when augmenting clozapine partial response than for other agents.
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