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Psychosis is a symptom of mental illnesses characterized by a distorted or non-existent sense of reality. Psychotic disorders have different etiologies, each of which demands a unique treatment approach. Common psychotic disorders include mood disorders (major depression or mania) with psychotic features, substance-induced psychosis, dementia with psychotic features, delirium with psychotic features, brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophrenia. Schizophrenia has a worldwide prevalence of 1% and is considered the prototypic disorder for understanding the phenomenology of psychosis and the impact of antipsychotic treatment, but patients with schizophrenia exhibit features that extend beyond those seen in other psychotic illnesses. Hallucinations, delusions, disorganized speech, and disorganized or agitated behavior comprise the types of psychotic symptoms found individually, or rarely together, in all psychotic disorders, and are typically responsive to pharmacotherapy. In addition to positive symptoms, schizophrenia patients also suffer from negative symptoms (apathy, avolition, alogia), and cognitive deficits, particularly deficits in working memory, processing speed, social cognition, and problem solving that test 1.5-2 standard deviations below population norms (Green et al., 2004). Cognitive dysfunction is the strongest predictor of functional impairment among schizophrenia patients, yet negative symptoms and cognitive deficits show limited improvement with antipsychotic treatment (Buchanan et al., 2007). That schizophrenia is not identical to other psychoses is important for appreciating the differential impact of antipsychotic medications on psychotic symptomatology, and for understanding the rationale for non-dopaminergic antipsychotic drugs based on the underlying pathophysiology of schizophrenia (Carpenter and Koenig 2008).
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The Dopamine Hypothesis. The development of our understanding of the neurobiology and pharmacotheorapy of psychoses profited from the synthesis of chlorpromazine in 1950 and of haloperidol in 1958. The DA hypothesis of psychosis derived from the fortuitous discovery of chlorpromazine's therapeutic efficacy in schizophrenia, and the subsequent elucidation by Carlsson that postsynaptic DA D2 receptor antagonism was the common mechanism that explained antipsychotic properties. Reserpine, derived from Rauwolfia, exhibited antipsychotic properties by decreasing dopaminergic neurotransmission; however, unlike D2 receptor antagonists, reserpine exerted its effects through depletion of monoamines from presynaptic nerve terminals. The dopamine theory of psychosis was reinforced by the high risk for drug-induced psychosis among substances that directly increased synaptic dopamine availability, including cocaine, amphetamines, and the Parkinson's disease treatment L-dopa (Carlsson, 1978).
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The dopamine (DA) overactivity hypothesis has led to the development of the first therapeutic class of antipsychotic agents, now referred to as typical or first-generation antipsychotic drugs. These medications differed in potency, but shared the common mechanism of significant DA D2 blockade and associated risk for extrapyramidal side effects. In the past, the term "neuroleptic" was also employed to refer to typical antipsychotic drugs, literally meaning to "take hold of the nerves" in Greek, but this has been dropped from contemporary usage (as has the term "major tranquilizer") in favor of "antipsychotic drug," a term that more accurately reflects the primary clinical use of these agents.
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While the DA hypothesis is an advance over earlier conceptualizations of psychosis, it has limitations, and does not account for the cognitive deficits associated with schizophrenia that appear to be related to decreased DA signaling in the prefrontal cortex. The DA hypothesis also does not explain the psychotomimetic effects of agonists of other pathways (e.g., d-lysergic acid, a potent serotonin 5-HT2 receptor agonist), or the effects of phencyclidine and ketamine, antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor. Advances in treatment have emerged from exploration of alternative (non-dopaminergic) mechanisms for psychosis and from experience with atypical antipsychotic agents such as clozapine. These newer antipsychotics potently antagonize the 5-HT2 receptor, while blocking D2 receptors less potently than older typical antipsychotic agents, resulting in the atypical clinical profile of antipsychotic efficacy with limited extrapyramidal side effects. Also promising are medications that target glutamate and 5-HT7 receptor subtypes, receptors for γ-aminobutyric acid (GABA) and acetylcholine (both muscarinic and nicotinic), and even peptide hormone receptors (e.g., oxytocin) (Carpenter and Koenig, 2008).
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Review of Relevant Pathophysiology
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Not all psychosis is schizophrenia, and the pathophysiology relevant to effective schizophrenia treatment may not apply to other psychotic disorders. The effectiveness of dopamine D2 antagonists for the positive symptoms of psychosis seen in most psychotic disorders suggests a common etiology for these symptoms related to excessive dopaminergic neurotransmission in mesolimbic dopamine pathways. In substance-induced psychotic disorders, the substance may directly increase postsynaptic DA activity through increased presynaptic neurotransmitter release (amphetamine), inhibition of presynaptic DA reuptake (methylphenidate, cocaine, and amphetamine), or increased DA availability (L-dopa). The NMDA antagonists phencyclidine and ketamine indirectly act to stimulate DA availability by decreasing the glutamate-mediated tonic inhibition of DA release in the mesolimbic DA pathway.
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The psychoses related to delirium and dementia, particularly dementia of the Alzheimer type, may share a common etiology: the deficiency in cholinergic neurotransmission, either due to anticholinergic properties of medications (Chew et al., 2008), age- or disease-related neuronal loss, or both (Barten and Albright, 2008; Hshieh et al., 2008). Among hospitalized elderly patients, increased plasma concentrations of anticholinergic medications are directly associated with increased delirium risk (Flacker and Lipsitz, 1999); however, unlike in Alzheimer's dementia, where psychotic symptoms are directly related to cholinergic neuronal loss and may respond to acetylcholinesterase therapy, delirium may have numerous precipitants besides medication-associated anticholinergic properties, all of which require specific treatment (e.g., infection, electrolyte imbalance, metabolic derangement) in addition to removal of offending anticholinergic medications.
Schizophrenia is a neurodevelopmental disorder with complex genetics and incompletely understood pathophysiology. Certain environmental exposures confer an increased risk of developing schizophrenia, including fetal second-trimester viral and nutritional insults, birth complications, and substance abuse in the late teen or early adult years (Fanous and Kendler, 2008). Rather than being the result of a single gene defect, mutations or polymorphisms of many genes appear to contribute to the risk for schizophrenia. Implicated are genes that regulate neuronal migration and synaptogenesis (neuregulin 1), synaptic DA availability (Val{108/158}Met polymorphism of catechol-O-methyltransferase, which increases DA catabolism), glutamate and DA neurotransmission (dystrobrevin binding protein 1 or dysbindin, particularly with schizophrenia patients with prominent negative symptoms), nicotinic neurotransmission (α7-receptor polymorphisms), and cognition (disrupted-in-schizophrenia-1) (Porteous, 2008). Schizophrenia patients also have increased rates of genome-wide DNA microduplications termed copy number variants (Need et al., 2009) and epigenetic changes, including disruptions in DNA methylation patterns in various brain regions (Porteous, 2008). This genetic variability is consistent with the clinical disease heterogeneity, and suggests that any one specific mechanism is unlikely to account for large amounts of disease risk. In addition to increased mesolimbic DA activity related to positive symptoms, schizophrenia patients have decreased DA D1 activity in the dorsolateral and ventromedial prefrontal cortex (PFC) that is associated with cognitive deficits and negative symptoms (Buchanan et al., 2007).
Cognitive dysfunction is the greatest predictor of poor functional outcome in schizophrenia and shows limited response to antipsychotic treatment. Experimental studies have provided new insights into the mechanisms of cognitive dysfunction. Glutamate NMDA receptor stimulation is involved in tonic inhibition of mesolimbic DA release, but facilitates mesocortical DA release (Sodhi et al., 2008). Ketamine infusion studies in animals and healthy volunteers demonstrate that decreased NMDA function results in a picture that more accurately encompasses all aspects of schizophrenia, including positive, negative, and cognitive symptoms, and social withdrawal. Several of the newer antipsychotic drugs remediate not only the positive psychotic symptoms but also the cognitive disruption induced by ketamine and other potent NMDA antagonists such as MK-801 (dizocilpine). These results have prompted the clinical investigation of agents without affinity for DA receptors, but with potent agonist properties at metabotropic glutamate receptor subtypes (Patil et al., 2007).
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Review of Psychosis Pathology and the General Goals of Pharmacotherapy
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Common to all psychotic disorders are positive symptoms, which may include hallucinatory behavior, disturbed thinking, and behavioral dyscontrol. For many psychotic disorders the state of psychosis is transient, and antipsychotic drugs are only administered during and shortly after periods of symptom exacerbation. Patients with delirium, dementia, mania or major depressive disorder with psychotic features, substance-induced psychoses, and brief psychotic disorder will typically receive short-term antipsychotic treatment that is discontinued after resolution of psychotic symptoms, although the duration may vary considerably based upon the etiology. In the majority of substance-induced psychoses, removal of the offending agent results in prompt improvement of psychotic symptoms with no further need for antipsychotic therapy. This may not apply to advanced Parkinson's disease patients, for whom L-dopa cannot be stopped and for whom ongoing antipsychotic treatment may be necessary (Chapter 22). Patients with psychosis related to mood disorders, in particular manic patients, may have antipsychotic treatment extended for several months after resolution of the psychosis, since antipsychotic medications are effective in controlling mania symptoms. Chronic psychotic symptoms in dementia patients may also be amenable to drug therapy, but potential benefits must be balanced with the documented risk of mortality and cerebrovascular events associated with the use of antipsychotic medications in this patient population (Jeste et al., 2008).
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Delusional disorder, schizophrenia, and schizoaffective disorder are chronic diseases that require long-term antipsychotic treatment, although there are few reliable studies of treatment outcomes for delusional disorder patients. Individuals with monosymptomatic delusions (e.g., paranoia, marital infidelity) do not have neurocognitive dysfunction and may continue to perform work and social functions unaffected by their illness, aside from behavioral consequences related to the specific delusional belief (American Psychiatric Association, 2000). These patients often have limited or no psychiatric contact outside of mandated legal interventions, thus limiting the opportunity for clinical trials. For schizophrenia and schizoaffective disorder, the goal of antipsychotic treatment is to maximize functional recovery by decreasing the severity of positive symptoms and their behavioral influence, improving negative symptoms, decreasing social withdrawal, and remediating cognitive dysfunction. That only 15% of chronic schizophrenia patients are employed in any capacity and 11% are married has been attributed to the relatively limited effect of treatment on core negative and cognitive symptoms of the illness (Lieberman et al., 2005). Nonetheless, continuous antipsychotic treatment reduces 1-year relapse rates from 80% among unmedicated patients, to ~15%. Poor adherence to antipsychotic treatment increases relapse risk, and is often related to adverse drug events, cognitive dysfunction, substance use, and limited illness insight.
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Regardless of the underlying pathology, the immediate goal of antipsychotic treatment is a decrease in acute symptoms that induce patient distress, particularly behavioral symptoms (e.g., hostility, agitation) that may present a danger to the patient or others. The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, clinical acuity, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects. With the exception of clozapine's superior efficacy in treatment-refractory schizophrenia (Leucht et al., 2009), neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent. As a result, avoidance of adverse effects based upon patient and drug characteristics, or exploitation of certain medication properties (e.g., sedation related to histamine H1 or muscarinic antagonism) are the principal determinants for choosing initial antipsychotic therapy.
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All commercially available antipsychotic drugs reduce dopaminergic neurotransmission (Figure 16–1). This finding implicates D2 blockade (or, in the case of aripiprazole, modulation of DA activity) as the primary therapeutic mechanism. Chlorpromazine and other early low-potency typical antipsychotic agents are also profoundly sedating, a feature that used to be considered relevant to their therapeutic pharmacology. The development of the high-potency typical antipsychotic agent haloperidol, a drug with limited H1 and M1 affinity and significantly less sedative effects, and the clinical efficacy of intramuscular forms of nonsedating newer antipsychotic drugs, aripiprazole and ziprasidone, demonstrate that sedation is not necessary for antipsychotic activity, although at times desirable.
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Delirium and Dementia. Disease variables have considerable influence on selection of antipsychotic agents. Psychotic symptoms of delirium or dementia are generally treated with low medication doses, although doses may have to be repeated at frequent intervals initially to achieve adequate behavioral control (Lacasse et al., 2006). Despite widespread clinical use, not a single antipsychotic drug has received approval for dementia-related psychosis. Moreover, all antipsychotic drugs carry warnings that they may increase mortality in this setting (Jeste et al., 2008). Because anticholinergic drug effects may worsen delirium (Hshieh et al., 2008) and dementia, high-potency typical antipsychotic drugs (e.g., haloperidol) or atypical antipsychotic agents with limited antimuscarinic properties (e.g., risperidone) are often the drugs of choice (Jeste et al., 2008; Lacasse et al., 2006).
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The best-tolerated doses in dementia patients are one-fourth of adult schizophrenia doses (e.g., risperidone 0.5-1.5 mg/day), although extrapyramidal neurological symptoms (EPS), orthostasis, and sedation are particularly problematic in this patient population (Chapter 22). Significant antipsychotic benefits are usually seen in acute psychosis within 60-120 minutes after drug administration. Delirious or demented patients may be reluctant or unable to swallow tablets, so oral dissolving tablet (ODT) preparations for risperidone, aripiprazole, and olanzapine, or liquid concentrate forms of risperidone or aripiprazole, are options. The dissolving tablets adhere to any moist tongue or oral surface, cannot be spit out, and are then swallowed along with oral secretions. Intramuscular (IM) administration of ziprasidone, aripiprazole, or olanzapine represents an option for treating agitated and minimally cooperative patients, and presents less risk for drug-induced parkinsonism than haloperidol. QTc prolongation associated with intramuscular droperidol and intravenous administration of haloperidol have curtailed use of those particular formulations. Treatment continues until agitated or hallucinatory behaviors are controlled and the underlying etiologies are addressed (Lacasse et al., 2006). (See "Use in Pediatric Populations" and "Use in Geriatric Populations" later in the chapter.)
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Mania. All atypical antipsychotic agents with the exception of clozapine and iloperidone have indications for acute mania, and doses are titrated rapidly to the maximum recommended dose over the first 24-72 hours of treatment. Acute mania patients with psychosis require very high daily doses, typically close to or at the maximum FDA-approved dose (Scherk et al., 2007). Typical antipsychotic drugs are also effective in acute mania, but often eschewed due to the risk for EPS. Clinical response (decreased psychomotor agitation and irritability, increased sleep, and reduced or absent delusions and hallucinations) usually occurs within 7 days, but may be apparent as early as day 2. Unlike patients with delirium, dementia, substance-induced psychosis, and brief psychotic disorder, patients with mania may need to continue on antipsychotic treatment for many months after the resolution of psychotic and manic symptoms, typically in combination with a mood stabilizer such as lithium or valproic acid preparations (e.g., divalproex). Oral aripiprazole and olanzapine have indications as monotherapy for bipolar disorder maintenance treatment (Keck et al., 2007; Tohen et al., 2003), but the use of olanzapine has decreased dramatically due to concerns over adverse metabolic effects (e.g., weight gain, hyperlipidemia, hyperglycemia). Long-acting injectable risperidone also has indications for maintenance monotherapy (and adjunctively with lithium or valproate) in bipolar I disorder patients. Combining an antipsychotic agent with a mood stabilizer often improves control of manic symptoms, and further reduces the risk of relapse (Scherk et al., 2007). Weight gain from the additive effects of antipsychotic agents and mood stabilizers (lithium, valproic acid) presents a significant clinical problem (Meyer, 2002). Antipsychotic agents with greater weight-gain liabilities (e.g., olanzapine, clozapine) should be avoided unless patients are refractory to preferred treatments. The recommended duration of treatment after resolution of bipolar mania varies considerably, but as symptoms permit, a gradual drug taper can frequently be attempted after 4 months of treatment.
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Major Depression. Patients with major depressive disorder with psychotic features require lower than average doses of antipsychotic drugs, given in combination with an antidepressant (Rothschild et al., 2004). Extended antipsychotic treatment is not usually required, but certain atypical antipsychotic agents provide adjunctive antidepressant benefit. It is worth noting that mood disorder patients may be more susceptible to EPS and other adverse drug events due to the fact that many of these individuals either have never taken antipsychotic drugs before ("drug-naïve") or have had only limited lifetime exposure to antipsychotic drugs. Regardless of the indication for therapy, clinicians must be alert to the emergence of adverse effects to avoid patient rejection of ongoing treatment.
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With few exceptions (e.g., loxapine, where the active metabolite amoxapine is a heterocyclic antidepressant), most antipsychotic drugs show limited antidepressant benefit as monotherapy agents. However, clinical data demonstrate efficacy of atypical antipsychotic agents as adjunct therapy in treatment-resistant depression. The clinical efficacy may be related to the fact that almost all atypical antipsychotic medications are potent 5-HT2A antagonists, with 5-HT2A occupancies exceeding 80% at modest dosages (Figure 16–2) (Mamo et al., 2007). Both 5-HT2A and 5-HT2C receptors are G-protein coupled, with stimulation resulting in increased production of intracellular inositol trisphosphate (IP3) (Marek et al., 2003). In vitro assays demonstrate that atypical agents are inverse agonists at both receptor subtypes, capable of lowering basal IP levels (Rauser et al., 2001; Weiner et al., 2001). For the purposes of functional description, the term antagonism will be used throughout this chapter with respect to actions at these two serotonin receptor subtypes, even though the underlying mechanism is inverse agonism (Chapter 3). 5-HT2A and 5-HT2C antagonism not only facilitates DA release but also increases noradrenergic outflow from the locus coeruleus. Decreased noradrenergic tone in locus coeruleus projections to PFC and limbic areas is considered an important aspect of depression pathophysiology. Pure 5-HT2A antagonists are not effective antidepressants, but administration of 5-HT2A and 5-HT2C antagonists in the form of low doses of atypical antipsychotic agents, along with selective serotonin reuptake inhibitors (SSRIs), increases responses rates in SSRI nonresponders (Berman et al., 2007; Mahmoud et al., 2007; Rothschild et al., 2004). A combination preparation of low-dose olanzapine and fluoxetine is approved for bipolar depression, and low-dose risperidone (i.e., 1 mg) increases clinical response rates when added to existing SSRI treatment in SSRI nonresponders. Aripiprazole is FDA-approved for adjunctive use in antidepressant nonresponders, again at low doses (2-15 mg). Unlike other atypical antipsychotic agents, aripiprazole's highest affinities at low doses (< 15 mg) are for D2 and D3 receptors, at which it is a partial agonist, with only 50% 5-HT2A receptor occupancy at 15 mg (Mamo et al., 2007) (Figure 16–2C). Aripiprazole and most other antipsychotic drugs are ineffective as monotherapy for bipolar depression, with quetiapine being the sole exception. Two large clinical trials demonstrated quetiapine's efficacy for bipolar depression at both 300 and 600 mg/day doses (Calabrese et al., 2005a; Thase et al., 2006). Quetiapine also has antidepressant efficacy in unipolar major depression trials, suggesting that it could be used as monotherapy for depression. The explanation is likely that its primary metabolite, norquetiapine, is a potent norepinephrine reuptake inhibitor (Jensen et al., 2008).
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Schizophrenia. The immediate goals of acute antipsychotic treatment are the reduction of agitated, disorganized, or hostile behavior, decreasing the impact of hallucinations, the improvement of organization of thought processes, and the reduction of social withdrawal. Doses used are often higher than those required for maintenance treatment of stable patients. Despite considerable debate, newer atypical antipsychotic agents are not more effective in the treatment of positive symptoms than typical agents (Rosenheck et al., 2006; Sikich et al., 2008), although there may be small but measurable differences in effects on negative symptoms and cognition (Leucht et al., 2009).
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Newer, atypical antipsychotic agents do offer a better neurological side-effect profile than typical antipsychotic drugs. Clinically effective doses of atypical agents show markedly reduced EPS risk (or nearly absent in the case of quetiapine and clozapine) compared to typical antipsychotic agents. Excessive D2 blockade, as is often the case with the use of high-potency typical agents (e.g., haloperidol), not only increases risk for motor neurological effects (e.g., muscular rigidity, bradykinesia, tremor, akathisia), but also slows mentation (bradyphrenia), and interferes with central reward pathways, resulting in patient complaints of anhedonia. Rarely used are low-potency typical agents (e.g., chlorpromazine), which also have high affinities for H1, M, and α1 receptors that cause many undesirable effects (sedation, anticholinergic properties, orthostasis). Concerns regarding QTc prolongation (e.g., thioridazine) further limit their clinical usefulness. In acute psychosis, sedation may be desirable, but the use of a sedating antipsychotic drug may interfere with a patient's cognitive function and social reintegration. Clinicians often prefer using nonsedating antipsychotic agents, and add low doses of benzodiazepines as necessary. As a result of the improved neurological risk profile and aggressive marketing, atypical antipsychotic agents have essentially replaced typical antipsychotic drugs in clinical practice in the U.S.
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Since schizophrenia requires long-term treatment, antipsychotic agents with greater metabolic liabilities, especially weight gain (discussed later), should be avoided as first-line therapies (Meyer et al., 2008). Ziprasidone and aripiprazole are the most weight and metabolically neutral atypical agents, with asenapine and iloperidone also having favorable metabolic profiles. Ziprasidone and aripiprazole are available in IM form, thus permitting continuation of same drug treatment initiated parenterally in the emergency room.
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Schizophrenia patients have a 2-fold higher prevalence of metabolic syndrome and type 2 diabetes mellitus (DM) and 2-fold greater cardiovascular (CV) related mortality rates than the general population (Meyer and Nasrallah 2009). For this reason, consensus guidelines recommend baseline determination of serum glucose, lipids, weight, blood pressure, and when possible, waist circumference and personal and family histories of metabolic and CV disease (American Diabetes Association et al., 2004). This cardiometabolic risk assessment should be performed for all schizophrenia patients despite the low metabolic risk for certain agents. With the low EPS risk among atypical antipsychotic agents, prophylactic use of anti-parkinsonian medications (e.g., benztropine, trihexyphenidyl) is not necessary; however, acute dystonic reactions can occur (see Table 16–4), typically among patients who have never before taken antipsychotic drugs, adolescents, and young adults. Lower dosages are recommended in these individuals. Drug-induced parkinsonism can also occur, especially among elderly patients exposed to antipsychotic agents that have high D2 affinity (e.g., typical antipsychotic drugs, risperidone, paliperidone); recommended doses are ~50% of those used in younger schizophrenia patients. (See also "Use in Pediatric Populations" and "Use in Geriatric Populations" later in the chapter.)
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The need for long-term treatment poses issues almost exclusively to the chronic psychotic illnesses, schizophrenia and schizoaffective disorder, although long-term antipsychotic treatment is sometimes used for manic patients, for ongoing psychosis in dementia patients, for L-dopa psychosis, and for adjunctive use in SSRI-unresponsive major depression. Safety concerns combined with limited long-term efficacy data have dampened enthusiasm for extended antipsychotic drug use in dementia patients (Jeste et al., 2008). The goal should be to optimize clinical and behavioral aspects of treatment in order to minimize the need for antipsychotic drugs in the dementia population. Justification for ongoing use, based on documentation of patient response to tapering of antipsychotic medication, is often mandated in long-term care settings. L-dopa psychosis represents a thorny clinical problem, as clinicians are caught between the Scylla of treatment-induced psychotic symptoms and the Charybdis of motoric worsening as a result of exposure to antipsychotic drugs. Parkinson disease patients who present with L-dopa psychosis usually have advanced disease and cannot tolerate reductions in dopamine agonist treatment without significant motoric worsening and on-off phenomena (Chapter 22). They are exquisitely sensitive to minute amounts of D2 blockade (Zahodne and Fernandez, 2008). Clozapine, used in doses ranging from 6.25-50 mg/day, has the most extensive clinical evidence base. The necessity for routine hematological monitoring for agranulocytosis has prompted the use of low doses of quetiapine, itself a very weak D2 antagonist, although the evidence for quetiapine's efficacy in L-dopa psychosis is not compelling. Anecdotal evidence also exists for using low doses of the D2 partial agonist aripiprazole (1-5 mg/day) in L-dopa psychosis (Zahodne and Fernandez, 2008).
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The choice of antipsychotic agents for long-term schizophrenia treatment is based primarily on avoidance of adverse effects and, when available, prior history of patient response. Since schizophrenia spectrum disorders are lifelong diseases, treatment acceptability is paramount to effective illness management. Whether atypical antipsychotic agents are superior to typical antipsychotic agents has been the subject of significant and contentious debate. Large meta-analyses of predominantly industry-funded studies find only minute differences in relapse risk (Leucht et al., 2003). Atypical antipsychotic agents offer significant advantages related to reduced neurological risk, with long-term tardive dyskinesia rates < 1%, or approximately one-fifth to one-tenth of that seen with typical antipsychotic drugs (for haloperidol, the annual incidence of tardive dyskinesia is 4-5% in non-geriatric adult patients; lifetime risk ~20%). This advantage of the atypical agents is magnified in elderly patients, in whom tardive dyskinesia incidence is 5-fold greater than in younger patients, and for whom annual tardive dyskinesia rates with typical antipsychotic agents exceed 20% per year. The decreased affinity for D2 receptors among atypical agents has also translated into reduced concerns over hyperprolactinemia with most atypical antipsychotic agents, although risperidone and paliperidone (9-OH risperidone) are exceptions; both agents cause dose-dependent increases in prolactin (see "Adverse Effects and Drug Interactions" later in the chapter).
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While concerns over EPS and tardive dyskinesia have abated with the introduction of the atypical antipsychotic agents into clinical practice, there has been increased concern over metabolic effects of antipsychotic treatment: weight gain, dyslipidemia (particularly hypertriglyceridemia), and an adverse impact on glucose-insulin homeostasis, including new-onset type 2 DM, and diabetic ketoacidosis (DKA), with reported fatalities from the latter (American Diabetes Association et al., 2004). Clozapine and olanzapine have the highest metabolic risk and are only used as last resort. Olanzapine has been relegated in most treatment algorithms to third-tier status, and is considered only after failure of more metabolically benign agents such as aripiprazole, ziprasidone, asenapine, iloperidone, risperidone, and paliperidone.
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Acutely psychotic patients usually respond within hours after drug administration, but weeks may be required to achieve maximal drug response, especially for negative symptoms, which respond much less robustly to drug therapy. While 6 weeks of therapy has been considered an adequate antipsychotic trial, analyses of symptom response in clinical trials indicate that the majority of response to any antipsychotic treatment in acute schizophrenia is seen by week 4 (Agid et al., 2003; Emsley et al., 2006). Failure of response after 2 weeks should prompt a clinical reassessment, including determination of medication adherence, before a decision is made to increase the current dose or consideration of switching to another agent. First-episode schizophrenia patients often respond to modest doses, and more chronic patients may require doses that exceed recommended ranges. While the acute behavioral impact of treatment is seen within hours to days, long-term studies indicate improvement may not plateau for 6 months, underscoring the importance of ongoing antipsychotic treatment in functional recovery for schizophrenia patients.
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Usual dosages for acute and maintenance treatment are noted in Table 16–1. Dosing should be adjusted based on clinically observable signs of antipsychotic benefit and adverse effects. For example, higher EPS risk is noted for risperidone doses that exceed 6 mg/day in non-elderly adult schizophrenia patients. However, in the absence of EPS, increasing the dose from 6-8 mg would be a reasonable approach in a patient with ongoing positive symptoms, albeit with appropriate monitoring for emerging EPS symptoms. Treatment-limiting adverse effects may include weight gain, sedation, orthostasis, and EPS, which to some degree can be predicted based on the potencies of the selected agent to inhibit neurotransmitter receptors (Table 16–2). The detection of dyslipidemia or hyperglycemia is based on laboratory monitoring (Table 16–1). Certain adverse effects such as hyperprolactinemia, EPS, orthostasis, and sedation may respond to dose reduction, but metabolic abnormalities improve only with discontinuation of the offending agent and a switch to a more metabolically benign medication. The decision to switch stable schizophrenia patients with antipsychotic-related metabolic dysfunction solely for metabolic benefit must be individualized, based on patient preferences, severity of the metabolic disturbance, likelihood of metabolic improvement with antipsychotic switching, and history of response to prior agents. Patients with refractory schizophrenia on clozapine are not good candidates for switching because they are resistant to other medications (see the definition of refractory schizophrenia later in this section).
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There are many reasons for psychotic relapse or inadequate response to antipsychotic treatment in schizophrenia patients. Examples are ongoing substance use, psychosocial stressors, inherent refractory illness, and poor medication adherence. Outside of controlled settings, the problem of medication nonadherence remains a significant barrier to successful treatment, yet one that is not easily assessed. Serum drug levels can be obtained for most antipsychotic medications, but there is limited dose-response data for atypical antipsychotic agents (except for clozapine), leaving clinicians little guidance about the interpretation of antipsychotic drug levels. Even low or undetectable levels may not reflect nonadherence, but rather can be the result of genetic variation or induction of hepatic CYPs that decrease drug availability, such as the high prevalence of CYP2D6 ultrarapid metabolizers among individuals from North Africa and the Middle East. Nevertheless, the common problem of medication nonadherence among schizophrenia patients has led to the development of long-acting injectable (LAI) antipsychotic medications, often referred to as depot antipsychotics. They are more widely used in the E.U. Only < 5% of U.S. patients receive depot antipsychotic treatment. There are currently four available LAI forms in the U.S.: decanoate esters of fluphenazine and haloperidol, risperidone-impregnated microspheres, and paliperidone palmitate. Patients receiving LAI antipsychotic medications show consistently lower relapse rates compared to patients receiving comparable oral forms and may suffer fewer adverse effects. LAI risperidone and paliperidone palmitate are currently the only atypical antipsychotic agents in depot form. However, clinical trials of LAI aripiprazole and olanzapine are in progress and these agents should become available in the near future. LAI risperidone is administered as biweekly intramuscular (IM) injections of 25-50 mg. Based on extensive kinetic modeling of clinical data, paliperidone palmitate therapy in acute schizophrenia is initiated with IM deltoid loading doses of 234 mg at day 1 and 156 mg at day 8 to provide serum paliperidone levels equivalent to 6 mg oral paliperidone during the first week, obviating the need for oral antipsychotic supplementation. Serum paliperidone levels from these two injections peak on day 15 at a level comparable to 12 mg oral paliperidone. Maintenance IM doses are given in deltoid or gluteus muscle every 4 weeks after day 8. Unlike acute IM preparations or paliperidone palmitate, all other LAI antipsychotic medications require several weeks to attain therapeutic levels and months to reach steady state, necessitating the use of oral medications for the initial 4 weeks of treatment.
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Lack of response to adequate antipsychotic drug doses for adequate periods of time may indicate treatment-refractory illness. Refractory schizophrenia is defined using the Kane criteria: failed 6-week trials of two separate agents and a third trial of a high-dose typical antipsychotic agent (e.g., haloperidol or fluphenazine 20 mg/day). In this patient population, response rates to typical antipsychotic agents, defined as 20% symptom reduction using standard rating scales (e.g., Positive and Negative Syndrome Scale [PANSS]), are 0%, and for any atypical antipsychotic except clozapine, are < 10% (Leucht et al., 2009). Due to the long titration involved to minimize orthostasis, and to sedation and other tolerability issues, adequate clozapine trials often require 6 months, but response rates in 26-week-long studies are consistently 60% in refractory schizophrenia patients. The therapeutic clozapine dose for a specific patient is not predictable, but various studies have found correlations between trough serum clozapine levels > 327-504 ng/mL and likelihood of clinical response. When therapeutic serum concentrations are reached, response to clozapine occurs within 8 weeks.
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In addition to agranulocytosis risk that mandates routine ongoing hematological monitoring, clozapine has numerous other adverse effects. Examples are high metabolic risk, dose-dependent lowering of the seizure threshold, orthostasis, sedation, anticholinergic effects (especially constipation), and sialorrhea related to muscarinic agonism at M4 receptors. As a result, clozapine use is limited to refractory schizophrenia patients.
Electroconvulsive therapy is considered a treatment of last resort in refractory schizophrenia and is rarely employed. Despite widespread clinical use of combining several antipsychotic agents, there is virtually no data supporting this practice, and metabolic risk increases with use of multiple antipsychotic agents (Correll et al., 2007). In one of few instances where a sound pharmacological rationale exists for combination treatment, the addition of a potent D2 antagonist (e.g., risperidone, haloperidol) to maximally tolerated doses of clozapine (a weak D2 blocker), the results have been decidedly mixed. That multiple antipsychotic agents ("polypharmacy") are commonly used in clinical practice attests to the limitations of current treatment. Lastly, antipsychotic drug therapy is the foundation of schizophrenia treatment, yet adequate management of schizophrenia patients requires a multimodal approach that also includes psychosocial, cognitive, and vocational rehabilitation to promote functional recovery.
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Pharmacology of Antipsychotic Agents
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Chemistry. In the past, the chemical structure of selected agents was informative regarding their antipsychotic activity, since most were derived from phenothiazine or butyrophenone structures. Phenothiazines have a tricyclic structure in which two benzene rings are linked by a sulfur and a nitrogen atom (Table 16–1). The chemically related thioxanthenes have a carbon in place of the nitrogen at position 10 with the R1 moiety linked through a double bond. Substitution of an electron-withdrawing group at position 2 increases the antipsychotic efficacy of phenothiazines (e.g., chlorpromazine). The nature of the substituent at position 10 also influences pharmacological activity, and the phenothiazines and thioxanthenes can be divided into three groups on the basis of substitution at this site. Those with an aliphatic side chain include chlorpromazine and are relatively low in potency. Those with a piperidine ring in the side chain include thioridazine, which has lower EPS risk, possibly due to increased central antimuscarinic activity, but is rarely used due to concerns over QTc prolongation and risk of torsade de pointes. Several potent phenothiazine antipsychotic compounds have a piperazine group in the side chain (fluphenazine, perphenazine, and trifluoperazine) and have reduced affinity for H1, M, and α1 receptors. Those with a free hydroxyl can also be esterified to long-chain fatty acids to produce LAI antipsychotic medications (e.g., fluphenazine decanoate). Thioxanthenes also have aliphatic or piperazine side-chain substituents. Piperazine-substituted thioxanthenes include the high potency agent thiothixene. Since thioxanthenes have an olefinic double bond between the central-ring C10 and the side chain, geometric isomers exist. The cis isomers are more active. The antipsychotic phenothiazines and thioxanthenes have three carbon atoms interposed between position 10 of the central ring and the first amino nitrogen atom of the side chain at this position; the amine is always tertiary. Antihistaminic phenothiazines (e.g., promethazine) or strongly anticholinergic phenothiazines have only two carbon atoms separating the amino group from position 10 of the central ring. Metabolic N-dealkylation of the side chain or increasing the size of amino N-alkyl substituents reduces antidopaminergic and antipsychotic activity. Additional tricyclic antipsychotic agents are the benzepines, containing a 7-member central ring, of which loxapine (a dibenzoxazepine) and clozapine (a dibenzodiazepine) are available in the U.S. Clozapine-like atypical antipsychotic agents may lack a substituent on the aromatic ring (e.g., quetiapine, a dibenzothiazepine), have an analogous methyl substituent (olanzapine), or have an electron-donating substituent at position 8 (e.g., clozapine). In addition to their moderate potencies at DA receptors, clozapine-like agents interact with varying affinities at several other classes of receptors (α1 and α2 adrenergic, 5-HT1A, 5-HT2A, 5-HT2C, M, H1). The prototypical butyrophenone (phenylbutylpiperidine) antipsychotic is haloperidol, originally developed as a substituted derivative of the phenylpiperidine analgesic meperidine. An analogous compound, droperidol, is a very short-acting and highly sedating agent that was used almost exclusively for emergency sedation and anesthesia until QTc and torsade de pointes concerns substantially curtailed its use and the use of the related diphenylbutylpiperidine pimozide. Several other classes of heterocyclic compounds have antipsychotic effects, of which only the indole molindone has generated any interest due to its unusual association with modest weight loss (Sikich et al., 2008a). The enantiomeric, substituted benzamides are another group of heterocyclic compounds that are relatively selective antagonists at central D2 receptors and have antipsychotic activity. Examples (not available in the U.S.) include sulpiride and its congener, amisulpride.
The introduction of clozapine stimulated research into agents with antipsychotic activity and low EPS risk. This search led to a series of atypical antipsychotic agents with certain pharmacological similarities to clozapine: namely lower affinity for D2 receptors than typical antipsychotic drugs and high 5-HT2 antagonist effects. The currently available atypical antipsychotic medications include the structurally related olanzapine, quetiapine, and clozapine; the benzisoxazoles risperidone, its active metabolite paliperidone, and iloperidone; ziprasidone (a benzisothiazolpiprazinylindolone derivative); asenapine (a dibenzo-oxepino pyrrole), and aripiprazole (a quinolinone derivative). Table 16–1.
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Presently, antipsychotic agents include many different chemical structures with a range of activities at different neurotransmitter receptors (e.g., 5-HT2A antagonism, 5-HT1A partial agonism). As a result, structure-function relationships that were relied upon in the past have become less important. Instead, receptor-function relationships and functional assays are more clinically relevant. Aripiprazole represents a good example of how an examination of the structure provides little insight into its mechanism, which is based on dopamine partial agonism (discussed later). Detailed knowledge of receptor affinities (Table 16–2) and the functional effect at specific receptors (e.g., full, partial or inverse agonism or antagonism) can provide important insight into the therapeutic and adverse effects of antipsychotic agents. Nevertheless, there are limits. For example, it is not known which properties are responsible for clozapine's unique effectiveness in refractory schizophrenia, although many hypotheses exist. Other notable antipsychotic properties not fully explained by receptor parameters include the reduced seizure threshold, the unexpected extent of prolactin elevation for risperidone and paliperidone, the effects of antipsychotic agents on metabolic function, and the increased risk for cerebrovascular events and mortality among dementia patients (see "Adverse Effects and Drug Interactions" later in the chapter).
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Mechanism of Action. While emerging data indicate that stimulation of glutamate or muscarinic receptors may confer antipsychotic properties, no clinically available effective antipsychotic is devoid of D2 antagonistic activity. This reduction in dopaminergic neurotransmission is presently achieved through one of two mechanisms: D2 antagonism or partial D2 agonism, of which aripiprazole is the only current example. Another partial agonist, bifeprunox, completed clinical trials but failed to gain FDA approval.
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Aripiprazole has an affinity for D2 receptors only slightly less than DA itself, but its intrinsic activity is ~25% that of dopamine. As depicted in Figure 16–3, when dopamine is given in increasing concentrations in an in vitro model, 100% stimulation of the available D2 receptors occurs (as measured by forskolin-stimulated cyclic AMP accumulation). In the absence of DA, aripiprazole produces a maximal level of D2 activity ~25% that of DA (Burris et al., 2002). The potent D2 antagonist haloperidol is capable of reducing dopamine's effect to zero, but when DA is incubated with increasing concentrations of aripiprazole, maximal inhibition of D2 activity did not exceed 25% of the DA response, that is, the level of agonism provided by aripiprazole. Aripiprazole's capacity to stimulate D2 receptors in brain areas where synaptic DA levels are limited (e.g., PFC neurons) or decrease dopaminergic activity when dopamine concentrations are high (e.g., mesolimbic cortex) is thought to be the basis for its clinical effects in schizophrenia. Evidence for its partial DA agonist properties is seen clinically as a reduction in serum prolactin levels. Unlike other antipsychotic agents, in which striatal D2 occupancy (i.e., reduction in postsynaptic D2 signal) > 78% is associated with EPS, aripiprazole requires significantly higher D2 occupancy levels. Even with 100% receptor occupancy, aripiprazole's intrinsic dopaminergic agonism can generate a 25% postsynaptic signal, implying a maximal 75% reduction in DA neurotransmission, below the 78% threshold that triggers EPS in most individuals, although rare reports of acute dystonia exist, primarily in antipsychotic-naïve, younger patients.
Animal models of antipsychotic activity have evolved over a half-century of antipsychotic drug development to incorporate emerging knowledge of psychosis pathophysiology. Prior to the elucidation of D2 antagonism as a common mechanism for antipsychotic agents, early behavioral paradigms exploited known animal effects that predicted clinical efficacy. As expected, these models, including catalepsy induction and blockade of apomorphine-induced stereotypic behavior, were subsequently found to be dependent on potent D2 receptor antagonism (Lieberman et al., 2008). Clozapine failed these early trials and was not suspected to possess antipsychotic activity until experimental human use in the mid-1960s revealed it to be an effective treatment for schizophrenia, particularly in patients who had failed other antipsychotic medications, and with virtually absent EPS risk. By 1989, the pharmacological basis for some of these atypical properties, namely clinical efficacy without EPS induction, was found to result from a significantly weaker D2 antagonism than existing antipsychotic agents, combined with potent 5-HT2 antagonism. Subsequent research demonstrated that 5-HT2A receptor antagonism is responsible for facilitation of dopamine release in both mesocortical and nigrostriatal pathways. The behavioral pharmacology of 5-HT2A antagonism and related 5-HT2C and 5-HT1A receptor agonism has since been characterized, and relevant animal behavioral assays developed. Clozapine possesses activity at numerous other receptors including antagonism and agonism at various muscarinic receptor subtypes and antagonism at dopamine D4 receptors; however, subsequent D4 antagonists that did not also have D2 antagonism lacked antipsychotic activity. Clozapine's active metabolite, N-desmethylclozapine, is a potent muscarinic M1 agonist (Li et al., 2005). Although N-desmethylclozapine failed clinical trials as schizophrenia monotherapy, it increased interest in cholinergic agonists as primary treatments or adjunctive cognitive enhancing medications for schizophrenia. Important targets of agents in preclinical and clinical drug development include M1 agonism (Janowsky and Davis 2009), M4 agonism (Chan et al., 2008), and α7- and α4β2-nicotinic receptor agonism (Buchanan et al., 2007).
The glutamate hypofunction hypothesis of schizophrenia has led to novel animal models that examine the influence of proposed antipsychotic agents, including those in clinical development with agonist properties at metabotropic glutamate receptors mGlu2 and mGlu3 (Patil et al., 2007) and other subtypes. Atypical antipsychotic drugs are better than typical antipsychotic medications at reversing the negative symptoms, cognitive deficits and social withdrawal induced by glutamate antagonists. At the present time, however, it is unclear whether glutamate agonist that lack direct D2 antagonist properties will prove as effective as serotonin-dopamine antagonists for schizophrenia treatment, or whether glutamate agonist mechanisms might be more useful when combined with D2 modulation, much in the same manner as 5-HT2A antagonism. Schizophrenia patients also exhibit specific neurophysiological abnormalities. For example, a disruption in the normal processing of sensory and cognitive information is exhibited in various preconscious inhibitory processes, including deficiencies in sensorimotor gating as assessed by prepulse inhibition (PPI) of the acoustic startle reflex. PPI is the automatic suppression of startle magnitude that occurs when the louder acoustic stimulus is preceded 30-500 ms by a weaker prepulse (Swerdlow et al., 2006). In schizophrenia patients, PPI is increased more robustly with atypical than typical antipsychotic agents, and in animal models, atypical antipsychotic agents are also more effective at opposing PPI disruption from NMDA antagonists. Increased understanding of the pharmacological basis for neurophysiological deficits provides another means for developing antipsychotic treatments that are specifically effective for schizophrenia and may not necessarily apply to other forms of psychosis.
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Dopamine Receptor Occupancy and Behavioral Effects. Dopaminergic projections from the midbrain terminate on septal nuclei, the olfactory tubercle and basal forebrain, the amygdala, and other structures within the temporal and prefrontal cerebral lobes and the hippocampus. The dopamine hypothesis has focused considerable attention on the mesolimbic and mesocortical systems as possible sites where antipsychotic effects are mediated. Recent research confirms that excessive dopaminergic functions in the limbic system are central to the positive symptoms of psychosis. The behavioral effects and the time course of antipsychotic response parallel the rise in D2 occupancy and include calming of psychomotor agitation, decreased hostility, decreased social isolation, and less interference from disorganized or delusional thought processes and hallucinations.
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Levels of central D2 occupancy estimated by positron emission tomography (PET) brain imaging in patients treated with antipsychotic drugs support conclusions arising from laboratory studies that receptor occupancy predicts clinical efficacy, EPS, and serum level-clinical response relationships. Occupation of > 78% of D2 receptors in the basal ganglia is associated with a risk of EPS across all dopamine antagonist antipsychotic agents, while occupancies in the range of 60-75% are associated with antipsychotic efficacy (Figure 16–2) (Kapur et al., 2000b). With the exception of aripiprazole, all atypical antipsychotic drugs at low doses have much greater occupancy of 5-HT2A receptors (e.g., 75-99%) than typical agents (Table 16–2). Among atypical agents, clozapine has the highest ratio of 5-HT2A/D2 binding. Clozapine's D2 occupancy 12-hours post-dose ranges from 51-63% (Kapur et al., 1999), providing evidence for its limited EPS risk. The trough D2 occupancy for quetiapine is even lower (< 30%), but PET studies obtained 2-3 hours after dosing reveal D2 receptor occupancies in the expected therapeutic range (54-64%), albeit transiently. Ziprasidone absorption is sensitive to the presence of food, but PET studies demonstrate that clinical efficacy occurs when D2 occupancy exceeds 60%, which corresponds to a minimum daily dose of 120 mg (with food) (Mamo et al., 2004).
Among the typical antipsychotic drugs, receptor occupancy is best studied for haloperidol. Haloperidol has complex metabolism and is susceptible to modulation by CYP inhibitors, inducers, and CYP polymorphisms (Table 16–3), complicating the establishment of dose-response relationships in patients. Nonetheless, the use of serum levels can predict D2 occupancy (Fitzgerald et al., 2000):
% D2 receptor occupancy = 100 × (Plasma haloperidol ng/mL)/(0.40 ng/mL + Plasma haloperidol ng/mL)
Similar formulas also exist for several atypical antipsychotic drugs, although their plasma concentrations are rarely measured in the clinical setting.
D3 and D4 Receptors in the Basal Ganglia and Limbic System. The discovery that D3 and D4 receptors are preferentially expressed in limbic areas has led to efforts to identify selective inhibitors for these receptors that might have antipsychotic efficacy and low EPS risk. As previously noted, clozapine has modest selectivity for D4 receptors, which are preferentially localized in cortical and limbic brain regions in relatively low abundance, and are up-regulated after repeated administration of most typical and atypical antipsychotic drugs (Tarazi et al., 2001). These receptors may contribute to clinical antipsychotic actions, but agents that are D4 selective (e.g., sonepiprazole) or mixed D4/5-HT2A antagonists (e.g., fananserin) lack antipsychotic efficacy in clinical studies. In contrast to effects on D2 and D4 receptors, long-term administration of typical and atypical antipsychotic drugs does not alter D3 receptor levels in rat forebrain regions (Tarazi et al., 2001). These findings suggest that D3 receptors are unlikely to play a pivotal role in antipsychotic drug actions, perhaps because their avidity for endogenous DA prevents their interaction with antipsychotic agents. The subtle and atypical functional activities of cerebral D3 receptors suggest that D3 agonists rather than antagonists may have useful psychotropic effects, particularly in antagonizing stimulant-reward and dependence behaviors. Aripiprazole possesses affinity and intrinsic activity at D3 receptors equivalent to that at D2; the clinical advantage of this property is not readily apparent, although preclinical data suggest some effects on substance use.
The Role of Non-Dopamine Receptors for Atypical Antipsychotic Agents. The concept of atypicality was initially based on clozapine's absence of EPS within the therapeutic range, combined with a prominent role of 5-HT2 receptor antagonism. As subsequent agents were synthesized using clozapine's 5-HT2/D2 ratio as a model, most of which possessed greater D2 affinity and EPS risk than clozapine, there has been considerable debate on the definition of an atypical antipsychotic agent and its necessary properties. Aripiprazole in particular is problematic for the model based on ratios of 5-HT2 to D2, since its action as partial agonist necessitates very high D2 affinity. Loxapine is another problematic agent for the model since its receptor pharmacology suggests atypical properties based on 5-HT2/D2 ratio; however, in clinical practice its use was associated with the expected higher level of EPS characteristic of typical antipsychotic drugs, perhaps related to the additive D2 antagonist properties of the active metabolite amoxapine. These dilemmas have lead some to suggest abandonment or modification of the atypical/typical antipsychotic terminology, perhaps in lieu of the designation by generation (e.g., first, second, etc.), as is used with antibiotics, or some other organizing scheme (Gründer et al., 2009). Nonetheless, the term "atypical" persists in common usage and designates lesser (but not absent) EPS risk and other decreased effects of excessive D2 antagonism, or more accurately, reduction in D2-mediated neurotransmission.
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The neuropharmacology and behavioral pharmacology of 5-HT2 antagonism provide insights into the advantageous properties of medications with these effects (Marek et al., 2003). Antipsychotic agents with appreciable 5-HT2 affinity have significant effects at both 5-HT2A and 5-HT2C receptors with individual medications varying in their relative potencies at each subtype (Tarazi et al., 2002). As discussed previously, atypical antipsychotic agents exhibit potent functional antagonism at both subtypes of 5-HT2 receptors, but in vitro assays suggest that these effects result from inverse agonism at these G-coupled receptors.
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5-HT2A receptors are widely distributed, but antagonism exerts the greatest effect on prefrontal and basal ganglia DA release and midbrain noradrenergic outflow, with recent data implicating 5-HT2A receptor polymorphisms in differential antidepressant response (McMahon et al., 2006). There are significant interrelationships between serotonin receptors, with evidence from animal studies that stimulation of either 5-HT1A or 5-HT2C receptors antagonizes the behavioral effects of 5-HT2A agonists (Marek et al., 2003). This can be seen with agents that have direct effects on 5-HT2A activity and also in studies of NMDA antagonists where there are opposing modulatory effects of 5-HT2A and 5-HT2C stimulation. By virtue of their impact on noradrenergic neurotransmission, 5-HT2A antagonists pass many preclinical in vivo assays of antidepressant activity; conversely, 5-HT2C antagonists exhibit a similar spectrum of antidepressant properties, although pure 5-HT2A or 5-HT2C agents are, by themselves, not effective antidepressants in human trials (Marek et al., 2003). Data also indicate that 5-HT2C agonism decreases mesolimbic DA neurotransmission, a mechanism that is being explored in clinical trials of vabicaserin, a pure 5-HT2C agonist. At the cellular level, stimulation of 5-HT2A and 5-HT1A receptors causes depolarization and hyperpolarization, respectively, of cortical pyramidal cells (Marek et al., 2003). No atypical antipsychotic agent is a potent agonist of 5-HT1A receptors, but several, including clozapine, ziprasidone and aripiprazole are partial agonists. The extent to which this contributes to any clinical effect is unknown, but more potent selective 5-HT1A agonists have anxiolytic effects and appear to exert procognitive effects in schizophrenia patients when added to existing antipsychotic treatment.
Based upon trials of the selective α2 adrenergic antagonist idazoxan, researchers have postulated effects of α2 blockade on mood, but ongoing research into this mechanism has not been promising. Risperidone is the one antipsychotic with relatively high affinity for α2 adrenergic receptors, at which it is an antagonist; however, the clinical correlate of this unique profile is unclear. Any benefit on major depressive symptoms from low-dose risperidone augmentation of SSRI antidepressants is more likely conveyed by effects at the 5-HT2A receptor, at which risperidone has > 100-fold greater potency than at α2 adrenergic receptors.
Tolerance and Physical Dependence. As defined in Chapter 24, antipsychotic drugs are not addicting; however, tolerance to the antihistaminic and anticholinergic effects of antipsychotic agents usually develops over days or weeks. Loss of efficacy with prolonged treatment is not known to occur with antipsychotic agents; however, tolerance to antipsychotic drugs and cross-tolerance among the agents are demonstrable in behavioral and biochemical experiments in animals, particularly those directed toward evaluation of the blockade of dopaminergic receptors in the basal ganglia (Tarazi et al., 2001). This form of tolerance may be less prominent in limbic and cortical areas of the forebrain. One correlate of tolerance in striatal dopaminergic systems is the development of receptor supersensitivity (mediated by upregulation of supersensitive DA receptors) referred to as D2High receptors (Lieberman et al., 2008). These changes may underlie the clinical phenomenon of withdrawal-emergent dyskinesias and may contribute to the pathophysiology of tardive dyskinesia. This may also partly explain the ability of certain chronic schizophrenia patients to tolerate high doses of potent DA antagonists with limited EPS.
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Absorption, Distribution, and Elimination. The pharmacokinetic constants for these drugs may be found in Appendix II. Table 16–3 outlines the metabolic pathways of atypical antipsychotic agents available in the U.S. and selected typical agents in common use. Most antipsychotic drugs are highly lipophilic, highly membrane- or protein-bound, and accumulate in the brain, lung, and other tissues with a rich blood supply. They also enter the fetal circulation and breast milk. Despite half-lives that may be short, the biological effects of single doses of most antipsychotic medications usually persist for at least 24 hours, permitting once-daily dosing for many agents once the patient has adjusted to initial side effects.
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Elimination from the plasma may be more rapid than from sites of high lipid content and binding, notably the CNS, as evidenced by PET pharmacokinetic studies that demonstrate half-lives in the CNS that exceed those in plasma. For example, mean single-dose plasma half-lives of olanzapine and risperidone are 24.2 and 10.3 hours respectively, whereas a 50% reduction from peak striatal D2 receptor occupancy requires 75.2 hours for olanzapine and 66.6 hours for risperidone (Tauscher et al., 2002). Similar discrepancies are seen between the time course of plasma levels and occupancy of extrastriatal D2 and 5-HT2A receptors (Tauscher et al., 2002). Metabolites of long acting injectable medications have been detected in the urine several months after drug administration was discontinued. Slow removal of drug may contribute to the typical delay of exacerbation of psychosis after stopping drug treatment. Depot decanoate esters of fluphenazine and haloperidol, paliperidone palmitate, as well as risperidone-impregnated microspheres, are absorbed and eliminated much more slowly than are oral preparations. For example, the t1/2 of oral fluphenazine is ~20 hours while the IM decanoate ester has a t1/2 of 14.3 days; oral haloperidol has a t1/2 of 24-48 hours in CYP2D6-extensive metabolizers (de Leon et al., 2004), while haloperidol decanoate has a t1/2 of 21 days (Altamura et al., 2003); paliperidone palmitate has a t1/2 of 25-49 days compared to an oral paliperidone t1/2 of 23 hours. Clearance of fluphenazine and haloperidol decanoate following repeated dosing can require 6-8 months. Effects of LAI risperidone (RISPERDAL CONSTA) are delayed for 4 weeks because of slow biodegradation of the microspheres and persist for at least 4-6 weeks after the injections are discontinued (Altamura et al., 2003). The dosing regimen recommended for starting patients on LAI paliperidone generates therapeutic levels in the first week, obviating the need for routine oral antipsychotic supplementation.
With the exception of asenapine, paliperidone and ziprasidone, all antipsychotic drugs undergo extensive phase 1 metabolism by CYPs and subsequent phase 2 glucuronidation, sulfation, and other conjugations (Table 16–3). Hydrophilic metabolites of these drugs are excreted in the urine and to some extent in the bile. Most oxidized metabolites of antipsychotic drugs are biologically inactive; a few (e.g., P88 metabolite of iloperidone, hydroxy metabolite of haloperidol 9-OH risperidone, N-desmethylclozapine, and dehydroaripiprazole) are active. These active metabolites may contribute to biological activity of the parent compound and complicate correlating serum drug levels with clinical effects. The active metabolite of risperidone, paliperidone (9-OH risperidone), is already the product of oxidative metabolism, and 59% is excreted unchanged in urine with a lesser amount (32%) excreted as metabolites or via phase 2 metabolism (≤ 10%). Ziprasidone's primary metabolic pathway is through the aldehyde oxidase system that is neither saturable nor inhibitable by commonly encountered xenobiotics, with ~ one-third of ziprasidone's metabolism through CYP3A4 (Meyer, 2007). Asenapine is metabolized primarily through glucuronidation (UGT4), with a minor contribution from CYP1A2. The potential for drug-drug interactions is covered in "Adverse Effects and Drug Interactions" later in the chapter.
Absorption for most agents is quite high, and concurrent administration of anticholinergic anti-parkinsonian agents does not appreciably diminish intestinal absorption. Most orally-disintegrating tablets (ODT) and liquid preparations provide similar pharmacokinetics since there is little mucosal absorption and effects depend on swallowed drug. Asenapine remains the only exception. It is only available as an ODT preparation administered sublingually, and all absorption occurs via oral mucosa, with bioavailability of 35% by this route. If swallowed, the first pass effect is > 98%, indicating that drug swallowed with oral secretions is not bioavailable. Intramuscular administration avoids much of the first-pass enteric metabolism and provides measurable concentrations in plasma within 15-30 minutes. Most agents are highly protein bound, but this protein binding may include glycoprotein sites. Kinetic studies indicate that antipsychotic drugs do not significantly displace other prealbumin- or albumin-bound medications. Antipsychotic medications are predominantly highly lipophilic with apparent volumes of distribution as high as 20 L/kg.
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The use of antipsychotic medications for the treatment of schizophrenia spectrum disorders, for mania treatment, and as adjunctive use for treatment-resistant major depression has been discussed previously. Antipsychotic agents are also utilized in several nonpsychotic neurological disorders and as antiemetics.
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Anxiety Disorders. There are two anxiety disorders in which double-blind, placebo-controlled trials have shown benefit of adjunctive treatment with antipsychotic drugs: obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). While SSRI antidepressants remain the only psychotropic medication with FDA approval for PTSD treatment, adjunctive low-dose quetiapine, olanzapine, and particularly risperidone significantly reduce the overall level of symptoms in SSRI-resistant PTSD (Bartzokis et al., 2005). OCD patients with limited response to the standard 12-week regimen of high dose SSRI also benefit from adjunctive risperidone (mean dose 2.2 mg), even in the presence of comorbid tic disorders (McDougle et al., 2000). For generalized anxiety disorder, double-blind placebo controlled clinical trials demonstrate efficacy for quetiapine as monotherapy, and for adjunctive low-dose risperidone.
Tourette's Disorder. The ability of antipsychotic drugs to suppress tics in patients with Tourette's disorder has been known for decades, and relates to reduced D2 neurotransmission in basal ganglia sites. In prior decades, the use of low-dose, high-potency typical antipsychotic agents (e.g., haloperidol, pimozide) was the treatment of choice, but these nonpsychotic patients were extremely sensitive to the impact of DA blockade on cognitive processing speed, and on reward centers. Safety concerns regarding pimozide's QTc prolongation and increased risk for ventricular arrhythmias have large ended its clinical use. While lacking FDA approval for tic disorders, risperidone and aripiprazole have indications for child and adolescent schizophrenia and bipolar disorder (acute mania) treatment, and these agents (as well as ziprasidone) have published data supporting their use for tic suppression. Given the enormous sensitivity of preadolescent and teenage patients to antipsychotic-induced weight gain, aripiprazole has an advantage in this patient population due to somewhat lower risk for weight gain, and low risk for hyperprolactinemia or concerns over QTc effects.
Huntington's Disease. Huntington's disease is another neuropsychiatric condition, which, like tic disorders, is associated with basal ganglia pathology. DA blockade can suppress the severity of choreoathetotic movements, but is not strongly endorsed due to the risks associated of excessive DA antagonism that outweigh the marginal benefit. Inhibition of the vesicular monoamine transporter type 2 (VMAT2) with tetrabenazine has replaced DA receptor blockade in the management of chorea (Chapter 22).
Autism. Autism is a disease whose neuropathology is incompletely understood, but in some patients is associated with explosive behavioral outbursts, and aggressive or self-injurious behaviors that may be stereotypical. Risperidone has FDA approval for irritability associated with autism in child and adolescent patients ages 5-16, with common use for disruptive behavior problems in autism and other forms of mental retardation. Initial risperidone daily doses are 0.25 mg for patients weighing < 20 kg, and 0.5 mg for others, with a target dose of 0.5 mg/day in those < 20 kg weight, and 1.0 mg/day for other patients, with a range 0.5-3.0 mg/day.
Anti-emetic Use. Most antipsychotic drugs protect against the nausea- and emesis-inducing effects of DA agonists such as apomorphine that act at central DA receptors in the chemoreceptor trigger zone of the medulla. Antipsychotic drugs are effective antiemetics already at low doses. Drugs or other stimuli that cause emesis by an action on the nodose ganglion, or locally on the GI tract, are not antagonized by antipsychotic drugs, but potent piperazines and butyrophenones are sometimes effective against nausea caused by vestibular stimulation. The commonly used antiemetic phenothiazines are weak DA antagonists (e.g., prochlorperazine) without antipsychotic activity, but can be associated with EPS or akathisia.
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Adverse Effects and Drug Interactions
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Adverse Effects Predicted by Monoamine Receptor Affinities
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Dopamine D2 Receptor. With the exception of the D2 partial agonist aripiprazole (and the commercially unavailable agent bifeprunox), all other antipsychotic agents possess D2 antagonist properties, the strength of which determines the likelihood for EPS, akathisia, long-term tardive dyskinesia risk, and hyperprolactinemia. The manifestations of EPS are described in Table 16-4, along with the usual treatment approach. Acute dystonic reactions occur in the early hours and days of treatment with highest risk among younger patients (peak incidence ages 10-19), especially antipsychotic-naïve individuals, in response to abrupt decreases in nigrostriatal D2 neurotransmission. The dystonia typically involves head and neck muscles, the tongue, and in its severest form, the oculogyric crisis, extraocular muscles, and is very frightening to the patient.
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Parkinsonism resembling its idiopathic form occurs when striatal D2 occupancy exceeds 78%, and often responds to dose reduction or switching to an antipsychotic with weaker D2 antagonism. In situations where this is neither possible nor desirable, anti-parkinsonian medication may be employed. Clinically, there is a generalized slowing and impoverishment of volitional movement (bradykinesia) with masked facies and reduced arm movements during walking. The syndrome characteristically evolves gradually over days to weeks as the risk of acute dystonia diminishes. The most noticeable signs are slowing of movements, and sometimes rigidity and variable tremor at rest, especially involving the upper extremities. "Pill-rolling" movements and other types of resting tremor (at a frequency of 3-5 Hz, as in Parkinson's disease) may be seen, although they are less prominent in antipsychotic-induced than in idiopathic parkinsonism. Bradykinesia and masked facies may be mistaken for clinical depression. Elderly patients are at greatest risk.
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The treatment of acute dystonia and antipsychotic-induced parkinsonism involves the use of anti-parkinsonian agents, although dose reduction should be considered as the initial strategy for parkinsonism. Muscarinic cholinergic receptors modulate nigrostriatal DA release, with blockade increasing synaptic DA availability. Important issues in the use of anticholinergics include the negative impact on cognition and memory, peripheral antimuscarinic adverse effects (e.g., urinary retention, dry mouth, cycloplegia, etc.), and the relative risk of exacerbating tardive dyskinesia. In patients receiving chronic anticholinergic therapy, there are also short-term risks of cholinergic rebound following abrupt anticholinergic withdrawal, which may include sleep disturbance (vivid dreams, nightmares) and also increased EPS if the patient continues to receive antipsychotic treatment. For parenteral administration, diphenhydramine (25-50 mg IM) and benztropine (1-2 mg IM) are the agents most commonly used. Diphenhydramine is an antihistamine that also possesses anticholinergic properties. Benztropine combines a benzhydryl group with a tropane group to create a compound which is more anticholinergic than trihexyphenidyl but less antihistaminic than diphenhydramine. The clinical effect of a single dose lasts 5 hours, thereby requiring 2 or 3 daily doses. Dosing usually starts at 0.5-1 mg bid, with a daily maximum of 6 mg, although slightly higher doses are used in rare circumstances. The piperidine compound trihexyphenidyl was one of the first synthetic anticholinergic agents available, and replaced the belladonna alkaloids for treatment of PD in the 1940s due to its more favorable side effect profile. Trihexyphenidyl inhibits the presynaptic DA reuptake transporter, and therefore has a concomitant higher risk of abuse than the antihistamines or benztropine. Trihexyphenidyl has good GI absorption, achieving peak plasma levels in 1-2 hours, with a serum t1/2 ~10-12 hours, generally necessitating multiple daily dosing to achieve satisfactory clinical results. The total daily dosage range is 5-15 mg, given 2-3 times a day as divided doses. Biperiden (akineton) is another drug in this class.
Amantadine (symmetrel), originally marketed as an antiviral agent toward influenza A, represents the most commonly used non-anticholinergic medication for antipsychotic-induced parkinsonism. Its mechanism of action is unclear but appears to involve presynaptic DA reuptake blockade, facilitation of DA release, postsynaptic DA agonism, and receptor modulation. These properties are sufficient to reduce symptoms of drug-induced parkinsonism, and only rarely have been reported to exacerbate psychotic symptoms. Amantadine is well absorbed after oral administration, with peak levels achieved 1-4 hours after ingestion; clearance is renal, with > 90% recovered unmetabolized in the urine. The plasma t1/2 is 12-18 hours in healthy young adults, but is sufficiently longer in those with renal impairment and the elderly that a 50% dose reduction is recommended. Starting dosage is 100 mg orally bid in healthy adults, which may be increased to 200 mg bid. A dose of 100 mg bid yields peak plasma levels of 0.5-0.8 μg/mL and trough levels of 0.3 μg/mL. Toxicity is seen at serum levels of 1.0-5.0 μg/mL. Amantadine's primary advantage, especially in older patients, is avoidance of adverse CNS and peripheral anticholinergic effects.
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Tardive dyskinesia is a situation of increased nigrostriatal dopaminergic activity as the result of postsynaptic receptor supersensitivity and up-regulation from chronically high levels of postsynaptic D2 blockade (and possible direct toxic effects of high-potency DA antagonists). Tardive dyskinesia occurs more frequently in older patients, and the risk may be somewhat greater in patients with mood disorders than in those with schizophrenia. Its prevalence averages 15-25% in young adults treated with typical antipsychotic agents for more than a year. The annual incidence was 3-5% with typical antipsychotic drugs, with a somewhat smaller annual rate of spontaneous remission, even with continued treatment. The risk is one-fifth to one-tenth that of a atypical antipsychotic drug.
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Tardive dyskinesia is characterized by stereotyped, repetitive, painless, involuntary, quick choreiform (tic-like) movements of the face, eyelids (blinks or spasm), mouth (grimaces), tongue, extremities, or trunk. There are varying degrees of slower athetosis (twisting movements), while tardive dystonia and tardive akathisia are rarely encountered as use of high-dose, high-potency typical antipsychotic medications has abated. The movements all disappear in sleep (as do many other extrapyramidal syndromes), vary in intensity over time, and are dependent on the level of arousal or emotional distress, sometimes reappearing during acute psychiatric illnesses following prolonged disappearance. The dyskinetic movements can be suppressed partially by use of a potent DA antagonist, but such interventions over time may worsen the severity, as this was part of the initial pharmacological insult. Switching patients from potent D2 antagonists to weaker agents, especially clozapine has at times proven effective. When possible, drug discontinuation may be beneficial, but usually cannot be offered to schizophrenia patients. Trials of the antioxidant vitamin E have proved ineffective and are not recommended, especially in light of adverse cardiovascular effects from chronic vitamin E exposure.
Unlike antipsychotic-induced parkinsonism and acute dystonia, the phenomenology and treatment of akathisia suggests involvement of structures outside the nigrostriatal pathway. Akathisia was seen quite commonly during treatment with high doses of high potency typical antipsychotic drugs, but also can be seen with atypical agents, including those with weak D2 affinities (e.g., quetiapine), and aripiprazole. Among the predominantly antipsychotic drug-naïve population with major depression in clinical studies with adjunctive aripiprazole, akathisia incidence was 23% using a starting dose of 5 mg, suggesting that dopaminergic partial agonism, rather than antagonism, may be etiologic for this medication (Berman et al., 2007; Marcus et al., 2008). Despite the association with D2 blockade, akathisia does not have a robust response to anti-parkinsonian drugs, so other treatment strategies must be employed, including the use of high-potency benzodiazepines (e.g., clonazepam), nonselective β blockers with good CNS penetration (e.g., propranolol), and also dose reduction, or switching to another antipsychotic agent. That clonazepam and propranolol have significant cortical activity and are ineffective for other forms of EPS, points to an extrastriatal origin for akathisia symptoms.
The rare neuroleptic malignant syndrome (NMS) resembles a very severe form of parkinsonism, with signs of autonomic instability (hyperthermia and labile pulse, blood pressure, and respiration rate), stupor, elevation of creatine kinase in serum, and sometimes myoglobinemia with potential nephrotoxicity. At its most severe, this syndrome may persist for more than a week after the offending agent is discontinued, and is associated with mortality. This reaction has been associated with various types of antipsychotic agents, but its prevalence may be greater when relatively high doses of potent agents are used, especially when they are administered parenterally. Aside from cessation of antipsychotic treatment and provision of supportive care, including aggressive cooling measures, specific pharmacological treatment is unsatisfactory, although administration of dantrolene and the dopaminergic agonist bromocriptine may be helpful. While dantrolene also is used to manage the syndrome of malignant hyperthermia induced by general anesthetics, the neuroleptic-induced form of hyperthermia probably is not associated with a defect in Ca2+ metabolism in skeletal muscle. There are anecdotal reports of NMS with atypical antipsychotic agents, but this syndrome is now rarely seen in its full presentation.
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Hyperprolactinemia results from blockade of the pituitary actions of the tuberoinfundibular dopaminergic neurons; these neurons project from the arcuate nucleus of the hypothalamus to the median eminence, where they deliver DA to the anterior pituitary via the hypophyseoportal blood vessels. D2 receptors on lactotropes in the anterior pituitary mediate the tonic prolactin-inhibiting action of DA. Correlations between the D2 potency of antipsychotic drugs and prolactin elevations are excellent. With the exception of risperidone and paliperidone, atypical antipsychotic agents show limited (asenapine, iloperidone, olanzapine, quetiapine, ziprasidone) to almost no effects (clozapine, aripiprazole) on prolactin secretion.
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The hyperprolactinemia from antipsychotic drugs is rapidly reversible when the drugs are discontinued. Hyperprolactinemia can directly induce breast engorgement and galactorrhea. Approximately 33% of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. By suppressing the secretion of gonadotropins and sex steroids, hyperprolactinemia can cause amenorrhea in women and sexual dysfunction or infertility in men. The development of amenorrhea is of concern as it represents low serum estradiol levels and ongoing risk for bone density loss. The development of amenorrhea becomes a sensitive marker for sex hormone levels, and should prompt clinical action, while asymptomatic measurable increases in serum prolactin levels do not necessarily merit any intervention. Dose reduction can be tried to decrease serum prolactin levels, but caution must be exercised to keep treatment within the antipsychotic therapeutic range. When switching from offending antipsychotic agents is not feasible, bromocriptine can be employed. There is also anecdotal evidence that aripiprazole augmentation may be effective.
All DA antagonist antipsychotic drugs possess antiemetic properties by virtue of their actions at the medullary chemoreceptor trigger zone (Figure 46–4). The D2 partial agonists aripiprazole (and bifeprunox), however, can be associated with nausea. For aripiprazole this effect was noted in clinical trials of oral medication for acute mania, bipolar maintenance, or schizophrenia (nausea incidence 15% for aripiprazole vs. 11% for placebo; vomiting incidence 11% for aripiprazole vs. 6% for placebo), and also in studies of pediatric bipolar mania in patients ages 10-17 (nausea incidence 11%) and in acute IM trials for agitation in schizophrenia or acute mania (nausea incidence 9%). Bifeprunox possessed a level of intrinsic DA agonism that was slightly greater than that for aripiprazole (25-28%), but was significant enough to cause clinical problems with nausea and vomiting, that a 10-day titration from an initial starting dose of 0.125 mg was necessary to reach the proposed effective dosage range of 10-30 mg (Glick and Peselow, 2008).
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H1 Receptors. Central antagonism of H1 receptors is associated with two major adverse effects: sedation and weight gain via appetite stimulation. Examples of sedating antipsychotic drugs include low-potency typical agents such as chlorpromazine and thioridazine, and the atypical agents clozapine and quetiapine. The sedating effect is easily predicted by their high H1 receptor affinities (Table 16–2). Some tolerance to the sedative properties will develop, a fact that must be kept in mind when switching patients to nonsedating agents.
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There is an extended-release quetiapine preparation available, with markedly reduced Cmax compared to the immediate-release form. Immediate-release quetiapine generates peak serum levels > 800 ng/mL within 2 hours of ingestion, while the extended release preparation has Cmax ~50% lower, with peak serum levels seen 4-8 hours after ingestion. In clinical practice the onset of sedation for extended-release quetiapine is delayed for at least 3 hours after oral administration, and subjectively the sedation is much less profound than with the immediate-release form (Mamo et al., 2008).
Rapid discontinuation of sedating antihistaminic antipsychotic drugs is inevitably followed by significant complaints of rebound insomnia and sleep disturbance. If discontinuation of sedating antipsychotic treatment is deemed necessary, except for emergency cessation of clozapine for agranulocytosis, the medication should be tapered slowly over 4-8 weeks, and the clinician should be prepared to utilize a sedative when the end of the titration is reached. Generous dosing of another antihistamine (hydroxyzine), or the anticholinergic antihistamine diphenhydramine are reasonable replacement sedative medications, but others can used, including benzodiazepines, non-benzodiazepine hypnotics that act at specific benzodiazepine sites (e.g., zolpidem, eszopiclone), and sedating antidepressants (e.g., trazodone). Sedation may be useful during acute psychosis, but excessive sedation can interfere with patient evaluation, may prolong emergency room and psychiatric hospital stays unnecessarily, and is poorly tolerated among elderly dementia and delirium patients, so appropriate caution must be exercised with the choice of agent and the dose.
Weight gain is a significant problem during long-term use of antipsychotic drugs and represents a major barrier to medication adherence, as well as a significant threat to the physical and emotional health of the patient. Weight gain has effectively replaced concerns over EPS as the adverse effect causing the most consternation among patients and clinicians alike. Appetite stimulation is the primary mechanism involved, with little evidence to suggest that decreased activity (due to sedation) is a main contributor to antipsychotic-related weight gain (Gothelf et al., 2002). Recent animal studies indicate that medications with significant H1 antagonism induce appetite stimulation through effects at hypothalamic sites (Kim et al., 2007). The low-potency phenothiazine chlorpromazine, and the atypical antipsychotic drugs olanzapine and clozapine, are the agents of highest risk, but weight gain of some extent is seen with nearly all antipsychotic drugs, partly related to the fact that acutely psychotic patients may lose weight; in placebo-controlled acute schizophrenia trials, the placebo cohort inevitably loses weight (Meyer, 2001). For clozapine and olanzapine, massive weight gains of 50 kg or more are not uncommon, and mean annual weight gains of 13 kg are reported in schizophrenia clinical trials, with 20% of subjects gaining ≥ 20% of baseline weight. High-potency typical antipsychotic drugs (e.g., haloperidol, fluphenazine), and newer atypical antipsychotics asenapine, ziprasidone, and aripiprazole, are associated with mean annual weight gains < 2 kg in schizophrenia patients, with mean gains of 2.5-3 kg noted for iloperidone, risperidone, and quetiapine (Meyer, 2001). For unknown reasons, molindone is associated with modest weight loss. Younger and antipsychotic drug-naïve patients are much more sensitive to the weight gain from all antipsychotic agents, including those which appear roughly weight neutral in adult studies, leading some to conjecture that DA blockade may also play a small additive role in weight gain. 5-HT2C antagonism is also thought to play an additive role in promoting weight gain for medications that possess high H1 affinities (e.g., clozapine, olanzapine), but appears to have no effect in the absence of significant H1 blockade, as seen with ziprasidone, a weight-neutral antipsychotic drug with extremely high 5-HT2C affinity. Switching to more weight-neutral medications can achieve significant results; however, when not feasible or when unsuccessful, behavioral strategies must be employed, and should be considered for all chronically mentally ill patients given the high obesity prevalence in this patient population.
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M1 Receptors. Muscarinic antagonism is responsible for the central and peripheral anticholinergic effects of medications. Most of the atypical antipsychotic drugs, including risperidone, paliperidone, asenapine, iloperidone, ziprasidone, and aripiprazole, have no muscarinic affinity and no appreciable anticholinergic effects, while clozapine and low-potency phenothiazines have significant anticholinergic adverse effects (Table 16–2). Quetiapine has modest muscarinic affinity, but its active metabolite norquetiapine is likely responsible for anticholinergic complaints (Jensen et al., 2008). Clozapine is particularly associated with significant constipation, perhaps due to the severely ill population under treatment. Routine use of stool softeners, and repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation. In general, avoidance of anticholinergic medications obviates the need to secondarily treat problems related to central or peripheral antagonism. Medications with significant anticholinergic properties should be particularly avoided in elderly patients, especially those with dementia or delirium.
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α1 Receptors. α1 Adrenergic antagonism is associated with risk of orthostatic hypotension and can be particularly problematic for elderly patients who have poor vasomotor tone. Compared to high-potency typical agents, low-potency typical agents have significantly greater affinities for α1 receptors and greater risk for orthostasis. While risperidone has a Ki that indicates greater α1-adrenergic affinity than chlorpromazine, thioridazine, clozapine, and quetiapine, in clinical practice risperidone is used at 0.01-0.005 times the dosages of these medications, and thus causes a relatively lower incidence of orthostasis in non-elderly patients. Since clozapine-treated patients have few other antipsychotic options, the potent mineralocorticoid fludrocortisone is sometimes tried at the dose of 0.1 mg/day as a volume expander.
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Adverse Effects Not Predicted by Monoamine Receptor Affinities
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Adverse Metabolic Effects. Such effects have become the area of greatest concern during long-term antipsychotic treatment, paralleling the overall concern for high prevalence of pre-diabetic conditions and type 2 diabetes mellitus, and 2-fold greater CV mortality among patients with schizophrenia (Meyer and Nasrallah, 2009). Aside from weight gain, the two predominant metabolic adverse seen with antipsychotic drugs are dyslipidemia, primarily elevated serum triglycerides, and impairments in glycemic control.
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Low-potency phenothiazines were known to elevate serum triglyceride values, but this effect was not seen with high-potency agents (Meyer and Koro, 2004). As atypical antipsychotic drugs became more widely used, significant increases in fasting triglyceride levels were noted during clozapine and olanzapine exposure, and to a lesser extent, with quetiapine (Meyer et al., 2008). Mean increases during chronic treatment of 50-100 mg/dL are common, with serum triglyceride levels exceeding 7000 mg/dL in some patients. Effects on total cholesterol and cholesterol fractions are significantly less, but show expected associations related to agents of highest risk: clozapine, olanzapine, and quetiapine. Risperidone and paliperidone have fewer effects on serum lipids, while asenapine, iloperidone, aripiprazole, and ziprasidone appear to have none (Meyer and Koro, 2004). Weight gain in general may induce deleterious lipid changes, but there is compelling evidence to indicate that antipsychotic-induced hypertriglyceridemia is a weight-independent adverse event that temporally occurs within weeks of starting an offending medication, and which similarly resolves within 6 weeks after medication discontinuation. The finding that serum triglycerides may change 70-80 mg/dL during a period when weight has changed relatively little propelled the search for adiposity-independent physiological mechanisms to explain this phenomenon.
In individuals not exposed to antipsychotic drugs, elevated fasting triglycerides are a direct consequence of insulin resistance since insulin-dependent lipases in fat cells are normally inhibited by insulin. As insulin resistance worsens, inappropriately high levels of lipolysis lead to the release of excess amounts of free fatty acids that are hepatically transformed into triglyceride particles (Smith, 2007). Elevated fasting triglyceride levels thus become a sensitive marker of insulin resistance, leading to the hypothesis that the triglyceride increases seen during antipsychotic treatment are the result of derangements in glucose-insulin homeostasis. The ability of antipsychotic drugs to induce hyperglycemia was first noted during low-potency phenothiazine treatment, with chlorpromazine occasionally exploited for this specific property as adjunctive presurgical treatment for insulinoma. As atypical antipsychotic drugs found widespread use, numerous case series documented the association of new-onset diabetes and diabetic ketoacidosis associated with treatment with atypical antipsychotic drugs, with most of cases observed during clozapine and olanzapine therapy (Jin et al., 2002, 2004). Analysis of the FDA MedWatch database found that reversibility was high upon drug discontinuation (~78%) for olanzapine- and clozapine-associated diabetes and ketoacidosis, supporting the contention of a drug effect. Comparable rates for risperidone and quetiapine were significantly lower. The mechanism by which antipsychotic drugs disrupt glucose-insulin homeostasis is not known, but recent in vivo animal experiments document immediate dose-dependent effects of clozapine and olanzapine on whole-body and hepatic insulin sensitivity (Houseknecht et al., 2007).
Antipsychotic-induced weight gain, and other diabetes risk factors (e.g., age, family history, gestational diabetes, obesity, race, ethnicity, smoking) all contribute to metabolic dysfunction. There may also be inherent disease-related mechanisms that increase risk for metabolic disorders among patients with schizophrenia, but the medication itself is the primary modifiable risk factor. As a result, all atypical antipsychotic drugs have a hyperglycemia warning in the drug label in the U.S., although there is essentially no evidence that asenapine, iloperidone, aripiprazole, and ziprasidone cause hyperglycemia. Use of the metabolically more benign agents is recommended for the initial treatment of all patients where long-term treatment is expected. Clinicians should obtain baseline metabolic data, including fasting glucose, lipid panel, and also waist circumference, given the known association between central obesity and future type 2 diabetes risk. Ongoing follow-up of metabolic parameters is commonly built into psychiatric charts and community mental health clinic procedures to insure that all patients receive some level of metabolic monitoring. As with weight gain, the changes in fasting glucose and lipids should prompt reevaluation of ongoing treatment, institution of measures to improve metabolic health (diet, exercise, nutritional counseling), and consideration of switching antipsychotic agents.
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Adverse Cardiac Effects. Ventricular arrhythmias and sudden cardiac death (SCD) are a concern with the use of antipsychotic agents. Most of the older antipsychotic agents (e.g., thioridazine) inhibit cardiac K+ channels, and all antipsychotic medications marketed in the U.S. carry a class label warning regarding QTc prolongation. A black box warning exists for thioridazine, mesoridazine, pimozide, IM droperidol, and IV (but not oral or IM) haloperidol due to reported cases of torsade de pointes and subsequent fatal ventricular arrhythmias (discussed next and in Chapter 29). Although the newer atypical agents are thought to have less effects on heart electrophysiology compared to the typical agents, a recent retrospective analysis found a dose-dependent increased risk for SCD among antipsychotic users of newer and older agents alike compared to antipsychotic nonusers, with a relative risk of 2 (Ray et al., 2009).
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Cardiac arrhythmia is the most common etiology for SCD, but it is important to determine whether the arrhythmia is primary or secondary to structural changes related to cardiomyopathy, myocarditis, or acute myocardial infarction. Secondary ventricular arrhythmia is probably the most frequent form of fatal tachyarrhythmia, but the exact distribution of SCD deaths by etiology among antipsychotic-treated patients is unclear in the absence of large autopsy samples. The true incidence of drug-induced ventricular arrhythmia can only be estimated, due partly to underreporting, and the fact that drug-induced torsade de pointes is rarely captured with confirmatory EKG (Nielsen and Toft, 2009).
Multiple ion channels are involved in the depolarization and repolarization of cardiac ventricular cells, which are discussed in detail in Chapter 29. Myoycte depolarization is seen as the QRS complex on EKG, and is primarily mediated by ion channels that permit rapid Na+ influx. Antagonism of these voltage-gated Na+ channels causes QRS widening and an increase in the PR interval, with increased risk for ventricular arrhythmia. Thioridazine has been shown to inhibit Na+ channels at high dosages, but other antipsychotic medications have not (Nielsen and Toft, 2009). Repolarization is mediated in part by K+ efflux via two channels: the rapid Ikr and the slow Iks channel. The Ikr channel is encoded by the human-ether-a-related-go-go gene (HERG), polymorphisms of which are involved in the congenital long QT syndrome associated with syncope and SCD. Many antipsychotic drugs block the Ikr channel to an extent comparable with that seen in congenital long QT syndrome. Antagonism of Ikr channels is the mechanism responsible for most cases of drug-induced QT prolongation, and is the suspected mechanism for the majority of antipsychotic-induced sudden cardiac deaths (Nielsen and Toft, 2009).
Aside from individual agents, where anecdotal and pharmacosurveillance data indicate risk for torsade de pointes (e.g., thioridazine, pimozide), most of the commonly used newer antipsychotic agents are associated with known risk for ventricular arrhythmias, including ziprasidone in overdose up to 12,000 mg. One exception is sertindole, an agent not available in the U.S. that was withdrawn in 1998 based on anecdotal reports of torsade de pointes, and then reintroduced in Europe in 2006 with strict EKG monitoring guidelines (Nielsen and Toft, 2009). Although in vitro data revealed sertindole's affinity for the K+ rectifier channel, several epidemiological studies published over the past decade were unable to confirm an increased risk of sudden death due to sertindole exposure, thereby providing justification for its reintroduction. Aside from sertindole, the apparent safety of newer antipsychotic medications appears at odds with retrospective findings of SCD among antipsychotic users (Ray et al., 2009), thus confronting the clinician with contradictory information regarding antipsychotic drug-related SCD risk, and leading to conflicting clinical recommendations. Currently, there are no data that would suggest a benefit of routine EKG monitoring for prevention of SCD among antipsychotic drug users.
Other Adverse Effects. Seizure risk is an unusual adverse effect of antipsychotic drugs, with anecdotal reports of uncertain causality present for many agents. In the U.S., there is a class label warning for seizure risk on all antipsychotic agents, with reported incidences well below 1%. Among commonly used newer antipsychotic drugs, only clozapine has a dose-dependent seizure risk, with an incidence of 3-5% per year. The structurally related olanzapine had an incidence of 0.9% in premarketing studies. Seizure disorder patients who commence antipsychotic treatment must receive adequate prophylaxis, with consideration given to avoiding carbamazepine and phenytoin due to their capacity to induce CYPs and P-glycoprotein. Carbamazepine is also contraindicated during clozapine treatment due to its bone marrow effects, particularly leucopenia. Redistribution and increased spacing of doses to minimize high peak serum clozapine levels can help, but patients may eventually require antiseizure medication. Valproic acid derivatives (e.g., divalproex sodium) are often used, but will compound clozapine-associated weight gain.
Clozapine possesses a host of unusual adverse effects aside from seizure induction, the most concerning of which is agranulocytosis. Clozapine's introduction in the U.S. was based on its efficacy in refractory schizophrenia, but came with FDA-mandated CBC monitoring that is overseen by industry-created registries. Now that several generic forms of clozapine are available in addition to proprietary CLOZARIL, clinicians must verify with each manufacturer the history of prior exposure. The overall agranulocytosis incidence is slightly under 1%, with highest risk during the initial 6 months of treatment, peaking at months 2-3 and diminishing rapidly thereafter. The mechanism is immune mediated, and patients who have verifiable clozapine-related agranulocytosis should not be rechallenged. Increased risk is associated with certain HLA types and advanced age. An extensive algorithm guiding clinical response to agranulocytosis, and lesser forms of neutropenia, is available from manufacturer web sites, and must be followed, along with the current recommended CBC monitoring frequency.
While rarely used due to its risk of QTc prolongation, thioridazine is also associated with pigmentary retinopathy at daily doses ≥ 800 mg/day. Low-potency phenothiazines are associated with the development of photosensitivity, which necessitated warnings regarding sun exposure. Phenothiazines are also associated with development of a cholestatic picture on laboratory assessments (e.g., elevated alkaline phosphatase), and rarely elevations in hepatic transaminases.
Increased Mortality in Dementia Patients. Perhaps the least understood adverse effect is the increased risk for cerebrovascular events and all-cause mortality among elderly dementia patients exposed to antipsychotic medications. All antipsychotic agents carry a mortality warning in the drug label regarding their use in dementia patients. The cerebrovascular adverse event rates in 10-week dementia trials range from 0.4-0.6% for placebo to 1.3-1.5% for risperidone, olanzapine and aripiprazole (Jeste et al., 2008). The mortality warning indicates a 1.6-1.7 fold increased mortality risk for drug versus placebo. Mortality is due to heart failure, sudden death, or pneumonia. The underlying etiology for antipsychotic-related cerebrovascular and mortality risk is unknown, but the finding of virtually equivalent mortality risk for typical agents compared to atypical antipsychotic drugs (including aripiprazole) suggests an impact of reduced D2 signaling regardless of individual antipsychotic mechanisms.
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Overdose with typical antipsychotic agents is of particular concern with low-potency agents (e.g., chlorpromazine) due to the risk of torsades de pointes, sedation, anticholinergic effects, and orthostasis. Patients who overdose on high-potency typical antipsychotic drugs (e.g., haloperidiol) and the substituted benzamides are at greater risk for EPS due to the high D2 affinity, but also must be observed for EKG changes. Overdose experience with newer agents, including ziprasidone, indicates a much lower risk for torsade de pointes ventricular arrhythmias compared to older antipsychotic medications; however, combinations of antipsychotic agents with other medications can lead to fatality, primarily through respiratory depression (Ciranni et al., 2009).
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Drug-Drug Interactions. Antipsychotic agents are not significant inhibitors of CYP enzymes with a few notable exceptions (chlorpromazine, perphenazine, and thioridazine inhibit CYP 2D6) (Otani and Aoshima, 2000). The plasma half-lives of a number of these agents are altered by induction or inhibition of hepatic CYPs and by genetic polymorphisms that alter specific CYP activities (Table 16–3). While antipsychotic drugs are highly protein bound, there is no evidence of significant displacement of other protein bound medications, so dosage adjustment is not required for anticonvulsants, warfarin, or other agents with narrow therapeutic indices. With respect to drug-drug interactions, it is important to consider the effects of environmental exposures (smoking, nutraceuticals, grapefruit juice), and changes in these behaviors.
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Changes in smoking status can be especially problematic for clozapine-treated patients, and will alter serum levels by 50% or more. Within 2 weeks of smoking discontinuation (e.g., hospitalization in nonsmoking environment), the absence of aryl hydrocarbons will cause upregulated CYP1A2 activity to return to baseline levels, with a concomitant rise in serum clozapine concentrations (Rostami-Hodjegan et al., 2004). For smoking patients with high serum clozapine levels, this loss of enzyme induction may result in nonlinear increases in clozapine levels, with potentially catastrophic results. Conversely, patients discharged from nonsmoking wards to the community will be expected to resume smoking behavior, with an expected 50% decrease in clozapine levels. Monitoring of serum clozapine concentrations, anticipation of changes in smoking habits, and dosage adjustment can minimize development of subtherapeutic or supratherapeutic levels.
Use in Pediatric Populations. Both risperidone and aripiprazole have indications for child and adolescent bipolar disorder (acute mania) for ages 10-17, and for adolescent schizophrenia (ages 13-17). Risperidone and aripiprazole are FDA-approved for irritability associated with autism in child and adolescent patients ages 5-16. As discussed in the sections on adverse effects, antipsychotic drug-naïve patients and younger patients are more susceptible to EPS and to weight gain. Use of the minimum effective dose can minimize EPS risk; aripiprazole and ziprasidone have the lowest risk, olanzapine the highest. Risperidone's effects on prolactin must be monitored by clinical inquiry, but long-term follow-up studies indicate some tolerance to hyperprolactinemia, with levels after 12 months of exposure significantly lower than peak levels, and close to baseline. Delayed sexual maturation was not seen in adolescents in clinical trials with risperidone, but should nevertheless be monitored.
Use in Geriatric Populations. The increased sensitivity to EPS, orthostasis, sedation, and anticholinergic effects are important issues for the geriatric population, and often dictate the choice of antipsychotic medication. Avoidance of drug-drug interactions is also important, as older patients on numerous concomitant medications have multiple opportunities for interactions. Dose adjustment can offset known drug-drug interactions, but clinicians must be attentive to changes in concurrent medications and the potential pharmacokinetic consequences. Vigilance must also be maintained for the additive pharmacodynamic effects of α1 adrenergic, antihistaminic, and anticholinergic properties of other agents. Elderly patients have an increased risk for tardive dyskinesia and parkinsonism, with TD rates ~5-fold higher than those seen with younger patients. With typical antipsychotics, the reported annual TD incidence among elderly patients in 20-25% compared to 4-5% for younger patients. With atypical antipsychotic, the annual TD rate in elderly patients is much lower (2-3%). Increased risk for cerebrovascular events and all-cause mortality is also seen in elderly patients with dementia (see "Increased Mortality in Dementia Patients"). Compared to younger patients, antipsychotic-induced weight gain is lower in elderly patients.
Use During Pregnancy and Lactation. Antipsychotic agents carry pregnancy class B or C warnings. Human data from anecdotal case reports and manufacturer registries indicate limited or no patterns of toxicity and no consistent increased rates of malformations. Nonetheless, the use of any medication during pregnancy must be balanced by concerns over fetal impact, especially first-trimester exposure, and the mental health of the mother. Haloperidol is often cited as the agent with the best safety record based on decades of accumulated human exposure reports, but newer antipsychotic drugs, such as risperidone, have not generated any signals of concern (Viguera et al., 2009). As antipsychotic drugs are designed to cross the blood-brain barrier, all have high rates of placental passage. Placental passage ratios are estimated to be highest for olanzapine (72%), followed by haloperidol (42%), risperidone (49%), and quetiapine (24%). Neonates exposed to olanzapine, the atypical agent with highest placental passage ratio, exhibit a trend towards greater neonatal intensive care unit admission (Viguera et al., 2009). Use in lactation presents a separate set of concerns due to the low level of infant hepatic catabolic activity in the first 2 postpartum months. While breast milk presents an important source of protective antibodies for the baby, the inability of the newborn to adequately metabolize xenobiotics presents a significant risk for antipsychotic drug toxicity. The available data do not provide adequate guidance on choice of agent.
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Major Drugs Available in the Class
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In the U.S., atypical antipsychotic drugs have largely replaced older agents, primarily due to their more favorable EPS profile, although typical agents are widely used throughout the world. Table 16–1 describes the acute and maintenance doses for adult schizophrenia treatment based on consensus recommendations.
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Acute IM forms exist for many typical antipsychotic drugs, and also for aripiprazole, ziprasidone, and olanzapine, with the latter being the most sedating due to its antihistaminic and anticholinergic properties. The standard IM doses are 9.75 mg for aripiprazole, 10 mg for olanzapine, and 20 mg for ziprasidone (Altamura et al., 2003). The 20-mg IM ziprasidone dose generates serum levels that exceed those from 160 mg/day orally, but has not been associated with reports of torsade de pointes or cardiac dysrhythmia. There are numerous LAI (long-acting injectable) formulations of typical antipsychotics, but in the U.S., the only available LAI typical agents are fluphenazine and haloperidol (as decanoate esters), with usual dosages 12.5-25 mg IM every 2 weeks and 50-200 mg (not to exceed 100 mg as the initial dose) IM monthly, respectively. Haloperidol decanoate has more predictable kinetics, while fluphenazine decanoate's serum level can increase within days after administration and induce adverse effects (Altamura et al., 2003). EPS remains a significant barrier for using these agents. LAI risperidone was studied at doses of 25, 50, and 75 mg IM biweekly, but the higher dose was found to be without increased efficacy and with greater EPS rates. Current available doses, all distributed as complete, single-dose kits, are 12.5, 25, 37.5, and 50 mg, given as a 2-mL water-based injection. LAI risperidone is impregnated into organic microspheres that require several weeks to liberate free drug. The impact of any dosage change (or missed dose) of LAI risperidone is seen 4 weeks later. LAI paliperidone has recently become available, and dosing is initiated with two loading IM deltoid injections given at days 1 (234 mg) and 8 (156 mg), followed by injections every 4 weeks starting at day 36. This loading strategy can be omitted if transitioning patients from another LAI antipsychotic, with LAI paliperidone given in lieu of the next injection, and the every 4 weeks thereafter. The package insert provides detailed information on dose equivalency with oral paliperidone, and on handling missed injections. ODT forms are available for aripiprazole, clozapine, olanzapine, and risperidone, and are the only form for asenapine. These ODT preparations are commonly used in emergency and inpatient settings where patients may be prone to cheeking or spitting out oral tablets.
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Clinical Summary: Treatmentof Psychosis
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The pharmacological profile of newer, atypical antipsychotic drugs has expanded the uses of antipsychotic medications during the last decade to include adjunctive use for major depression and bipolar depression, with supporting data for certain anxiety disorders. Considerable debate exists over the clinical superiority touted for the newer antipsychotic drugs for the treatment of schizophrenia compared to older, typical agents. What is clear is that the more favorable therapeutic indices of newer agents (e.g., fewer neurological adverse effects) permit clinicians to avoid the effects of excessive antagonism of D2 dopamine receptors. Aside from refractory schizophrenia, where clozapine exhibits superior effectiveness, drug choice primarily revolves around the avoidance of adverse effects, concerns regarding drug-drug interactions, and the availability of acute injectable, long-acting injectable, or orally dissolving tablet forms. Atypical antipsychotic drugs have generated considerable interest in non-dopaminergic mechanisms of action, including the useful property of 5-HT2A antagonism. The greater understanding of schizophrenia pathophysiology has furthered investigation into glutamatergic and cholinergic agents, some of which have advanced to later-stage clinical trials. Knowledge of receptor binding affinities combined with neuroimaging data on CNS receptor occupancy provide a guide to gauging the risk of most adverse effects of a particular drug. However, the pathophysiology for adiposity-independent effects on glucose-insulin homeostasis seen with certain antipsychotic medications has yet to be elucidated. Given the inherent cardiometabolic risk factors common among the severely mentally ill, close medical monitoring during long-term antipsychotic therapy is considered the standard of care, regardless of the metabolic risk of the specific antipsychotic agent. Judicious use of antipsychotic drugs with more favorable risk profiles is the primary guide to medication choice.