Which of the following medications is an atypical antipsychotic utilized in the treatment of schizophrenia?

Treating acute episodes of schizophrenia

The advantages of hospitalization for many patients with first episodes or any significant relapse of schizophrenia are summarized below (Box 19.7). Antipsychotic (AP) treatment with a single AP drug should be initiated as soon as the diagnosis of schizophrenia is established because there is evidence that the duration of untreated psychotic symptoms determines time to recovery, extent of recovery and risk of relapse (Loebel et al 1992). Agitated and/or anxious patients may also require oral or parenteral benzodiazepines. Severely ill patients who are agitated and/or unwilling to accept oral AP therapy may require a parenterally administered antipsychotic drug (see below and Chs 36 and 39).

Atypical AP drugs have been recommended as first-line treatment for almost all patients with schizophrenia by the National Institute for Health and Clinical Excellence (NICE 2002, 2010). Treatment should commence with an adequate dose of a single atypical AP drug. If this is ineffective after 2–3 weeks the dose should be increased and treatment continued for a further 2–3 weeks. If treatment remains ineffective this drug should be discontinued, a second atypical AP drug should be prescribed and the same two-stage process repeated. If the second atypical AP drug proves ineffective, treatment with clozapine should be commenced. If the first atypical AP drug is not tolerated the patient should be switched to a second atypical AP drug. If this is not tolerated the patient should be switched to clozapine. Partial or non-response to AP therapy may indicate:

Misdiagnosis

Co-morbidity

Non-compliance

Inadequate dosage

Inadequate duration of treatment

Concurrent use of psychotomimetic drugs

Inefficacy.

These problems may be addressed by reassessment of diagnosis and exclusion of co-morbidity, by use of liquid or parenteral preparations to enhance compliance, by increasing dosage, by waiting and/or by careful monitoring to exclude abuse of psychotomimetic drugs. An alternative AP drug should be prescribed if these problems have been addressed and response remains inadequate.

Olanzapine and risperidone

Atypical antipsychotic drugs are occasionally used off-label for obsessive symptoms. From an initial sample of 96 Italian patients with obsessive–compulsive disorder who underwent a 16-week first phase of treatment with SSRIs, 50 were judged to be resistant and were randomized to additional risperidone (mean age 36 years; mean daily dose 2.1 mg; n = 25) or olanzapine (mean age 34 years; mean daily dose 5.3 mg; n = 25) in an 8-week, single-blind, second phase [93c]. Adverse experiences were reported by 52% of those who took additional risperidone and 64% of those who took olanzapine; adverse events motivated withdrawal in two patients taking olanzapine (reduced sexual desire and weight gain).

The adverse effects of atypical antipsychotics on the brain

The defendant was administered risperidone (Risperdal®) while in the burn unit before the police interrogation. Risperidone is an atypical antipsychotic drug. First of all, a typical antipsychotic agent is a drug that acts as an antagonist at dopamine receptors. As you might remember from Chapter 1, in the Drug Effects on Brain and Behavior section, dopamine is a major neurotransmitter in the brain and an overabundance of dopamine underlies the pathology of schizophrenia. Therefore it makes sense that the first drug treatment for schizophrenia was typical antipsychotic drugs that block (antagonize) dopamine at its receptors.

Atypical antipsychotics were developed after typical antipsychotic drugs and are more effective at treating schizophrenics who are resistant to previous typical antipsychotics and exhibit the more insidious signs of schizophrenia such as catatonia, abject apathy, anhedonia, and social withdrawal.32 The atypical antipsychotics like risperidone generally have less serious adverse effects than the typical antipsychotics.

Risperidone (trade name Risperdal®) is FDA approved for the treatment of schizophrenia, for the short-term treatment of acute manic or mixed episodes associated with bipolar disorder in adults, and for the treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years.33 It is also more generally classified as a psychotropic agent, that is, an agent that has activity on the brain and mental functions. Antipsychotics are also classified as CNS depressants.34 Oral administration of risperidone reaches a peak concentration in the blood after about 1 h. Risperidone is mainly metabolized in the liver and yields an active metabolite. Risperidone and its active metabolite remain in the body a very long time. The elimination half-life of risperidone and its active metabolite shows a mean half-life value of 20 h.

The acute effects of risperidone given to normal healthy volunteers produced dizziness in 40% of subjects and sleepiness (somnolence) in 50% of subjects.35 There was also a decrement in various psychomotor functions (finger-tapping, cursor tracking) and measures of learning and memory. There is some improvement in the prior baseline cognitive abilities of schizophrenics after treatment with risperidone or other antipsychotic drugs,36 but long-term treatment of schizophrenic patients with typical and atypical antipsychotics for 9 years showed a significant decrement in verbal learning and memory compared to predrug baseline cognitive ability.37

Metabolism

Atypical antipsychotic drugs have been linked to obesity, hyperlipidemia, type 2 diabetes mellitus, and diabetic ketoacidosis (SEDA-26, 56; SEDA-28, 60). While the incidence of new-onset diabetes mellitus appears to be increasing in patients with schizophrenia taking certain atypical antipsychotic drugs, it is unclear whether these agents directly affect glucose metabolism or simply increase risk factors for diabetes, such as obesity, lipid abnormalities, and reduced activity secondary to sedative effects. Glucose metabolism in 36 out-patients with schizophrenia aged 18–65 years taking clozapine (n=12), olanzapine (n=12), or risperidone (n=12) has been examined in a cross-sectional study (14c). There was no significant difference in fasting baseline plasma glucose concentrations. Those taking clozapine or olanzapine had significant insulin resistance compared with those taking risperidone. There were no significant differences in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or serum triglyceride concentrations; however, controlling for sex, there was a significant difference (clozapine > olanzapine > risperidone). Insulin resistance is a major but not necessary risk factor for type 2 diabetes; leptin, in turn, is important for the control of body weight and the authors proposed that leptin could be considered to be a link between obesity, insulin resistance syndrome, and treatment with some antipsychotic drugs. However, consistent with other results, the small sample size, the cross-sectional design, and the exclusion of obese subjects may limit the generalizability of these findings.

In patients, particularly children, taking the new antipsychotic drugs, obesity is a focus of special interest. A thorough search for studies that addressed obesity in children and adolescents in relation to the new antipsychotic drugs showed that risperidone is associated with less weight gain than olanzapine (15R).

Mechanism of action and effects

The antipsychotic action of atypical antipsychotic drugs, like that of conventional antipsychotics, arises primarily from blockade of CNS dopamine D2 receptors in mesolimbic pathways. However, the atypical antipsychotic drugs have a lower affinity for D2 receptors and transient receptor occupancy. Therefore they are less likely than conventional antipsychotics to produce extrapyramidal movement disorders at usual doses. Antagonist activity at serotonin 5-HT2 receptors may contribute to their antipsychotic action, particularly in improving negative features such as apathy and blunted emotions.

Atypical antipsychotic drugs have different patterns of activity at a variety of receptors:

Aripiprazole has partial agonist activity at D2 receptors, which limits the degree of receptor antagonism. It also has weak partial agonist activity at 5-HT1A receptors but is an antagonist at 5-HT2A receptors.

Clozapine is a relatively weak D2-receptor antagonist with selective cortical receptor occupancy and shows greater antagonist activity at D1 receptors. It has greater antagonist activity at serotonin 5-HT2A receptors, α1-adrenoceptors and muscarinic receptors.

Olanzapine has a similar profile to clozapine, with additional antagonist activity at histamine H1 receptors.

Quetiapine has moderate affinity for D1 and D2 receptors, and is an antagonist at 5-HT2A and 5-HT2C receptors, α1-adrenoceptors and histamine H1 receptors.

Risperidone has relatively high affinity for D2 receptors. It also has antagonist activity at several 5-HT2 receptor subtypes, α1-adrenoceptors and histamine H1 receptors.

Adherence to treatment with atypical antipsychotics is greater than for conventional antipsychotics, probably as a result of less marked unwanted effects, which may explain their apparently greater efficacy. Clozapine, however, is uniquely superior to all other drugs for the treatment of refractory schizophrenia.

Comparative studies

The impact of new neuroleptic drugs on the pattern of neuroleptic drug use has been studied in Spain [24]. The use of neuroleptic drugs rose by 146% from 1990 to 2001; the atypical neuroleptic drugs accounted for 49% of the total consumption of neuroleptic drugs in 2001 and 90% of the costs. There is a similar pattern worldwide. This is surprising, since there is no clear evidence that atypical neuroleptic drugs are more effective or better tolerated than conventional neuroleptic drugs [25]. Moreover, a recent meta-analysis of typical and atypical neuroleptic drugs (31 studies, 2320 participants) showed that optimum doses of low-potency conventional neuroleptic drugs might not induce more extrapyramidal signs than newer drugs [26]; mean doses less than 600 mg/day of chlorpromazine equivalents had no higher risk of extrapyramidal signs than newer neuroleptic drugs.

Atypical neuroleptic drugs caused more severe adverse reactions than typical neuroleptic drugs did in a program intended to monitor adverse reactions to neuroleptic drugs in routine clinical practice [27]. From 1993 to 2000, 86 439 patients who took at least one neuroleptic drug were monitored in 35 psychiatric hospitals in Germany and Switzerland. Overall, 975 clinically severe adverse reactions were identified (1.1%). As to individual drugs in monotherapy, the incidences were:

haloperidol, 0.2%;

perazine, 0.4%;

olanzapine, 0.5%;

risperidone, 0.5%;

clozapine, 0.9%.

The authors stated that their results were in accordance with those of a meta-analysis of 52 randomized trials [28].

Coming from the same program, separate estimates have been made for different reactions:

Severe galactorrhea occurred in 27 cases (0.03%); haloperidol, 0%; clozapine, 0%; perazine, 0.01%; olanzapine, 0.03%; risperidone, 0.09% [29].

Severe neutropenia (neutrophils < 1.5 × 109/l) occurred in 43 cases (0.05%); haloperidol, 0.01%; risperidone, 0.01%; olanzapine, 0.05%; perazine, 0.07%; clozapine, 0.16% [30].

Severe and uncommon involuntary movement disorders occurred in 115 cases (0.13%); clozapine, 0.01%; perazine, 0.02%; olanzapine, 0.04 %; risperidone, 0.09%; haloperidol, 0.18% [31].

These estimates are very low, since only those reactions rated as probably or definitely drug related were considered.

The primary and main outcomes of the Clinical Antipsychotic Trials of Intervention Effectiveness both in schizophrenic patients and in patients with dementia have been released. In the first study, 1493 patients with schizophrenia recruited at 57 US sites were randomly allocated to olanzapine (7.5–30 mg/day), perphenazine (8–32 mg/day), quetiapine (200–800 mg/day) and ziprasidone (40–160 mg/day) for up to 18 months [32]. The main conclusion of the study was that patients with chronic schizophrenia discontinued their neuroleptic drug medication at a high rate, indicating substantial limitations in the effectiveness of the drugs. In fact, overall 74% of patients withdrew within 18 months; the time to withdrawal for any cause was significantly longer with olanzapine than quetiapine or risperidone but not perphenazine or ziprasidone. The time to withdrawal because of intolerable adverse reactions was similar across the groups (olanzapine, 19%; quetiapine, 15%; risperidone, 10%; perphenazine, 16%; ziprasidone, 15%). The authors suggested that the ways in which clinicians, patients, families, and policymakers evaluate the trade-offs between efficacy and adverse reactions, as well as drug prices, will determine future patterns of use.

Pharmacology of 5-HT2 receptors and aggression

Atypical antipsychotic agents (e.g., risperidone) with significant antagonist action at 5-HT2A receptors have been successfully used to reduce aggressive behaviors in patients of varying ages and with a wide range of diagnoses, such as depression, schizophrenia, dementia and mental retardation, and post-traumatic stress disorder (Czobor et al., 1995; Buckley et al., 1997; Fava, 1997; De Deyn et al., 1999; Keck et al., 2000; Buitelaar et al., 2001; Zarcone et al., 2001). In animal models, risperidone decreases aggressive behaviors but has been shown to concomitantly reduce mobility (Rodriguez-Arias et al., 1998). 5-HT2A specific antagonists, such as ketanserin, ritanserin and MDL 100907, reduced aggressive behavior in monoamine oxidase A (MAOA)-deficient mice (Shih et al., 1999) and in socially isolated mice (White et al., 1991; Sakaue et al., 2002).

DOI and other substituted phenylisopropylamines, agonists that act at both 5-HT2A and 5-HT2C receptors, also reduce aggressive behavior in several species, including flies, amphibians, mice and rats (Sanchez et al., 1993; Bonson et al., 1994; de Almeida and Lucion, 1994; Muehlenkamp et al., 1995; Olivier et al., 1995; Ten Eyck, 2008b; Johnson et al., 2009). However, similar to 5-HT1A agonists, the effects of 5-HT2 ligands are not behaviorally specific and are accompanied by sedative effects at the doses that exert anti-aggressive effects. Local administration of 5-HT2A/2C agonist into periaqueductal gray (PAG) reduced maternal aggression in rats (de Almeida et al., 2005), whereas microinjections into the medial hypothalamus and also into the PAG increased defensive hissing in cats (Shaikh et al., 1997; Hassanain et al., 2003; Figure 4). This latter effect is likely related to the role of 5-HT2A/2C receptors in anxiety-like behavior (Lucki and Wieland, 1990; Nogueira and Graeff, 1995). The development of more selectively acting pharmacological tools will allow a more adequate differentiation of 5-HT2 receptor subtypes. These novel tools promise to dissociate the anti-aggressive and sedative effects.

Olanzapine

The atypical antipsychotic drug olanzapine is also metabolized by CYP1A2.

A 21-year-old woman with schizophrenia and depression, who had been taking fluvoxamine (150 mg/day) and olanzapine (15 mg/day) for several months, developed an extrapyramidal movement disorder, including rigidity and tremor [51]. The plasma fluvoxamine concentration was 70 ng/ml (usual target range is 20–500 ng/ml), while that of olanzapine was 120 ng/ml (usual target range is 9–25 ng/ml). The dosage of olanzapine was reduced to 5 mg/day and the plasma olanzapine concentration fell to 38 ng/ml, with resolution of the tremor and rigidity. When fluvoxamine was replaced with paroxetine (20 mg/day) the olanzapine concentration fell further to 22 ng/ml.

Of the SSRIs, fluvoxamine is the most potent inhibitor of CYP1A2 and is therefore likely to increase plasma olanzapine concentrations. The extrapyramidal effects in this case were presumably due to excessive blockade of dopamine D2 receptors by raised olanzapine concentrations.

18 How are second-generation antipsychotic agents used in delirium?

Newer atypical antipsychotic agents (e.g., risperidone, ziprasidone, quetiapine, and olanzapine) may also prove helpful for delirium. The advantage over haloperidol is theoretic and may be related to its effect not only on dopamine but also on other neurotransmitters such as serotonin, acetylcholine, and norepinephrine. Studies need to be repeated with larger patient populations before any concrete recommendations can be made regarding the efficacy of typical or atypical antipsychotics in delirium.

Key Points

Delirium

Delirium is a disturbance of consciousness with inattention, accompanied by a change in cognition or perceptual disturbances that develop over a short period of time and fluctuate over days.

Delirium is associated with significant morbidity and mortality.

Diagnosis of delirium is a two-step process. Level of arousal is first measured, and, if the patient is arousable, delirium evaluation is performed with use of validated instruments.

Pharmacologic treatment should be used only after giving adequate attention to correction of modifiable contributing factors.

Pharmacologic treatments:

Haloperidol is considered to be the first-line drug and should be started at a low dose.

Atypical antipsychotics have also been used when risk for adverse events such as QTc prolongation or extrapyramidal side effects is estimated to be high. These drugs include olanzapine, risperidone, quetiapine, and ziprasidone.

Benzodiazepines should be reserved for use only in delirium associated with alcohol withdrawal.

Websites

ICU Delirium and Cognitive Impairment Study Group: www.icudelirium.org

American Psychiatric Association guidelines (including treatment of delirium): www.psych.org/psych_pract/treatg/pg/prac_guide.cfm

Olanzapine versus amisulpride

Two atypical antipsychotic drugs, olanzapine and amisulpride, which have different receptor occupancy profiles, have been compared in a double-blind, randomized, 6-month study in 72 different centers in 11 European and African countries [54]. Schizophrenic patients, mainly with acute psychotic symptoms, were assigned to olanzapine (mean dose 13 mg/day; mean age 37 years, 64% men; n = 188) or amisulpride (mean dose 504 mg/day; mean age 38 years, 66% men; n = 189). The incidence and reasons for withdrawal were similar in both groups (63 patients in the olanzapine group and 72 in the amisulpride group left the study prematurely). The two drugs produced similar symptomatic improvement and similar adverse event frequencies (56% with olanzapine and 57% with amisulpride); patients taking olanzapine had more weight gain (50 versus 30 patients; mean weight gain 3.9 versus 1.6 kg), but less amenorrhea (0 versus 4), extrapyramidal symptoms (1 versus 11), insomnia (10 versus 14), and constipation (5 versus 10); there was somnolence in 12 patients in each group and serum aminotransferase activities were raised in 32 patients taking olanzapine and seven taking amisulpride. Three patients (two taking amisulpride and one taking olanzapine) left the study because of extrapyramidal symptoms. Diabetes was aggravated in one patient taking olanzapine. Two patients died during the study, one from cerebral hemorrhage (taking amisulpride) and one because of suicide (taking olanzapine).

There were moderate but significant improvements in neurocognition (including executive function, working memory, and declarative memory) in a randomized, double-blind, 8-week study in 52 patients with schizophrenia assigned either to olanzapine (10–20 mg/day; n = 18) or amisulpride (400–800 mg/day; n = 18) [55]. Of 16 dropouts, six were due to adverse events: olanzapine—sedation (n = 2) and increased aminotransferases (n = 1); amisulpride—rash, extrapyramidal symptoms, and galactorrhea (n = 1 each).