Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

50. Schizophrenia

M. Lynn Crismon, Tami R. Argo, and Peter F. Buckley


 Images Although multiple neurotransmitter dysfunctions are involved in schizophrenia, the etiology is more likely mediated by multiple subcellular processes that are influenced by different genetic polymorphisms.

 Images The clinical presentation of schizophrenia is characterized by positive symptoms, negative symptoms, and impairment in cognitive functioning.

 Images Comprehensive care for individuals with schizophrenia must occur in the context of a multidisciplinary mental healthcare environment that offers comprehensive psychosocial services in addition to psychotropic medication management.

 Images A thorough patient evaluation (e.g., history, mental status examination, physical examination, psychiatric diagnostic interview, and laboratory analysis) should occur to establish a diagnosis of schizophrenia and to identify potential co-occurring disorders, including substance abuse and general medical disorders.

 Images Given that it is challenging to differentiate among antipsychotics based on efficacy, side effect profiles become important in choosing an antipsychotic for an individual patient.

 Images Pharmacotherapy guidelines should emphasize monotherapies with antipsychotics of optimal efficacy-to-side effect ratios and progress to medications with greater side effect risks, and combination regimens should only be used in the most treatment-resistant patients.

 Images Adequate time on a given medication at a therapeutic dose is the most important variable in predicting medication response.

 Images Long-term maintenance antipsychotic treatment is necessary for the vast majority of patients with schizophrenia in order to prevent relapse.

 Images Thorough patient and family psychoeducation should be implemented, and methods such as motivational interviewing that focus on patient-driven outcomes that allow patients to achieve life goals should be employed.

 Images Pharmacotherapy decisions should be guided by systematic monitoring of patient symptoms, preferably with the use of brief symptom rating scales and systematic assessment of potential adverse effects.

Schizophrenia is one of the most complex and challenging of psychiatric disorders. It represents a heterogeneous syndrome of disorganized and bizarre thoughts, delusions, hallucinations, inappropriate affect, and impaired psychosocial functioning. From the time that Kraepelin first described dementia praecox in 1896 until publication of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) in 2000, the description of this illness has continuously evolved.1 Scientific advances that increase our knowledge of CNS physiology, pathophysiology, and genetics will likely improve our understanding of schizophrenia in the future.


According to the Epidemiologic Catchment Area Study, the lifetime prevalence of schizophrenia using strict diagnostic criteria ranges from 0.6% to 1.9%. If a broader definition is used, the lifetime rate rises to 2% to 3%.2 The worldwide prevalence of schizophrenia is remarkably similar among most cultures. Schizophrenia most commonly has its onset in late adolescence or early adulthood and rarely occurs before adolescence or after the age of 40 years. Although the prevalence of schizophrenia is equal in males and females, the onset of illness tends to be earlier in males. Males most frequently have their first episode during their early 20s, whereas with females it is usually during their late 20s to early 30s.1,3


Although the etiology of schizophrenia is unknown, research has demonstrated various abnormalities in brain structure and function.4 However, these changes are not consistent among all individuals with schizophrenia. The cause of schizophrenia is likely multifactorial, that is, multiple pathophysiologic abnormalities can play a role in producing the similar but varying clinical phenotypes we refer to as schizophrenia.

A neurodevelopmental model has been evoked as one possible explanation for the etiology of schizophrenia.4 This model proposes that schizophrenia has its origins in some as yet unknown in utero disturbance, possibly occurring during the second trimester of pregnancy. Evidence for this is provided by the abnormal neuronal migration demonstrated in studies of schizophrenic brains. This “schizophrenic lesion” can result in abnormalities in cell shape, position, symmetry, connectivity, and functionally to the development of abnormal brain circuits.4 Changes are consistent with a cell migration abnormality during the second trimester of pregnancy, and some studies associate upper respiratory infections during the second trimester of pregnancy with a higher incidence of schizophrenia.5 Other studies associate low birth weight (LBW; less than 2.5 kg [5.5 lb]), obstetric complications, or neonatal hypoxia with schizophrenia.2 Maternal stress, perhaps related to the effects of circulating glucocorticoids in utero, may be a risk factor for schizophrenia. Maternal “stress” could derive from a variety of external and internal noxious events (malnutrition, infection, etc.). The resulting secondary “synaptic disorganization” associated with such insults is thought not to produce overt clinical manifestations of psychosis until adolescence or early adulthood because this is the corresponding time period of neuronal maturation.

Although studies have shown decreased cortical thickness and increased ventricular size in the brains of many patients with schizophrenia, this occurs in the absence of widespread gliosis.4 One hypothesis is that obstetric complications and hypoxia, in combination with a genetic predisposition, could activate a glutamatergic cascade that results in increased neuronal pruning. It is hypothesized that this genetic predisposition may be related to genes controlling N-methyl-D-aspartate (NMDA) receptor activity. As a part of the normal neurodevelopmental process, pruning of dendrites occurs. In normal individuals, approximately 35% of the peak number of dendrites at 2 years of age are pruned by midadolescence. Some studies have shown a higher percentage of pruning in individuals with schizophrenia. Furthermore, synaptic pruning predominantly involves glutamatergic dendrites. Hypoxia or other prenatal insult can result in a decreased number of basal neurons from which to start, and glutamatergic activation can exaggerate the pruning process.4,5 There is also renewed interest in the immune system and schizophrenia. Studies have shown an increased susceptibility to immune/autoimmune disorders in schizophrenia, as well as abnormalities of autoantibodies and cytokine functioning.6 The immune hypothesis of schizophrenia also emphasizes integration of mental and physical well-being.

Numerous studies have shown neuropsychological abnormalities and impairment in reaching normal motor milestones and abnormal movements in young children who later develop schizophrenia.3Abnormalities in brain function occur long before the onset of psychotic symptomatology and provide empirical evidence for schizophrenia being a neurodevelopmental disorder.4 However, the progressive clinical deterioration in many patients suggests that this illness can also have a neurodegenerative component. This is consistent with recent brain imaging studies that show deteriorative brain changes in patients with frequent relapses.2,4,7 These changes may be most pronounced among adolescents with early onset schizophrenia.8 Schizophrenia may be an illness exhibiting neurodegenerative propensity based on a vulnerable neurodevelopmental predisposition.2,9,10 Although a specific abnormality has not been discovered, evidence suggests a genetic basis for schizophrenia. Although the risk of developing schizophrenia is 0.6% to 1.9% in the U.S. population, the risk is approximately 10% if a first-degree relative has the illness and 3% if a second-degree relative has the illness.2,11 If both parents have schizophrenia, the risk of producing an offspring with schizophrenia increases to approximately 40%. Twin studies in dizygotic twins report that the risk of the second twin developing schizophrenia if one twin has the illness is between 12% and 14%. However, in monozygotic twins the risk increases to 48%.11 Numerous adoption studies indicate that the risk for schizophrenia lies with the biologic parents, and change in the environment during the child’s developmental stages does not alter this. If schizophrenia occurs in siblings, the onset of illness tends to occur at the same age in each, thus lessening the possibility of an environmental precipitant.

Numerous approaches have been utilized to study the genetics of schizophrenia, including genome-wide association studies (GWAS), copy number variant (CNV) studies, and gene candidate studies.12Genetic etiologies in schizophrenia are likely heterogeneous, but present with similar clinical phenotypes, and involve epigenetic interactions.12 GWAS have identified nearly 20 genetic loci that reach genome-wide significance (P = 5 × 108), but only some of these have been replicated in multiple studies.13 GWAS indicate susceptible genes for schizophrenia on chromosome 6, and common genes underlying psychosis on ZNF804A, CACN1A2, NRGN, and PBRM1.12 Risk for schizophrenia has been demonstrated in CNV studies for deletions on chromosomes 1, 15, and 22. Polymorphism in the VAL/MET alleles of the catecholamine-O-methyl transferase gene may explain some of the frontal lobe functional deficits in a subset of individuals with schizophrenia.11 Other recent studies have shown abnormalities in several genes that code for neurodevelopment and for trophic factors.11,14 For example, dysbindin is a neurodevelopmental protein gene that is found on chromosome 6, and it has been termed a NMDA-related schizophrenia susceptibility gene.15 Alleles associated with decreased dysbindin RNA in the dorsolateral prefrontal cortex have been reported in patients with schizophrenia and their families.15 Another recent GWAS of a large pedigree showed increased signal at chromosome 8p, close to the gene that encodes for neuregulin—another neurodevelopmental gene. Interest is burgeoning regarding how genetic vulnerability might interact with environmental stressors, such as cannabis abuse.16


Advances in imaging technology and changes in research methodology have resulted in varying results from brain imagining studies over time, although most recent studies have found decreases in gray matter and increases in ventricular size. A recent meta-analysis of systematic reviews conducted since the year 2000 found consistent decreases in gray matter in multiple brain areas, including the frontal lobes, cingulate gyri, and medial temporal regions among others. A corresponding increase in ventricular size was also observed as well as decreased white matter in the corpus callosum.17 Changes in hippocampal volume may correspond with impairment in neuropsychological testing.2 Rather than a decrease in the number of neurons in affected brain areas, a decrease in axonal and dendritic communications between cells can result in a loss of connectivity that can be important with respect to neuronal adaptivity and CNS homeostasis.2,4 These changes are likely consistent with the evidence for abnormal neuronal pruning.4 Four dopaminergic pathways and five major dopamine (DA) receptor subtypes are of primary interest. Table 50-1 outlines the origin, innervation, and primary functional activity of each pathway, as well as the effects of DA antagonists.18

TABLE 50-1 Dopaminergic Tracts and Effects of Dopamine Antagonists


Evidence supports the presence of a DA-receptor defect in schizophrenia. Numerous positron emission tomography (PET) studies have shown regional brain abnormalities, including increased glucose metabolism in the caudate nucleus and decreased blood flow and glucose metabolism in the frontal lobe and left temporal lobe.3 This can indicate dopaminergic hyperactivity in the head of the caudate nucleus and dopaminergic hypofunction in the frontotemporal regions. PET studies using dopamine-2 (D2)-specific ligands suggest increased densities of D2 receptors in the head of the caudate nucleus with decreased densities in the prefrontal cortex.3,4 However, a recent meta-analysis showed an increase in presynaptic DA synthesis and release in the striatum with only a small increase in D2/3 receptor availability.19 PET studies assessing dopamine-1 (D1) function suggest that subpopulations of schizophrenics may have decreased densities of D1 receptors in the caudate nucleus and the prefrontal cortex. Hypofrontality can be associated with lack of volition and cognitive dysfunction, core features of schizophrenia. It is unknown whether these changes represent a primary event or secondary processes related to other pathophysiologic abnormalities in schizophrenia. Because of the heterogeneity in the clinical presentation of schizophrenia, it has been suggested that the DA hypothesis may be more applicable to “neuroleptic-responsive psychosis,” with multiple different etiologies possibly being responsible for causing schizophrenia.2 Attempts have been made to develop relationships between these abnormal findings and behavioral symptoms present in schizophrenic patients. The positive symptoms are possibly more closely associated with DA-receptor hyperactivity in the mesocaudate, whereas negative symptoms and cognitive impairment are most closely related to DA-receptor hypofunction in the prefrontal cortex. Presynaptic D1 receptors in the prefrontal cortex are thought to be involved in modulating glutamatergic activity, and this can be important with regard to working memory in individuals with schizophrenia.2

The glutamatergic system is one of the most widespread excitatory neurotransmitter systems in the brain. Alterations in its function, either hypoactivity or hyperactivity, can result in toxic neuronal reactions.3Dopaminergic innervation from the ventral striatum decreases the limbic system’s inhibitory activity (perhaps through γ-aminobutyric acid [GABA] interneurons); thus, dopaminergic stimulation increases arousal. The corticostriatal glutamate pathways have the opposite effect, inhibiting dopaminergic function from the ventral striatum, therefore allowing the limbic system to have increased inhibitory activity. Descending glutamatergic tracts interact with dopaminergic tracts directly as well as through GABA interneurons. Glutamatergic deficiency produces symptoms similar to those of dopaminergic hyperactivity and possibly those seen in schizophrenia. Clinical support for this comes from the fact that phencyclidine, a potent psychotomimetic, is a noncompetitive antagonist at the NMDA receptor, a major glutamate receptor. Similarly, abuse of ketamine, a veterinary anesthetic, can resemble schizophrenia. Ketamine, a competitive antagonist at glutamatergic NMDA receptors, has been shown to lead to reduction in D1neurotransmission through glutamatergic inhibition of DA release.20 It is proposed that schizophrenia may involve some in utero assault that leads to a developmental defect in NMDA receptor function—so-called NMDA hypofunction. This defect is proposed to have latent clinical expression with the psychotic manifestations from NMDA hypofunction not being seen until late adolescence or early adulthood. MicroRNAs, small noncoding RNAs, are critical to neurodevelopment as well as to regulation of adult neuronal processes. NMDA-regulated microRNA miR-132 is significantly downregulated in individuals with schizophrenia as compared with controls. Several genes are regulated by miR-132, and this altered expression may be related to NMDA hypofunction and the abnormal synaptic pruning seen in the brains of individuals with schizophrenia.21

Serotoninergic receptors are present on dopaminergic axons, and stimulation of these receptors decreases DA release, at least in the striatum.22 Although somewhat more diffuse, the distribution of serotonergic neurons is similar to that of dopaminergic neurons, thus allowing these two neurotransmitter systems to innervate the same areas. In fact, 5-hydroxytryptamine2 (serotonin-2; 5-HT2) receptors and D4 receptors have been found to be colocalized in the cortex.2,22 Patients with schizophrenia with abnormal brain scans have higher whole-blood serotonin (5-HT) concentrations, and these concentrations are correlated with increased ventricular size.22

Images Schizophrenia is a complex disorder, and multiple etiologies likely exist. Based on current knowledge, it is naive to think that any currently proposed etiology can adequately explain the genesis of this complex disease. Molecular research involving genetically determined subtle changes in microRNA, G proteins, protein metabolism, and other subcellular processes can eventually identify the biologic disturbances associated with schizophrenia.2,4,9,21


Schizophrenia is the most common functional psychosis, and great variability occurs in clinical presentation. Despite numerous attempts to portray a stereotype in movies and on television, the stereotypic schizophrenic essentially does not exist. Moreover, schizophrenia is not a “split personality.” It is a chronic disorder of thought and affect with the individual having a significant disturbance in interpersonal relationships and ability to function in society.

The first psychotic episode can be sudden in onset with few premorbid symptoms, or commonly can be preceded by withdrawn, suspicious, peculiar behavior (schizoid). During acute psychotic episodes, the patient loses touch with reality, and in a sense, the brain creates a false reality to replace it. Acute psychotic symptoms can include hallucinations (especially hearing voices), delusions (fixed false beliefs), and ideas of influence (beliefs that one’s actions are controlled by external influences). Thought processes are disconnected (loose associations), the patient may not be able to carry on logical conversation (alogia), and can have simultaneous contradictory thoughts (ambivalence). The patient’s affect can be flat (no emotional expression), or it can be inappropriate and labile. The patient is often withdrawn and inwardly directed (autism). Uncooperativeness, hostility, and verbal or physical aggression can be seen because of the patient’s misperception of reality. Self-care skills are impaired, and the patient is frequently dirty and unkempt, and in general has poor hygiene. Sleep and appetite are often disturbed. When the acute psychotic episode remits, the patient typically has residual features. This is an important point in differentiating schizophrenia from other psychotic disorders. Although residual symptoms and their severity vary, patients can have difficulty with anxiety management, suspiciousness, and lack of volition, motivation, insight, and judgment. Therefore, they often have difficulty living independently in the community. Because of poor anxiety management and suspiciousness, they are frequently withdrawn socially, and have difficulty forming close relationships with others. In addition, impaired volition and motivation contribute to poor self-care skills and make it difficult for the patient with schizophrenia to maintain employment.

Patients with schizophrenia frequently experience a lack of historicity, or difficulty in learning from their experiences. They can repeatedly make the same mistakes in social conduct and situations requiring judgment. They have difficulty understanding the importance of treatment, including medications, in maintaining their ability to function in society. Therefore, they tend to discontinue medications and other treatments, and this increases the risk of relapse and rehospitalization. The co-occurrence of substance abuse (predominantly alcohol or polysubstance—alcohol, cannabis, cocaine) in patients with schizophrenia is very common and is another frequent reason for relapse and hospitalization.1,2 This effect can be caused by direct toxic effects of these drugs on the brain,23 but is also caused by the medication nonadherence that is associated with substance abuse.

Although the course of schizophrenia is variable, the long-term prognosis for many patients is poor. It is marked by intermittent acute psychotic episodes and impaired psychosocial functioning between acute episodes, with most of the deterioration in psychosocial functioning occurring within 5 years after the first psychotic episode.23 By late life, the patient can appear “burned out,” that is, the patient ceases to have acute psychotic episodes, but residual symptoms persist. In a subpopulation of patients, probably 5% to 15%, psychotic symptoms are nearly continuous, and response to antipsychotics is poor.23

Schizophrenia is a chronic disorder, and the patient’s history must be carefully assessed for dysfunction that has persisted for longer than 6 months. After their first episode, patients with schizophrenia rarely have a level of adaptive functioning as high as before the onset of the disorder. Table 50-2 summarizes the DSM-IV-TR criteria for schizophrenia.1

TABLE 50-2 DSM-IV-TR Diagnostic Criteria for Schizophrenia


Images The DSM-IV-TR classifies the symptoms of schizophrenia into two categories: positive and negative. Recently greater emphasis has been placed on a third symptom category, cognitive dysfunction (Table 50-3).23 The areas of cognition found to be abnormal in schizophrenia include attention, working memory, and executive function. Positive symptoms have traditionally attracted the most attention and are the ones most improved by antipsychotics. However, negative symptoms and impairment in cognition are more closely associated with poor psychosocial function. Along with these characteristic features of schizophrenia, many patients also have comorbid psychiatric and general medical disorders.23 These include depression, anxiety disorders, substance abuse, and general medical disorders such as respiratory disorders, cardiovascular disorders, and metabolic disturbances. These comorbidities substantially complicate the clinical presentation and course of schizophrenia.

TABLE 50-3 Schizophrenia Symptom Clusters


It has been suggested that symptom complexes can correlate with prognosis, cognitive functioning, structural abnormalities in the brain, and response to antipsychotic drugs. Negative symptoms and cognitive impairment can be more closely associated with prefrontal lobe dysfunction and positive symptoms with temporolimbic abnormalities. Many patients demonstrate both positive and negative symptoms. Patients with negative symptoms frequently have more antecedent cognitive dysfunction, poor premorbid adjustment, low level of educational achievement, and a poorer overall prognosis.23


Desired Outcome

Pharmacotherapy is the mainstay of treatment in schizophrenia, and it is impossible in most patients to implement effective psychosocial rehabilitation programs in the absence of antipsychotic treatment.23 Images A pharmacotherapeutic treatment plan should be developed that delineates drug-related aspects of therapy. Most deterioration in psychosocial functioning occurs during the first 5 years after the initial psychotic episode, and treatment should be particularly assertive during this period.23 The individualized treatment plan created for each patient should have explicit end points defined, including realistic goals for the target symptoms most likely to respond, and the relative time course for response.23,24 Other desired outcomes include avoiding unwanted side effects, integrating the patient back into the community, increasing adaptive functioning to the extent possible, and preventing relapse.

Nonpharmacologic Therapy

Psychosocial rehabilitation programs oriented toward improving patients’ adaptive functioning are the mainstay of nondrug treatment for schizophrenia. These programs can include case management, psychoeducation, targeted cognitive therapy, basic living skills, social skills training, basic education, work programs, supported housing, and financial support. In particular, programs aimed at employment and housing have been the more effective interventions and are considered “best practices.” Programs that involve families in the care and life of the patient have been shown to decrease rehospitalization and improve functioning in the community. For particularly low-functioning patients, assertive intervention programs, referred to as active community treatment (ACT), are effective in improving patients’ functional outcomes. ACT teams are available on a 24-hour basis and work in the patient’s home and place of employment to provide comprehensive treatment, including medication, crisis intervention, daily living skills, and supported employment and housing.23,24 Medication treatment cannot be successful without proper attention to these other aspects of care. People with schizophrenia need comprehensive care, with coordination of services across psychiatric, addiction, medical, social, and rehabilitative services. The level of coordination in the United States is often insufficient, and patients become at risk to “fall through the cracks.” National policy documents have called for greater coordination of care.25 Additionally, emphasis is growing on the role that the patient plays in a recovery-based system of care, where the person’s lifetime aspirations and goals become the center of care, rather than symptom reduction being the primary focus. This recovery-based approach recognizes the strengths and resilience of people with schizophrenia.26 It also acknowledges how people with schizophrenia can also be a support to others who are coping with the illness.27 It is important to frame clinical decision making in the context of a mutual process involving patient and clinician—rather than a unilateral “here’s a prescription … please take these tablets” approach. It is increasingly recognized that cognitive behavioral therapy can help some patients. A list of psychotherapeutic approaches to the treatment of schizophrenia is given in Table 50-4.

TABLE 50-4 Psychotherapeutic Approaches to the Treatment of Schizophrenia


Pharmacologic Therapy

Images The importance of initial accurate diagnostic assessment cannot be overemphasized. A thorough mental status examination (MSE), psychiatric diagnostic interview, physical and neurologic examination, complete family and social history, and laboratory workup must be performed to confirm the diagnosis and exclude general medical or substance-induced causes of psychosis. Laboratory tests, biologic markers, and commonly available brain imaging techniques do not assist in the diagnosis of schizophrenia or selection of medication. A pretreatment patient workup not only is important in excluding other pathology but also serves as a baseline for monitoring potential medication-related side effects, and should include vital signs, complete blood count, electrolytes, hepatic function, renal function, electrocardiogram (ECG), fasting serum glucose, serum lipids, thyroid function, and urine drug screen.

Both first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) (with the exception of clozapine) are first-line agents in the treatment of schizophrenia.24,28 No absolute criterion distinguishes atypical (second-generation) from typical (traditional or FGA) antipsychotics, and no universally accepted definition exists for an atypical antipsychotic.22 Therefore, second-generation antipsychotic is a more appropriate term. Common to all definitions is the ability of the drug to produce antipsychotic response with few or no acutely occurring extrapyramidal side effects (EPS). Other attributes that have been ascribed to SGAs include enhanced efficacy (particularly for negative symptoms and cognition), absence or near absence of propensity to cause tardive dyskinesia, and lack of effect on serum prolactin.22 To date, the only approved SGA that fulfills all of these criteria is clozapine.22Although early studies suggested that SGAs might have a superior effect on negative symptoms and cognition, this has not been confirmed in more recent studies.2,24 The major factor in distinguishing among antipsychotics is adverse effects.29 The major advantage of SGAs is their lower risk of neurologic side effects, particularly effects on movement. However, this is offset by increased risk of metabolic side effects with some SGAs, including weight gain, hyperlipidemias, and diabetes mellitus. Images Side effect profiles differ among antipsychotics, and this information in combination with individual patient characteristics should be used in deciding which drug to use in an individual patient.

Results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study indicate that olanzapine, compared with quetiapine, risperidone, ziprasidone, and the FGA perphenazine, has modest, but not statistically significant, superiority in maintenance therapy when treatment persistence is the primary clinical outcome.29 However, increased metabolic adverse effects occurred with olanzapine.

No known differences exist in efficacy between low- and high-potency FGAs. Previous patient or family history of response to an antipsychotic is helpful in the selection of an agent. Table 50-5 lists antipsychotics and their usual dosage ranges.

TABLE 50-5 Available Antipsychotics and Dosage Ranges


Published Guidelines and an Algorithm Example

Images Figure 50-1 outlines a suggested pharmacotherapeutic algorithm for schizophrenia. This algorithm is based on the compilation of three evidence-based guidelines, the 2009 update of the practice guideline from the American Psychiatric Association (APA),30 the 2009 update of the Patient Outcomes Research Team (PORT) guidelines,28 and the 2012 update of the guidelines from the World Federation of Biological Psychiatry.31


FIGURE 50-1 Suggested pharmacotherapy algorithm for treatment of schizophrenia. Schizophrenia should be treated in the context of an interprofessional model that addresses the psychosocial needs of the patient, necessary psychiatric pharmacotherapy, psychiatric comorbidities, treatment adherence, and any medical problems the patient may have. See the text for a description of the algorithm stages. (Data from references 28, 30, and 31.)

Stage 1A of the treatment algorithm applies to those patients experiencing their first acute episode of schizophrenia. All available antipsychotics except clozapine are recommended for monotherapy treatment in stage 1A. The clinician needs to evaluate the relative risk of EPS with FGAs versus the risk of metabolic side effects with different SGAs in making a decision for drug selection. The World Federation favors SGAs because of the reduced risk of EPS.31 The 2009 PORT recommendations advise against the use of olanzapine in first episode because of weight gain and metabolic side effects.28,31 Compared with SGAs, haloperidol produced more pseudoparkin-sonism and a higher 1-year discontinuation rate in the European First Episode Schizophrenia Trial (EUFEST).30,31 If an FGA is used, it is better to use a moderate-potency antipsychotic such as loxapine or perphenazine. Among the more established SGAs, aripiprazole and ziprasidone produce the least weight gain. Because of the sensitivity to antipsychotic-induced EPS in first-episode patients, antipsychotic dosing should be initiated at the lower end of the dose range.31

Clinical Controversy

With no clear difference in efficacy among first-line antipsychotics, adverse effect profiles become the primary variable in choosing an antipsychotic. While the World Federation of Psychiatry Guidelines favor the SGAs as first-line antipsychotics, the PORT guidelines offer no preference, but do not recommend olanzapine in first psychotic break patients.

Stage 1B addresses those patients who have been previously treated with an antipsychotic, are currently off medications, and are experiencing a recurrent acute psychotic episode. Any antipsychotic monotherapy except clozapine is recommended. However, an antipsychotic that previously produced nonresponse or intolerance should not be used.31

Stage 2 addresses pharmacotherapy in a patient who had inadequate clinical improvement with the antipsychotic used in stage 1A or 1B. Stage 2 recommends an alternate antipsychotic monotherapy with the exception of clozapine.28,31 Because of safety concerns and the need for white blood cell (WBC) monitoring, it is recommended that patients be tried on two different monotherapy antipsychotic trials before proceeding to a trial of clozapine (stage 3).28,31 However, clozapine has superior efficacy in decreasing suicidal behavior, and it should be considered at stage 2 for the suicidal patient.28 Clozapine can also be considered at stage 2 in patients with a history of violence or comorbid substance abuse.28

If partial or poor adherence contributes to inadequate clinical improvement, then long-acting injectable antipsychotics should be considered.24,28,31 In addition to individuals who are identified as partially adherent, some patients may elect long-acting injections instead of taking daily oral medication.

In stage 3, treatment failure on two different antipsychotics from different classes meets the definition of treatment resistance, and the recommended treatment is clozapine.28,30,31

In stage 4, only minimal evidence exists for any treatment options for those patients who do not have adequate symptom improvement with clozapine. Additional treatment options that are tried, again with minimal evidence, include electroconvulsive therapy augmentation, mood stabilizer augmentation, and another antipsychotic combined with clozapine.28,31 The use of antipsychotic combinations is controversial, as limited evidence supports increased efficacy for combination antipsychotic treatment.28,31

Predictors of Response

Obtaining a thorough medication history is important, and previous antipsychotic treatment should help guide the selection of drug therapy, in that either a good prior response favors the use of the same agent or a negative prior response suggests the selection of a dissimilar drug. Nonprescription and illicit drug use can influence psychiatric presentation and thus diagnosis or antipsychotic response. Amphetamines and other CNS stimulants, cocaine, corticosteroids, digitalis glycosides, indomethacin, marijuana, pentazocine, phencyclidine, and other drugs can induce psychosis in susceptible individuals or exacerbate psychosis in patients with preexisting psychiatric illness.32Patients with schizophrenia who continue to abuse alcohol or drugs usually have a poor response to medications and a poor prognosis. Alcohol, caffeine, and nicotine use potentially results in drug interactions.

Individual differences in patient response have been either proposed or identified, which can be clinically useful predictors of response.23,24 Acute onset and short duration of illness, presence of acute stressors or precipitating factors, later age of onset, family history of affective illness, and good premorbid adjustment as reflected in stable interpersonal relationships or employment are all predictors of good response.23,24

Although controversial, affective symptoms can correlate with an overall good response. Negative symptoms and neuropsychological deficits related to cognition and neurologic soft signs can correlate with poor antipsychotic response.23,24 A patient’s subjective response within the first 48 hours after being administered an FGA can be associated with drug responsiveness.33 An initial dysphoric response, demonstrated by stating a dislike of the medication, or feeling worse or zombie-like, combined with anxiety or akathisia-like symptoms, is associated with poor drug response, adverse effects, and nonadherence.

The importance of developing a therapeutic alliance between the patient and the clinician cannot be underestimated. Patients who form positive therapeutic alliances are more likely to be adherent with all aspects of therapy, experience a better outcome at 2 years, and require smaller antipsychotic doses.

A certain minority of patients fail to benefit from antipsychotic therapy, and their psychosocial functioning can actually worsen. Unfortunately, no accepted method is available to identify these people before treatment.23,24Recent evidence suggests that pharmacogenetics can play a role in predicting treatment response, both with respect to symptom improvement and with liability to develop side effects.34,35However, insufficient information is available to recommend routine clinical testing.

Initial Treatment in an Acute Psychotic Episode

The goals during the first 7 days of treatment should be decreased agitation, hostility, combativeness, anxiety, tension, and aggression, and normalization of sleep and eating patterns. The usual recommendation is to initiate therapy and to titrate dose over the first few days to an average effective dose, unless the patient’s physiologic status or history indicates that this dose can result in unacceptable adverse effects. Because of its strong α1-antagonism and resulting risk of hypotension, iloperidone and clozapine should be titrated more slowly than other antipsychotics. Table 50-5 lists the usual dosage range, and an average dose is typically midrange. Because of increased sensitivity to side effects, particularly EPS, in first-episode psychotic patients, typical dosing ranges are approximately 50% of the doses used in chronically ill individuals.28,31 If “cheeking” of medication is suspected, liquid formulations and orally disintegrating tablets of different antipsychotics are available. If a patient has shown absolutely no improvement after 2 to 4 weeks at therapeutic doses, then an alternative antipsychotic should be considered (i.e., moving to the next treatment stage in the algorithm; see Fig. 50-1).22,23

Clinical Controversy

Minimal research evidence supports the use of antipsychotic doses beyond the dose range in the FDA-approved product labeling. However, clinicians frequently titrate doses above the approved range, and frequently attest to symptom improvement when this is done. It is unclear whether the observed symptom improvement is due to the increased dose, time on the antipsychotic, or just pure chance.

Although some clinicians believe that larger daily doses are necessary in more severely symptomatic patients, data are not available to support this practice. Some symptoms, such as agitation, tension, aggression, and increased motor activity, can respond more quickly, but side effects can be more common with higher doses. However, interindividual differences in dosage and patient response do occur. In partial but inadequate responders who are tolerating the chosen antipsychotic, it may be reasonable to titrate above usual dose ranges. However, this tactic should be time-limited (i.e., 2 to 4 weeks), and if the patient does not achieve further improvement, either the dose should be decreased or an alternative treatment strategy should be tried. In general, rapid titration of antipsychotic dosage is not indicated.23,28However, intramuscular antipsychotic administration (e.g., aripiprazole 5.25 to 9.75 mg IM, haloperidol 2 to 5 mg IM, olanzapine 2.5 to 10 mg IM, or ziprasidone 10 to 20 mg IM) can be used to assist in calming a severely agitated patient. Agitation can be manifested as loud, physically or verbally threatening behavior, motor hyperactivity, or physical aggression. Although this technique can assist in calming an acutely agitated psychotic patient, it does not improve the extent of remission, or time to remission, or the length of hospitalization. If haloperidol IM is used, the occurrence of EPS can eliminate some of the advantages of using an oral SGA. If the patient is receiving an antipsychotic within the usual therapeutic range, the use of lorazepam 2 mg IM as needed in combination with the maintenance antipsychotic is a rational alternative to an injectable antipsychotic. Hypotension, respiratory depression, CNS depression, and death are possible when injectable lorazepam is used in combination with either olanzapine or clozapine; thus, this parenteral combination is not recommended.30,31

The initial Risk Evaluation and Mitigation Strategy (REMS) for inhaled loxapine powder was approved by the FDA with an indication of treatment of acute agitation associated with schizophrenia or bipolar disorder. Because of the risk of bronchospasm, pulmonary distress, and pulmonary arrest, the medication can only be administered in a healthcare facility and through the FDA-approved REMS. Before administration, patients must be screened for a history of asthma, chronic obstructive pulmonary disease, or other lung disease associated with bronchospasm, and use is limited to one 10 mg inhaled dose per 24-hour period.36 It is not known whether inhaled loxapine offers any therapeutic advantages in acute agitation compared with currently available IM or oral products. Similarly, the safety of this product when used in routine clinical practice is unclear.

Stabilization Therapy

Improvement is usually a slow but steady process over 6 to 12 weeks or longer. During the first 2 to 3 weeks, goals should include increased socialization and improvement in self-care habits and mood. Improvement in formal thought disorder should follow and can take an additional 6 to 8 weeks to respond. Patients who are early in the course of their illness can experience a more rapid resolution of symptoms than individuals who are more chronically ill. In general, if a patient has no improvement with treatment after 2 to 4 weeks at therapeutic doses, or has achieved only a partial decrease in positive symptoms within 12 weeks at adequate doses, then the next algorithm stage should be considered. In more chronically ill patients, symptoms may continue to improve over 3 to 6 months. During acute stabilization, usual FDA-labeled doses of SGAs are recommended (see Table 50-5).24 An optimum dose of the chosen drug should be estimated in the initial treatment plan. If the patient begins to show adequate response before or at this dosage, then the patient should remain at this dosage as long as symptoms continue to improve. Images In general, adequate time on a therapeutic antipsychotic dose is the most important factor in predicting medication response. However, if necessary, dose titration can continue within the therapeutic range every 1 or 2 weeks as long as the patient has no side effects.

Before changing medications in a poorly responding patient, the following should be considered: Were the initial target symptoms indicative of schizophrenia or did they represent manifestations of a different diagnosis, a long-standing behavioral problem, a substance abuse disorder, or a general medical condition? Is the patient adherent with pharmacotherapy? Are the persistent symptoms poorly responsive to antipsychotics (e.g., impaired insight or judgment, or fixed delusions)? How does the patient’s current status compare with response during previous exacerbations? Would this patient potentially benefit from a change to a different treatment stage (see Fig. 50-1)? Does this patient have a treatment-resistant schizophrenic illness?

The conclusion that a partially responding patient has achieved as much symptomatic improvement as possible is one that must be made with great care. Treatment goals must be realistic. Medications are effective at decreasing many of the symptoms of schizophrenia (and are thus referred to as palliative), but they are not curative, and all symptoms may not abate. Although one should aim to achieve none to minimal residual positive symptoms with effective treatment, it is still unclear what a realistic goal is with regard to maximum improvement in negative symptoms.

It is important to screen patients for co-occurring mental disorders, and their presence can become more apparent during the stabilization or maintenance phases of schizophrenia treatment. Examples include substance abuse disorders, depression, obsessive-compulsive disorder, and panic disorder. As co-occurring disorders will limit symptom and functional improvement and increase the risk of relapse, it is critical that treatment for the co-occurring disorder be implemented in combination with evidence-based treatment for schizophrenia.

Maintenance Treatment

Maintenance drug therapy prevents relapse, as shown in numerous double-blind studies. The average relapse rate after 1 year is 18% to 32% with active drug (including some nonadherent patients) versus 60% to 80% for placebo.24,37 Avoiding relapses is thus a major goal of treatment.38

After treatment of the first psychotic episode in a patient with schizophrenia, medication should be continued for at least 12 months after remission.24,29,31 Images Many schizophrenia experts recommend that patients with robust medication response be treated for at least 5 years. In chronically ill individuals, continuous or lifetime pharmacotherapy is necessary in the majority of patients to prevent relapse. This should be approached with the lowest effective dose of the antipsychotic that is likely to be tolerated by the patient.24,29,31

Antipsychotics should be tapered slowly before discontinuation. Abrupt discontinuation of antipsychotics, especially clozapine, can result in withdrawal symptoms, felt to be a manifestation of rebound cholinergic outflow. Insomnia, nightmares, headaches, GI symptoms (e.g., abdominal cramps, stomach pain, nausea, vomiting, and diarrhea), restlessness, increased salivation, and sweating are reported. Although available evidence does not indicate a best way to switch from one antipsychotic to another, it is often recommended to taper and discontinue the first antipsychotic over at least 1 to 2 weeks while the second antipsychotic is initiated and the dose titrated.24,31 Tapering needs to occur more slowly with clozapine.24

Long-Acting Injectable Antipsychotics

Long-acting antipsychotics are recommended for patients who are unreliable in taking oral medication on a daily basis, and thus are not usually used as first-line therapy. Before a long-acting antipsychotic is initiated, it should be determined whether the patient’s medication nonadherence is because of side effects. If so, an alternative medication with a more favorable side effect profile should be considered before a long-acting injectable antipsychotic. The patient’s motivation for treatment is a major factor influencing outcome. Conversion from oral therapy to a long-acting injectable is most successful in patients who have been stabilized on oral therapy. The ideal patient for a long-acting injectable is the individual who does not like the daily reminder of oral medication or is unreliable in taking medications.

Paliperidone palmitate is a long-acting injectable that has the advantage of once-monthly injections and easy conversion from oral to IM treatment.39 Olanzapine pamoate monohydrate is a long-acting injectable that is administered every 2 or 4 weeks. It is associated with a postinjection sedation/delirium syndrome occurring in approximately 2% of patients.40 The risk of occurrence does not appear related to dose or duration of treatment. One hypothesis is that its occurrence may be associated with accidental entry of the drug into the bloodstream.40 The product labeling contains an FDA black box warning regarding this syndrome. Olanzapine pamoate is subject to a REMS, and the FDA labeling restricts the availability of long-acting olanzapine to a restricted distribution program. The injection must be administered in a registered healthcare facility, and the patient must be observed by a health professional for at least 3 hours after administration.41 A long-acting formulation of aripiprazole is under FDA review at the time of publication, and a once-weekly oral formulation is in development.

Conversion from an oral antipsychotic to a long-acting medication should start with stabilization on an oral dosage form of the same agent, for a short trial (3 to 7 days), to determine whether the patient tolerates the medication without significant side effects. With long-acting risperidone, measurable serum concentrations are not seen until approximately 3 weeks after single-dose administration. Thus, it is important that the oral antipsychotic be administered for at least 3 weeks after beginning the injections. Dose adjustments are recommended to be made no more often than once every 4 weeks.42 The recommended starting dose with risperidone long-acting injection is 25 mg, and clinical experience suggests that titration to doses greater than or equal to 37.5 mg per injection may be necessary for maintenance treatment. Long-acting risperidone has demonstrated efficacy, with an optimum dose range between 25 and 50 mg given IM every 2 weeks. Doses above 50 mg every 2 weeks are not recommended, as research indicates no greater efficacy but more EPS.42

Paliperidone palmitate can be injected into either the deltoid or the gluteal muscle, and treatment is initiated with 234 mg on day 1 and 156 mg a week later. No overlap with oral drug is necessary. Monthly IM doses are then titrated according to response within a range of 39 to 234 mg.39 Olanzapine pamoate monohydrate is recommended for deep gluteal injection, and the initial injectable dose varies from 210 to 405 mg depending on the oral olanzapine daily maintenance dose and the frequency of injectable administration. The official product information should be consulted regarding preparation and administration information.40,41

For fluphenazine decanoate, the simplest dosing conversion method recommends 1.2 times the oral fluphenazine daily dose for stabilized patients, rounding up to the nearest 12.5-mg interval, administered in weekly doses for the first 4 to 6 weeks; or 1.6 times the oral daily dose for more acutely ill patients.43 Subsequently, fluphenazine decanoate can be administered once every 2 to 3 weeks. Oral fluphenazine can be overlapped for 1 week. For haloperidol decanoate, a factor of 10 to 15 times the oral haloperidol daily dose is commonly recommended, rounding up to the nearest 50-mg interval, administered in a once-monthly dose with an oral haloperidol overlap for the first month. A more assertive conversion method recommends 20 times the oral daily dose, but dividing the injection into consecutive doses of 100 to 200 mg every 3 to 7 days until the entire amount is given.44 With this method, oral medication overlap is unnecessary. The haloperidol decanoate dose is decreased by 25% at both second and third months.

Methods to Enhance Patient Adherence

It is often challenging for individuals with chronic illnesses to maintain appropriate medication adherence, and partial compliance is a reality in the treatment of all chronic illnesses.31 Individuals with serious mental disorders have somewhat higher nonadherence rates than those with general medical disorders, with the following explanations provided: denial of illness, lack of insight, grandiosity or paranoia, no perceived need for medication, perceived lack of input into choice of medication or dosage, side effects, misperceived “allergies,” or the number of medications prescribed or doses received daily. It is estimated that half of patients with schizophrenia or schizoaffective disorder take their medication less than 70% of the time.31 Clinicians should expect partial medication compliance to be the norm. This should be approached in a nonjudgmental manner, with the clinician actively engaging the patient in care and using motivational interviewing techniques as mechanisms to enhance therapeutic alliance and patient adherence.

Numerous different methods have been used in an attempt to improve treatment adherence of patients with schizophrenia. Interventions that provide continuous focus on adherence and that are of long duration have shown benefit. These should incorporate problem solving techniques and be accompanied by technical learning aids. Pharmacy-based interventions and ones using nurse case managers have shown promise in improving adherence.45 It has been suggested that programs need to include a focus on patient-driven outcomes, and not just medication adherence. For example, interventions should include efforts to allow patients to achieve life goals and function. This requires that programs be tailored to the needs of individual patients.45 Psychoeducation strategies should include motivational interview techniques in individual counseling as well as group activities. Images

Some studies suggest that compliance therapy, targeted cognitive behavioral therapy focusing on medication adherence, can improve patient adherence, but the success seen in early studies has not been consistently replicated.45

Groups facilitated by trained individuals who have the illness are alleged to be more effective in enhancing awareness and acceptance of schizophrenia and necessary treatment than groups led only by professionals. Active involvement of family members further increases the likelihood of patient adherence with treatment. In addition to programs provided by community mental health centers, support groups operated by consumer groups such as the National Alliance on Mental Illness (NAMI) are available in most urban areas. In the hospital, self-medication administration can reinforce the patient’s perception of his or her active role in his or her own treatment. When patients miss outpatient appointments, active outreach interventions must be implemented to enhance patient engagement in treatment.24,45

Management of Treatment-Resistant Schizophrenia

In general, “treatment resistant” describes a patient who has had inadequate symptom response from multiple antipsychotic trials.24 Traditionally, treatment resistance has been defined as lack of improvement in positive symptoms, but it can be defined by poor improvement in negative symptoms, or even by medication intolerance. Between 10% and 30% of patients receive minimal symptomatic improvement after multiple FGA monotherapy trials.24 An additional 30% to 60% of patients have partial but inadequate improvement in symptoms or unacceptable side effects associated with antipsychotic use.24,31 In those patients failing two or more pharmacotherapy trials, a treatment-refractory evaluation should be performed to reexamine diagnosis, substance abuse, medication adherence, and psychosocial stressors. Targeted cognitive behavioral therapy or other psychosocial augmentation strategies should be considered.31


Only clozapine has shown superiority over other antipsychotics in randomized clinical trials for the management of treatment-resistant schizophrenia. Most other SGAs have either not been studied in treatment-refractory patients or been evaluated in small open trials. In a seminal study, clozapine was effective in approximately 30% of patients with treatment-resistant schizophrenia, compared with only 4% treated with a combination of chlorpromazine and benztropine.46 The criteria for treatment resistance require two treatment failures, and include both FGAs and SGAs. Other treatment candidates for clozapine include those patients who cannot tolerate neurologic side effects of even conservative doses of other antipsychotics.

Clinical Controversy

Although clozapine is the only treatment that has evidence of proven benefit in patients with treatment-resistant schizophrenia, and its use in treatment-resistant schizophrenia is recommended in all treatment guidelines, it is underutilized by clinicians in practice. Although the reasons for its underutilization are not totally understood, factors may include clinician fear of clozapine’s potential adverse effects, the WBC monitoring required by the FDA, and mental health treatment systems that do not support use of the drug.

Symptomatic improvement with clozapine in the treatment-resistant patient often occurs slowly, and as many as 60% of patients may improve if clozapine is used for up to 6 months. This, in combination with clozapine’s adverse effect profile, provides sufficient information to conclude that clozapine is not a panacea for schizophrenia. Polydipsia and hyponatremia (psychogenic water drinking) is a frequent problem among treatment-resistant patients, and clozapine reportedly decreases water drinking and increases serum sodium in such patients.47

Because of the risk of orthostatic hypotension, clozapine is usually titrated more slowly than other antipsychotics, particularly on an outpatient basis. If a 12.5-mg test dose does not produce hypotension, then clozapine 25 mg at bedtime is recommended, increased to 25 mg twice a day after 3 days, and then increased in 25 to 50 mg/day increments every 3 days until a dose of at least 300 mg/day is reached. Because high doses are associated with significantly increased side effects, including seizures, a clozapine serum concentration is recommended before exceeding 600 mg/day. If the clozapine serum concentration is less than 350 ng/mL (350 mcg/L; 1.07 μmol/L), then the dose should be increased as side effects allow to achieve this serum concentration.31

Augmentation and Combination Strategies

Little empirical evidence exists to guide treatment decisions for patients who do not respond to clozapine.28,31 Augmentation therapy involves the addition of a nonantipsychotic drug to an antipsychotic drug in a poorly or partially responsive patient, whereas combination treatment involves using two antipsychotics simultaneously.

Mood stabilizers are frequently used as an augmentation strategy. Lithium does not enhance antipsychotic effect but may improve labile affect and agitated behavior in selected patients.48 Valproic acid and carbamazepine have also been used. A large placebo-controlled trial supports faster symptom improvement, but no difference in maintenance treatment, when divalproex was used in combination with either olanzapine or risperidone.49 Enzyme induction with carbamazepine can cause a decrease in antipsychotic serum concentrations and potentially worsen psychotic symptoms in some patients.24,31 The 2009 PORT recommendations do not endorse the use of mood stabilizer augmentation in treatment-resistant patients.28

Only limited data are available to support antidepressant augmentation of antipsychotics.31 Consistently positive results have been reported when using selective serotonin reuptake inhibitors (SSRIs) to treat obsessive-compulsive symptoms that worsen or arise during clozapine treatment.

Combining an FGA with an SGA and combining different SGAs have been suggested as intervention strategies for treatment-resistant patients. Pharmacodynamically, there is limited rationale for explaining how combinations of antipsychotics would produce enhanced efficacy, and increased side effects, particularly increased EPS, metabolic effects, and hyperprolactinemia, are possible results.50 Clinically, no evidence exists to prove that antipsychotic combinations are superior to monotherapy, and the 2009 PORT recommendations do not support their use.28 However, a recent meta-analysis did find a modest benefit for the use of polypharmacy in schizophrenia.51 This remains a highly contentious area and one where clinicians’ practice is not aligned with available evidence. In general, a series of antipsychotic monotherapies, including clozapine, are preferred over antipsychotic combinations.28 However, when clozapine fails to produce desired outcomes, a time-limited combination trial is sometimes considered.31Such antipsychotic combination treatment trials should be time-limited (e.g., maximum 12 weeks) and the patient carefully evaluated with rating scales for changes in symptomatology. If no apparent improvement is observed, then one of the medications should be tapered and discontinued. However, if the patient has a partial response (greater than or equal to 20% improvement in positive symptoms) after 12 weeks with combination treatment, medications should be titrated to doses at the upper end of the therapeutic range, and treatment should continue for an additional 12 weeks before a change in treatment is considered.

Clinical Controversy

Although insufficient evidence exists to support the use of antipsychotic combination treatment and guidelines such as PORT do not recommend this practice, antipsychotic polypharmacy is common. It is well known that clinicians frequently do not follow evidence-based treatment guidelines.

Patients with Schizophrenia who are Violent

Most patients with schizophrenia do not exhibit violent behavior—perhaps this is even surprising given the severity and stress of hearing voices, being paranoid, etc. That said, there are nevertheless patients who do become violent, and then, as a group, patients with schizophrenia are more likely to be violent than the general population. Risk factors for violence include those associated with violence in the general population (e.g., childhood trauma and exposure to violence, alcohol and substance abuse, psychopathy, access to firearms) and (to some lesser extent) psychotic symptoms.52 Patients are at risk to become violent when they relapse and so keeping patients with schizophrenia clinically stable is a major consideration. Some states even have outpatient commitment laws where patients at risk of violence are “forced” to get ongoing care, and if they default, they are sent back to the hospital. Patients who are really dangerous are invariably contained either in the legal system itself or legally as “forensic” patients where they are held by court order in a psychiatric facility.

Antipsychotic Mechanism of Action

The exact mechanism of action of antipsychotics is unknown. It has been suggested that antipsychotics be classified into three different categories: (a) typical or traditional (high D2 antagonism and low 5-HT2A antagonism); (b) atypical (moderate to high D2 antagonism and high 5-HT2A antagonism); and (c) atypical clozapine-like (low D2 antagonism and high 5-HT2A antagonism).53,54 With the exception of aripiprazole, all current SGAs have a greater affinity for 5-HT2A receptors than D2 receptors.

Studies of antipsychotic receptor binding in humans have used PET scans to examine neurotransmitter receptor binding at steady state, 12 hours postdose in small numbers of individuals. At least 60% to 65% D2 receptor occupation is necessary to decrease positive psychotic symptoms, whereas blockade of approximately 77% or more of D2 receptors is associated with EPS.53,55 FGAs are DA receptor antagonists with high affinity for D2 receptors. During chronic treatment with these agents, between 70% and 90% of D2 receptors in the striatum are usually occupied. In contrast, during clozapine treatment only 38% to 47% of D2 receptors are occupied, even with high doses. Newer SGAs have variable D2 binding. With low-dose risperidone (2 to 5 mg/day), D2 binding ranges from 60% to 79%, but with doses greater than 6 mg daily, binding commonly exceeds the 77% threshold associated with the development of EPS. Risperidone 2 mg/day produces 5-HT2A binding greater than 70%, and with 4 mg/day it is nearly 100%.53,56Olanzapine 10 to 20 mg/day produces D2 binding ranging from 71% to 80%, whereas at 30 to 40 mg/day, it ranges from 83% to 88%. At 5 mg/day, 5-HT2A receptors are near saturation of binding.53Ziprasidone has the highest 5-HT2A-to-D2 affinity ratio of any of the currently available antipsychotics. It is also a potent 5-HT1Aagonist.57

Quetiapine has the lowest D2 binding. At doses of 300 to 600 mg/day, 12-hour postdose D2 binding ranges from 0% to 27%. Even at quetiapine 800 mg/day, only 30% of D2 receptors are occupied. At these same daily doses, 45% to 90% of 5-HT2A receptors are occupied. However, when quetiapine D2 binding is examined 2 to 3 hours postdose, 58% and 64% of receptors were occupied with 400 and 450 mg, respectively. Transient blockade of DA receptors may be adequate to produce antipsychotic effect, but long-term D2 blockade is required for production of EPS and sustained hyperprolactinemia. Low D2binding, and thus atypicality, can be directly associated with how rapidly the antipsychotic disassociates from the D2 receptor.53,56 The availability of aripiprazole, a partial agonist at D2 receptors, represents a further elaboration of the DA hypothesis of antipsychotic action.54,58 It is proposed that aripiprazole works as a functional partial agonist. Aripiprazole is a rather weak 5-HT2A antagonist but a potent 5-HT1Aagonist.54,58

Iloperidone has high affinity for D2, D3, and 5-HT2A receptors, and moderate affinity for D4, 5-HT6, 5-HT7, and α1-receptors.59 Asenapine has high affinity for 5-HT2A and D2 receptors as well as for α1- and histamine-1 receptors. D2 occupancy of approximately 80% is predicted to occur with a sublingual dose of 5 to 10 mg twice daily.60 It is clear that the SGAs differ in their mechanisms of action and most likely in the manner in which they produce an atypical clinical profile.

The primary therapeutic effects of FGAs are thought to occur in the limbic system, including the ventral striatum, whereas EPS are thought to be related to DA blockade in the dorsal striatum. 5-HT2Aantagonism in combination with modest D2 blockade leads to release of DA in the prefrontal cortex, and this is one explanation for the decrease in negative symptoms and improvement in cognition reported with atypical antipsychotics.

Antipsychotics vary in their effects on other neurotransmitter receptor systems.53,54,56 Although the significance of these different mechanisms on efficacy is unclear, they do potentially explain differences in side effect profiles. These differences in pharmacodynamic profiles point out that the SGAs are not all alike, and patients obtaining an inadequate clinical response (either efficacy or side effects) with one antipsychotic may have a superior response on an alternate drug. Thus, serial SGA monotherapy trials should be tried in patients receiving a suboptimal clinical response (see Fig. 50-1).


As a class, antipsychotics are highly lipophilic and highly bound to membranes and plasma proteins. They distribute readily into most tissues with a high blood supply and can accumulate in tissues; therefore, they have large volumes of distribution.61 Most antipsychotics are largely metabolized, primarily through the cytochrome P450 (CYP) pathways in the liver, except for ziprasidone, which is largely metabolized by aldehyde oxidase. Fluphenazine, perphenazine, and risperidone are metabolized through CYP2D6, and thus are susceptible to polymorphic metabolism.62 This is also one of the major pathways for the metabolism of aripiprazole and iloperidone.59 Thirty percent to 35% of Africans and Asians are slow to intermediate metabolizers. Approximately 0% to 5% of African Americans, 1% of Asians, and 5% to 10% of whites are poor metabolizers.62,63 In addition, some people of Swedish descent and up to 30% of those from Northern Africa may be ultrarapid metabolizers.63 Polymorphism in CYP1A2 can potentially result in a decrease in the metabolic rate of clozapine, and increased clozapine metabolic rate in smokers has been linked to a specific genotype.62 The possibility of genetic polymorphism should be considered when dosing and monitoring the clinical effects of antipsychotics. Table 50-6 outlines the prominent metabolic pathways of selected antipsychotics.

TABLE 50-6 Pharmacokinetic Parameters of Selected Antipsychotics


Asenapine is unique in that it has less than 2% bioavailability after oral administration, but has a bioavailability of approximately 35% sublingually—the FDA-approved route of administration. Eating and drinking within 10 minutes after sublingual administration will reduce bioavailability.60

Most antipsychotics have fairly long elimination half-lives, generally 24 hours or more, with the exception of quetiapine and ziprasidone, which have short half-lives.58,61 Among the SGAs, only clozapine has an established therapeutic serum concentration, with efficacy being associated with a clozapine plasma concentration greater than 350 ng/mL (350 mcg/L; 1.07 μmol/L).61 Whether a potential maximum therapeutic clozapine serum concentration exists is unknown. Clozapine serum concentration should be obtained before exceeding 600 mg daily, in patients who develop unusual or severe adverse side effects, in patients who are taking concomitant medications that can cause drug interactions, in patients who have age or pathophysiologic changes suggesting a change in pharmacokinetics, or for assessment of patient adherence.37,61

Adverse Effects

Table 50-7 presents the relative incidence of common categories of antipsychotic side effects. Side effects are discussed below with respect to organ system affected. A general approach to monitoring and assessing side effects requires prospective monitoring by clinicians, preferably using a thorough review of systems approach. Patient-oriented self-rated side effect scales can be helpful, as many patients with schizophrenia do not readily complain of side effects.

TABLE 50-7 Relative Side Effect Incidence of Commonly Used Antipsychoticsa,b


With the variety of antipsychotics currently available, using an alternative antipsychotic should be considered in patients who complain of poorly tolerated side effects. Because medication side effects are one of the primary predictors of patient nonadherence, the clinician should take advantage of the treatment options currently available in an attempt to improve patient outcomes. As we learn more about relative side effect risks (e.g., weight gain, glucose intolerance, QTc prolongation, acute EPS, and tardive dyskinesia), it will be necessary to regularly reconsider which antipsychotics should be considered first-line treatment alternatives.

Endocrine System

DA blockade in the tuberoinfundibular tract results in increased prolactin levels as DA is the major prolactin-inhibiting factor. Hyperprolactinemia may occur in up to 87% of patients treated with FGAs, risperidone, or paliperidone. The major side effects associated with hyperprolactinemia are gynecomastia, galactorrhea, menstrual irregularities, decreased libido, and sexual dysfunction. Although not conclusive, chronic hyperprolactinemia has been associated with decreased bone mineral density. Tolerance does not appear to develop to antipsychotic-induced hyperprolactinemia. Newer antipsychotics including asenapine, iloperidone, and lurasidone have not been shown to induce clinically meaningful changes in prolactin levels.59,60,64 Switching to an SGA that has minimal sustained effect on prolactin is a reasonable treatment option.65

Weight gain is frequently reported in both adults and children receiving antipsychotics.65,66 Although the exact mechanism is uncertain, weight gain has been associated with antihistaminic effects, antimuscarinic effects, and blockade of 5-HT2C receptors including 5-HT2C receptor polymorphism. However, dietary factors and activity levels can play a significant role in this population, as does renourishment after a period of poor self-care. In particular, significant weight gain, as defined by greater than or equal to 7% of the baseline body weight, after 1 year of treatment has been seen in as many as 80% of patients treated with olanzapine, 58% treated with risperidone, 50% treated with quetiapine, and 21% treated with iloperidone.65,67 The risk of weight gain may be greater in patients with their first psychotic episode. Ziprasidone and aripiprazole, as well as newer agents asenapine and lurasidone, are associated with minimal weight gain.60,64

The risk of cardiovascular-related mortality is higher in individuals with schizophrenia,65,68 and this is further aggravated by drug-related weight gain and the high prevalence of smoking. Additionally, obesity is a risk factor for diabetes mellitus.65 Weight gain during treatment is concerning for patients and a major reason for poor medication adherence.69

Several different genetic variations have been correlated with predisposition for antipsychotic-associated weight gain. Recent meta-analysis of all genetic studies looking at the –759 C/T promoter region polymorphism of the 5-HT2C receptor gene confirmed an association of 5-HT2C in antipsychotic-induced weight gain.70 Polymorphisms in leptin and leptin receptor genes have also been linked with clozapine- and olanzapine-associated weight gain.71,72Alfa-2a-adrenergic receptor gene, G protein β3 subunit gene, and brain-derived neurotrophic factor (BDNF) gene have been genetic targets; however, results are inconsistent as to whether a relationship exists with these polymorphisms and antipsychotic-associated weight gain.7376

Several approaches have been recommended to address weight gain. Stroup et al. have shown that switching the antipsychotic to another agent with less weight gain liability is one choice.77 Another choice is to add one of the weight-reducing agents.7880 Dietary restriction, exercise, and behavior modification programs are reported to be successful in small short-term studies.81 An American Diabetes Association consensus task force recommends consideration of a change in antipsychotic if a patient gains more than 5% of baseline body weight after starting the drug.82

Clinical Controversy

Although weight gain with antipsychotics is a major challenge in psychiatry, no clear consensus currently exists regarding how to address weight gain in these patients.

Patients with schizophrenia have a higher prevalence of type 2 diabetes than the nonschizophrenic population. Beyond this, antipsychotics may adversely affect glucose levels in diabetic patients. The extent to which these effects are related to drug-induced weight increase is unclear.66,81 Data collected from the FDA MedWatch Drug Surveillance System for clozapine, olanzapine, quetiapine, and risperidone indicate that nearly 60% of the new-onset diabetes reported occurred within the first 6 months of treatment initiation.65 Clozapine and olanzapine have the highest risk of new-onset diabetes followed by risperidone and then quetiapine. Although likely less than with the other SGAs, inadequate data are available to accurately estimate the risk with ziprasidone and aripiprazole.65 The 2009 PORT recommendations do not recommend olanzapine as a first-line antipsychotic option.28 In March 2004, the FDA issued a safety alert requiring revisions in the labeling of all SGAs that describes the increased risk of diabetes mellitus in patients taking atypical antipsychotics.83 Designing care models and standards for managing diabetes in patients with schizophrenia is important in addressing this major health problem.

Cardiovascular System

Orthostatic Hypotension Orthostatic hypotension is thought to be caused by α-adrenergic blockade, and may occur in up to 75% of treated patients.84 Clozapine, iloperidone, quetiapine, and risperidone appear to have the greatest risk and should have their doses titrated over several days to decrease the risk of symptomatic hypotension.85 Antipsychotic combination treatment may result in a greater risk of orthostasis.84 Orthostatic hypotension can occur in any patient, but diabetic patients with preexisting cardiovascular disease and the elderly seem particularly predisposed. Other risk factors may include dehydration and presence of alcoholic neuropathy.85 Patients should be advised to slowly move to the standing position to allow for adaptation. Tolerance to this effect may occur within 2 to 3 months. If not, lower doses or a change to an antipsychotic with less α-blockade can be attempted. Fluid resuscitation or increasing salt intake may also help minimize orthostatic blood pressure changes.85

Electrocardiographic Changes Among the antipsychotics, thioridazine, clozapine, iloperidone, and ziprasidone are most likely to cause ECG changes. ECG changes include increased heart rate (through sinus tachycardia from anticholinergic effects, or reflex tachycardia from α-adrenergic blockade), flattened T waves, ST segment depression, and prolongation of QT and PR intervals. The most clinically important of these potential changes is prolongation of the QTc, which has been associated with ventricular arrhythmias, including torsade de pointes syndrome. This is thought to occur as a result of blockade of the cardiac delayed potassium rectifier channel.86 Thioridazine has been shown to prolong the QTc on average approximately 20 milliseconds longer than haloperidol, risperidone, olanzapine, or quetiapine.84,86Thioridazine’s effect on QTc prolongation is dose related, and has led to a black box warning in the FDA-approved product labeling. In the same study, ziprasidone prolonged the QTc by approximately 10 milliseconds or about one half of the effect of thioridazine.84 Widespread clinical use suggests that ziprasidone’s effects on the ECG are not commonly associated with clinical sequelae, unless the patient has baseline risk factors.84 Iloperidone has a dose-related effect on QTc, with an average prolongation of about 9 milliseconds at a dose of 20 to 24 mg/day.59 Iloperidone is subject to polymorphic metabolism and there may be an increased risk of QTc prolongation in CYP2D6 slow metabolizers.87 High IV doses of haloperidol elevate the risk of prolonged QTc, which also carries a black box warning in the FDA-approved product labeling.88 Although the precise point at which QTc prolongation becomes clinically dangerous is unclear, it has been recommended to discontinue a medication associated with QTc prolongation if the interval consistently exceeds 500 milliseconds.

Greater caution regarding antipsychotic choice and use is necessary in the elderly, in patients with preexisting cardiac or cerebrovascular disease (including bradycardia and second- or third-degree AV block), and in patients taking diuretics or medications that may prolong the QTc.84,88 Being female confers a longer QTc, and twice the risk of medication-induced torsade de pointes.88 In patients older than 50 years of age, a pretreatment ECG is recommended, as are baseline serum potassium and magnesium levels. These factors should be considered in antipsychotic selection.

Sudden Cardiac Death A large retrospective analysis found that the risk of sudden cardiac death (SCD) with use of FGAs and SGAs was twice that of nonusers,84,89 with risk increasing with escalated dose. It has been estimated that 15 cases of SCD occur per 10,000 years of antipsychotic exposure.86 Further meta-analysis has conferred a lack of evidence for differential effects on cardiovascular mortality favoring one class of antipsychotics over the other.84,89 Further prospectively designed studies are needed to confirm a dose-dependent increase in cardiovascular sudden death with antipsychotic use, and to determine whether certain antipsychotics are associated with a greater risk than others.

Lipid Changes

Treatment with at least some SGAs and phenothiazines appears associated with elevations in serum triglycerides and cholesterol. Oxidation of apolipoprotein B lipoproteins and elevations in sterol regulatory element binding protein-controlled gene expression are among the purported mechanisms by which these lipid changes occur during antipsychotic treatment.90,91 Among the SGAs, less risk for change in serum lipid or cholesterol levels can occur with risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, and lurasidone.60,64,65,67,68 In the CATIE trial, olanzapine was associated with greater and significant adverse effects on metabolic parameters, including lipids, blood glucose, and body weight versus the other study treatments, but these differences in tolerability did not affect discontinuation rates.29

The occurrence of weight gain, diabetes, and lipid abnormalities during antipsychotic therapy is consistent with the development of metabolic syndrome (i.e., syndrome X). Cohorts of patients with schizophrenia have shown elevated prevalence of metabolic syndrome as compared with general population cohorts. Prevalence rates of metabolic syndrome in U.S. populations treated with antipsychotics range from 28% to 60%, with 40.9% reported in the prospectively designed CATIE trial.92

Metabolic syndrome consists of raised triglycerides (greater than or equal to 150 mg/dL [1.70 mmol/L]), low HDL cholesterol (less than or equal to 40 mg/dL [1.03 mmol/L] for males, less than or equal to 50 mg/dL [1.29 mmol/L] for females), elevated fasting glucose (greater than or equal to 100 mg/dL [5.6 mmol/L]), blood pressure elevation (greater than or equal to 130/85 mm Hg), and weight gain (abdominal circumference greater than 102 cm [40 in] for males, greater than 88 cm [35 in] in females).65,68 These abnormalities dictate an important role for general health screening and monitoring in patients with schizophrenia, and prompt intervention when such abnormalities occur. The propensity of individual antipsychotics to produce metabolic disturbances should be considered in the context of individual patient risk factors at the time of drug selection.

Anticholinergic Effects

Patients receiving antipsychotics or antipsychotics in combination with anticholinergics can experience anticholinergic side effects (e.g., dry mouth, constipation, tachycardia, blurred vision, inhibition or impairment of ejaculation, urinary retention, or impaired memory). This is particularly so with low-potency FGAs, and the elderly are especially sensitive to these effects. Of the SGAs, clozapine and olanzapine have moderately high rates of causing anticholinergic effects. Constipation, caused by slowed peristaltic movement and decreased intestinal fluid content, should be closely monitored and treated, especially in the elderly. Paralytic ileus and necrotizing enterocolitis can also occur.


Extrapyramidal System

Dystonia Dystonia is a state of abnormal tonicity, sometimes described simplistically as a severe “muscle spasm.”93,94 More accurately, dystonias are prolonged tonic contractions, with a rapid onset, usually within 24 to 96 hours of dosage initiation or dosage increase. They can be life-threatening, as in the case of pharyngeal–laryngeal dystonias, and can contribute to patient nonadherence. Types of dystonic reactions include trismus, glossospasm, tongue protrusion, pharyngeal–laryngeal dystonia, blepharospasm, oculogyric crisis, torticollis, and retrocollis. Dystonic reactions occur primarily with FGAs. Risk factors include younger patients (especially males), the use of high-potency agents, and high dosage. The overall incidence from the 1960s to the mid-1970s ranged from 2.3% to 10%, but as higher-potency traditional antipsychotics became more widely used, the rate increased to as high as 64%.

Intramuscular or IV anticholinergics (Table 50-8) or benzodiazepines are the treatments of choice for dystonia. Benztropine 2 mg or diphenhydramine 50 mg can be given intramuscularly or IV. Diazepam 5 to 10 mg by slow IV push or lorazepam 1 to 2 mg intramuscularly is a treatment alternative. Relief is typically seen within 15 to 20 minutes of an intramuscular injection and within 5 minutes of IV administration. The antipsychotic can be continued, with concomitant short-term use of oral anticholinergic agents. In general, prophylactic anticholinergic medications are not recommended routinely with all FGAs. However, prophylaxis is reasonable when using high-potency FGAs (e.g., haloperidol or fluphenazine) in young men, and in patients with a history of dystonia.94 Dystonias can also be minimized by the use of lower initial FGA doses. Anticholinergics are good choices for prophylaxis, whereas amantadine has not been proven effective for this purpose. The risk of dystonia is greatly reduced with SGAs.

TABLE 50-8 Agents Used to Treat Extrapyramidal Side Effects


Akathisia Akathisia is defined as the inability to sit still and as being functionally motor restless. The most accurate diagnosis is made by combining subjective complaints with objective symptoms (pacing, shifting, shuffling, or tapping feet). Subjectively, patients may describe a feeling of inner restlessness or disquiet or a compulsion to move or remain in constant motion. Akathisia occurs in 20% to 40% of patients treated with high-potency FGAs.93,94 It is frequently accompanied by dysphoria.

Akathisia responds poorly to anticholinergics.93,94 Traditionally, reduction in antipsychotic dosage has been considered the best intervention; however, this might not be a realistic goal in an acutely psychotic patient. A logical alternative is to switch to an antipsychotic with a lower risk of akathisia, or an antipsychotic previously used in the patient without adverse effect. Akathisia can occasionally occur with SGAs, particularly aripiprazole and risperidone. Quetiapine and clozapine appear to have the lowest risk of producing akathisia.93,94

Benzodiazepines have been used for treatment of akathisia, but the high prevalence of co-occurring substance abuse in schizophrenia discourages their prescribing.94 The β-blockers (e.g., propranolol in doses up to 160 mg daily, nadolol in doses up to 80 mg daily, and metoprolol in β2-selective doses of 100 mg daily or less) are reported as effective.94

Pseudoparkinsonism Pseudoparkinsonism, produced by D2 blockade in the nigrostriatum, resembles idiopathic Parkinson’s disease. A patient with pseudoparkinsonism can present with any of four cardinal symptoms: (a) akinesia, bradykinesia, or decreased motor activity including difficulty initiating movement, as well as extreme slowness, mask-like facial expression, micrographia, slowed speech, and decreased arm swing; (b) tremor, known as pill-rolling type, that is predominant at rest and decreases with movement, usually involving the fingers and hands, although tremors can also be seen in the arms, legs, neck, head, and chin; (c) cogwheel rigidity, seen as the patient’s limbs yielding in jerky, ratchet-like fashion when passively moved by the examiner; and (d) postural abnormalities and instability manifested as stooped posture, difficulty in maintaining stability when changing body position, and a gait that ranges from slow and shuffling to festinating. Fatigue and weakness can be noted, as well as oral abnormalities including dysphagia, dysarthria, and abnormal palmomental and glabellar reflexes. The overall incidence of pseudoparkinsonism from FGAs ranges from 15.4% to 36%, depending on the drug and dose. Akinesia alone can be seen in 59% of patients on high-potency FGAs. Other risk factors include increasing age and possibly female gender. The onset of symptoms is typically 1 to 2 weeks after initiation of antipsychotic therapy or a dose increase.

The efficacy of anticholinergic medications in treating symptoms of pseudoparkinsonism is well established.93,94 Interestingly, recent meta-analyses and trial data, such as a secondary analysis of data from the CUtLASS-1 and CATIE studies, are not reporting marked differences in rates of EPS between FGAs and SGAs when FGA treatments are accompanied by appropriate use of anticholinergic medications.95

Benztropine’s long half-life allows once- to twice-daily dosing. Typical dosing is 1 to 2 mg twice a day up to a usual maximum dosage of 8 mg daily. Trihexyphenidyl (2 to 5 mg three times a day), diphenhydramine (25 to 50 mg three times a day), and biperiden (2 mg three times a day) usually require thrice-daily administration. Diphenhydramine produces more sedation than the other agents. All of the anticholinergics have been abused for their euphoriant effects.96 Symptoms typically begin to resolve within 3 to 4 days after initiation of treatment, but a minimum of at least 2 weeks of treatment is normally required for full response. Amantadine is generally as efficacious for pseudoparkinsonism as anticholinergics, with significantly less effect on memory function.94 The need for prophylactic use of these agents against pseudoparkinsonism is less convincing than with dystonias, and is unnecessary when using SGAs.94 The long-term treatment of pseudoparkinsonism with antiparkinsonism medication is somewhat controversial, and an attempt should be made to taper and discontinue these agents 6 weeks to 3 months after symptom resolution. If symptoms reappear, then switching to an SGA should be considered. The risk of pseudoparkinsonism with SGAs is low. When risperidone is used in doses greater than 6 mg/day, the risk of pseudoparkinsonism symptoms approaches that with FGAs. Quetiapine, aripiprazole, and clozapine are reasonable alternatives in a patient experiencing EPS with other SGAs.58,93,94

Tardive Dyskinesia Tardive dyskinesia is a syndrome characterized by abnormal involuntary movements occurring late in onset in relation to initiation of antipsychotic therapy. It is sometimes irreversible and continues to be a controversial issue.

The classic description of tardive dyskinesia is the buccal–-lingual–masticatory (BLM) syndrome, or orofacial movements. The onset of BLM movements is usually insidious. Typically, they are the first detectable signs of tardive dyskinesia and begin with mild forward, backward, or lateral movements of the tongue. If the disorder progresses, more obvious or frank BLM movements appear, including tongue thrusting, rolling, or fly-catching movements, and chewing or lateral jaw movements. Tardive dyskinesia symptoms can interfere with the patient’s ability to chew, speak, or swallow. Further complications include oral ulcerations, inability to wear dentures, and inflammation and loosening of mandibular joints. Eating difficulties and malnutrition can be severe complications. Weight loss can be seen in patients with esophageal or respiratory manifestations. Facial movements include frequent blinking, brow arching, grimacing, upward deviation of the eyes, and lip smacking. Involvement of the extremities sometimes occurs, with the appearance of restless choreiform and distal athetosis of limbs including twisting, spreading, flexion and extension of fingers, toe tapping, and toe dorsiflexion. Unusual posture, hyperextension, pelvic thrusting, axial hyperkinesia ballismus, exaggerated lordosis, rocking, and swaying are occasionally observed. Among the differential diagnoses are withdrawal dyskinesias occurring after short-term use of antipsychotics, spontaneous orofacial dyskinesias in the elderly, orofacial dyskinesias in the edentulous, stereotypic movements in schizophrenics, Huntington’s disease, and congenital torsion dystonia. Orofacial movements are more common in older patients, whereas the truncal axial movements are classically reported in young adults. Movements can worsen with stress, decrease with sedation, and disappear during sleep. Concentration on motor tasks or attempts to suppress the movements can actually increase them.

Early signs of tardive dyskinesia can be reversible but if allowed to persist, they can become irreversible, even with drug discontinuation. When the antipsychotic dose is decreased or tapered and discontinued, worsening of abnormal movements can occur, followed by possible slow improvement after months or years if the patient remains on lower doses or discontinues treatment. No standardized diagnostic criteria for tardive dyskinesia are available. Abnormal involuntary movements can be detected early through physical assessment and the use of rating scales. Available rating scales include the Abnormal Involuntary Movement Scale (AIMS) and the Dyskinesia Identification System: Condensed User Scale (DISCUS).97 Neither scale is diagnostic in itself.

Risk factors include increasing age, the occurrence of acute EPS, poor antipsychotic drug response, diagnosis of organic mental disorder, diabetes mellitus, mood disorders, and possibly female gender.93Duration of antipsychotic therapy, daily dosage, and possibly total cumulative dosage are probably the most significant risk factors. Polymorphisms of the DA D3 receptor, 5-HT2C receptor, and the superoxide dismutase-2 genes have all been implicated in varying the risk of TD with antipsychotic use.98 Overall morbidity and mortality are greater in tardive dyskinesia patients.

With FGAs, the reported prevalence of tardive dyskinesia ranges from 0.5% to 62%.93 In a first episode of schizophrenia, the incidence is estimated at about 5% per year, with the overall prevalence ranging from 20% to 25% with long-term treatment. Among the elderly, the overall risk of tardive dyskinesia is higher.93,94 Tardive dyskinesia is not always permanent, with remission of symptoms observed in 25% of patients after 5 years of continued treatment.31,93,94

The risk of tardive dyskinesia with SGAs may be significantly lower.93 A systematic review of 12 studies with SGAs lasting 1 year or more found an overall risk of tardive dyskinesia to be approximately 2.98% per year in nonelderly adults as compared with 7.7% for FGAs.99 Although lower than the FGAs, the PORT guidelines report no difference in the risk of tardive dyskinesia among SGAs.28,31

Prevention of tardive dyskinesia is important, as treatment of the movements once they occur is difficult. One of the more compelling arguments for the first-line use of SGAs is their lower risk of tardive dyskinesia.31,100 Regular neurologic examinations (AIMS or other scales) should be performed at baseline and at least quarterly to assess for possible early signs of tardive dyskinesia. At the first signs of tardive dyskinesia, the need for continuing antipsychotic treatment should be reassessed. In such situations, if the patient is taking an FGA and continuing treatment is indicated, the medication should be switched to an SGA.

Numerous drugs have been used in an attempt to treat tardive dyskinesia. In two controlled trials lasting 22 to 52 weeks, clozapine decreased abnormal involuntary movements.28,31,96 Switching antipsychotic therapy to clozapine is a favored first-line pharmacotherapeutic strategy in patients with moderate to severe dyskinesias.31,96

Sedation and Cognition Chlorpromazine, thioridazine, clozapine, olanzapine, and quetiapine are the most sedating antipsychotics. Administration of most or all of the daily dosage at bedtime can decrease daytime sedation and in some patients eliminate the need for hypnotic agents. Sedation occurs early in treatment and can decrease over time. Oversedation can play a large role in cognitive, perceptual, and motor dysfunction. However, positive effects of medication on cognition are seen with chronic administration, evidenced by improvements in tasks involving visual motor skills, attention to task, and working memory. Compared with FGAs, several studies have shown cognitive benefits of SGAs. However, results from the CATIE trial showed no differences in cognitive improvement between SGAs and the FGA perphenazine.101 Comparative effects of different SGAs on cognition are as yet unclear, but available studies suggest that different SGAs can have effects on varying cognitive domains.31

As discussed in Long-Acting Injectable Antipsychotics above, olanzapine pamoate monohydrate injectable is associated with a postinjection sedation/delirium syndrome.40,41

Seizures An increased risk of drug-induced seizures occurs in all patients treated with antipsychotics. However, this risk is greater if the following predisposing factors are present: preexisting seizure disorder, history of drug-induced seizure, abnormal electroencephalogram (EEG), and preexisting CNS pathology or head trauma. Seizures are more closely associated with the use of higher doses, rapid dosage increases, and on initiation of treatment. When an isolated seizure occurs, a dosage decrease is first recommended; routine prophylactic use of anticonvulsant therapy is not recommended. Although spontaneously occurring seizures have been reported with most antipsychotics, the highest potential risk for an antipsychotic-related seizure is with clozapine or chlorpromazine. If a change in antipsychotic therapy is required because of a drug-induced seizure, risperidone, thioridazine, haloperidol, pimozide, trifluoperazine, and fluphenazine are associated with the lowest potential.94

Thermoregulation Poikilothermia, the body temperature adjusting to the ambient temperature, can be a serious side effect of antipsychotic therapy in temperature extremes.102 Hyperpyrexia can be a danger in hot weather or during exercise. Inhibition of sweating, a result of anticholinergic properties impairing the peripheral mechanisms of heat dissipation, can contribute to this problem, which in its severest form can lead to heat stroke. Hypothermia is a risk in cold temperatures, particularly in the elderly. All patients receiving antipsychotics should be educated about these potential problems. Thermoregulatory problems are reportedly more common with the use of low-potency FGAs and can occur with the more anticholinergic SGAs.

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) occurs in 0.5% to 1% of patients receiving FGAs. NMS can occur more frequently in patients receiving high-potency FGAs, injectable or depot FGAs, and in patients who are dehydrated, with physical exhaustion, or organic mental disorders. Although less common, NMS has been reported with SGAs, including clozapine. The onset of symptoms varies from early in treatment to months later. It develops rapidly, over the course of 24 to 72 hours. NMS can occur after antipsychotic discontinuation, especially when depot agents are used. Possible mechanisms of NMS include disruption of the central thermoregulatory process or excess production of heat secondary to skeletal muscle contractions. The differential diagnosis includes heat stroke, lethal catatonia, anesthetic-associated malignant hyperthermia, anticholinergic toxicity, and monoamine oxidase inhibitor drug interactions. Cardinal signs and symptoms of NMS are body temperature exceeding 38°C (100.4°F), altered level of consciousness, autonomic dysfunction (tachycardia, labile blood pressure, diaphoresis, tachypnea, or urinary or fecal incontinence), and rigidity. Laboratory evaluation, although nonspecific, frequently shows leukocytosis with or without a left shift, increases in creatine kinase (CK), aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and myoglobinuria.94

Treatment should begin with antipsychotic discontinuation and supportive care. In many cases that alone is effective. The role of adjunctive agents is unclear, yet they are often used. The DA agonist bromocriptine reduces rigidity, fever, or CK in up to 94% of patients, whereas the use of amantadine has been successful in up to 63% of patients. Dantrolene has been used as a skeletal muscle relaxant, with positive effects on temperature, heart rate, respiratory rate, and CK in up to 81% of patients.94 Wide recognition and rapid antipsychotic discontinuation has drastically reduced mortality from 20% 25 years ago to 4% in the mid-1990s.

Many patients with schizophrenia, despite having had NMS, will require future antipsychotic pharmacotherapy. A review of antipsychotic rechallenges suggests that the risk of rechallenge is acceptable in most patients, provided that the patient is observed for an extended period of time (2 weeks or more is suggested) without antipsychotics, that there is careful monitoring and slow dose titration, and that the patient is maintained on the lowest possible dose.94 A different antipsychotic, an SGA or a low-potency FGA, should be used for rechallenge following an episode of NMS.

Psychiatric Side Effects Antipsychotic-induced akathisia, akinesia, and dysphoria can have unfortunate sequelae, resulting in what has been termed “behavioral toxicity.”33 Akinesia, characterized by “diminished spontaneity,” results in symptoms of apathy and withdrawal, often mistaken for the negative symptoms of schizophrenia; these patients can actually appear depressed. Delirium and psychosis are reported with larger doses of FGAs or combinations of anticholinergics with FGAs. Chronic confusion and disorientation can occur in the elderly as a result of antipsychotic treatment.103 Unfortunately, the link is not always made with antipsychotic therapy, and the patient is misdiagnosed with delirium from a different etiology. This clinical presentation, called a pseudodementia, may be reversible on discontinuation of the antipsychotic.

Ophthalmologic Effects Anticholinergic effects of antipsychotics or concomitant antiparkinson medications can exacerbate narrow-angle (angle-closure) glaucoma. Antipsychotics with low anticholinergic effects should be used in such individuals, and they should be appropriately monitored.104

Opaque deposits in the cornea and lens occur with chronic phenothiazine treatment, most frequently with chlorpromazine. Although visual acuity is not usually affected, periodic slit-lamp ophthalmologic examinations are frequently recommended in patients receiving long-term treatment with phenothiazines, as fully formed cataracts are a possibility.104

Because of cataract development and lenticular changes in animals, baseline and periodic eye examinations are recommended in the product labeling for quetiapine.105 However, clinical use of quetiapine since marketing has not shown a significant risk of cataracts.105 Retinitis pigmentosa can result from use of thioridazine doses greater than 800 mg daily. It is caused by melanin deposits and can result in permanent visual impairment or blindness.

Genitourinary System

Urinary hesitancy and retention, secondary to anticholinergic effects, are reported with low-potency FGAs and with clozapine. Men with benign prostatic hypertrophy are especially prone to this effect.106

Urinary incontinence is thought to be caused by α-blockade, and among the SGAs, it appears to be particularly problematic with clozapine. The incidence has been reported to be as high as 44%, and it can be persistent in 25% of patients.107

Although inadequately studied, multiple mechanisms are likely responsible for sexual dysfunction, including dopaminergic blockade, hyperprolactinemia, histaminergic blockade (sedation), anticholinergic effects, and α-adrenergic blockade. Unmedicated individuals with schizophrenia report decreased libido. Most but not all studies show a relationship between hyperprolactinemia and sexual dysfunction, including decreased libido, erectile dysfunction, difficulty achieving orgasm, and ejaculatory abnormalities. Risperidone produces at least as much sexual dysfunction as FGAs; other SGAs, with weak effects on prolactin, produce less sexual dysfunction. Patients experiencing sexual dysfunction with FGAs or risperidone should be switched to an SGA with less effect on prolactin.108

Priapism, a sustained and painful erection which is unprovoked and persists for longer than an hour, is increasingly reported with antipsychotic medication use. This is believed to occur as a result of α1-adrenergic receptor blockade, leading to intracavernosal blood stasis.109 This can evolve into a urologic emergency, due to the ischemic nature of the priapism. Patients on antipsychotics with other risk factors, including sickle-cell disease and history of prolonged erections,109 and perhaps those patients taking other medications with α1-blocking properties should be counseled regarding this rare but important adverse reaction. If left untreated, priapism may lead to permanent impotence.

Hematologic System

Transient leukopenia can occur during initial treatment with antipsychotics; however, it typically does not progress to be clinically significant.110 The three antipsychotics with highest relative risk of neutropenic are in rank order clozapine, chlorpromazine, and olanzapine.111 If the WBC count is less than 3,000/mm3 (3 × 109/L), or if the absolute neutrophil count (ANC) is less than 1,000/mm3 (1 × 109/L), the antipsychotic should be discontinued, and the WBC monitored closely until it returns to normal. Agranulocytosis reportedly occurs in 0.01% of patients receiving FGAs, and more frequently with chlorpromazine and thioridazine. The onset is usually within the first 8 weeks of therapy. Agranulocytosis can initially manifest as a local infection, with sore throat, leukoplakia, erythema, and ulcerations of the pharynx. These symptoms in any patient receiving antipsychotics should signal the immediate need for a WBC count. If either the WBC count or ANC falls below these parameters, the drug should be discontinued immediately and the patient monitored closely for the development of secondary infections. Isolated rare cases of thrombocytopenia and eosinophilia have also been reported.

Agranulocytosis with clozapine significantly limits the usefulness of this agent. The risk of developing neutropenia or agranulocytosis with clozapine is approximately 3% and 0.8%, respectively.111 Increasing age and female gender are associated with greater risk. The time period for greatest risk is between months 1 and 6 of treatment, and weekly WBC monitoring for the first 6 months of therapy is mandated in the FDA-approved product labeling. After the first 6 months, the labeling allows the frequency of WBC monitoring to be decreased to every 2 weeks for months 7 to 12, after which it can be decreased to monthly if all WBCs are normal. If the total WBC count drops to less than 2,000/mm3 (2 × 109/L), or the ANC is less than 1,000/mm3 (1 × 109/L), clozapine should be discontinued and the patient monitored closely. Granulocyte colony-stimulating factor filgrastim has been used to hasten recovery. In cases of moderate neutropenia (granulocytes 2,000 to 3,000/mm3 [2 × 109/L to 3 × 109/L], or ANC 1,000 to 1,500/mm3 [1 × 109/L to 1.5 × 109/L]), which occurs in up to 2% of patients, clozapine should be discontinued with daily monitoring of complete blood counts until values return to normal.

Dermatologic System

Allergic reactions are rare and usually occur within 8 weeks of initiating therapy, manifesting as maculopapular, erythematous, pruritic rashes that are evident on the face, neck, trunk, or extremities. Contact dermatitis, including the oral mucosa, can occur in patients or medical personnel. For patients, mixing the antipsychotic concentrate in a sufficient quantity of a nonacidic liquid and swallowing it quickly decreases problems in susceptible patients. Care should be taken in the handling and preparation of liquid FGAs.

Phenothiazine can absorb ultraviolet light, resulting in the formation of free radicals, which can have damaging effects on the skin. All antipsychotics can cause photosensitivity. Erythema and severe sunburns can occur. Exposure to sunlight should be limited, and patients should be educated about the use of a maximally blocking sunscreen, hats, protective clothing, and sunglasses.112

Blue-gray or purplish skin coloration in areas exposed to sunlight occurs in patients receiving higher doses of low-potency phenothiazines during long-term administration, especially with chlorpromazine. It commonly occurs with concurrent corneal or lens pigmentation.

Miscellaneous Adverse Effects

A sometimes troubling side effect with clozapine is sialorrhea, which can occur in up to 54% of patients. The mechanism of clozapine-induced drooling is unclear. Although both anticholinergics and α-agonists have been used to treat clozapine-related sialorrhea, research evidence is insufficient to make specific recommendations.113

Toxicity with Overdose

Acute overdose with antipsychotics rarely results in serious symptomatology. Mild intoxication manifests as sedation, hypotension, and miosis, whereas with severe intoxication, agitation and delirium can typically progress to motor retardation, seizures, cardiac arrhythmias, respiratory arrest, and coma. Dystonias and pseudoparkinsonism symptoms also occur. Supportive measures, gastric lavage, and activated charcoal are recommended. Induction of emesis can be difficult because of effects on the chemoreceptor trigger zone, and dialysis is ineffective because of the degree of drug–protein binding. Phenytoin or sodium bicarbonate is useful in the treatment of quinidine-like cardiac conduction effects on the QRS or QTc. Physostigmine is not generally recommended to reverse anticholinergic toxicity because of deleterious effects on arrhythmias and seizure threshold.112

Use in Pregnancy and Lactation

Minimal data exist regarding the effects of pregnancy on schizophrenia. However, disorganized thought processes, impaired cognition, and negative symptoms can have a detrimental effect on the functioning and self-care of the mother, and therefore adversely affect the fetus.114 Currently available data assessing the risk of teratogenesis with antipsychotic agents are insufficient. Epidemiologic studies show a slightly increased risk of birth defects with low-potency FGAs. Haloperidol is the best studied of all antipsychotics, and no relationship between its use and teratogenicity has been found. One study indicates a greater than twofold elevated risk of preterm birth in women with schizophrenia taking FGAs as compared with unaffected mothers not taking antipsychotics.114

SGAs have increasing information regarding safety in pregnancy; however, very few large studies and very few prospective studies have been performed to evaluate possible teratogenicity of SGAs. Two prospectively designed nonrandomized, observational studies have reported no increased risk of teratogenic birth defects with SGA exposure.115,116 One large registry data study performed in Sweden found a significantly increased risk of cardiovascular defects with FGA or SGA exposure117; however, when stratifying by antipsychotic class, it was found that all defects were found in those exposed to FGAs, while no cardiovascular defects were reported with SGAs.118 Definitive data are still lacking.

Studies have shown differing results in regard to infant outcomes in fetuses exposed to SGAs. Women with schizophrenia taking SGAs showed no significant risk of LBW, preterm birth, or infant considered small or large for gestational age (LGA) when compared with infants born to unaffected and unexposed mothers.114 One prospectively designed study found a higher rate of LBW infants in mothers taking SGAs (10%) than in the reference group (2%),115 while another prospective study reported higher rates of LGA infant births in women taking SGAs compared with those in the FGA and reference groups.119

Other potential interests in studying early and late exposure to antipsychotics include postnatal and gestational complications. Weight gain associated with olanzapine and clozapine and the potential risk of gestational diabetes should be considered in drug selection.120 A recent retrospective cohort study reported nearly twofold odds of gestatational diabetes in women who used antipsychotics during pregnancy.120

Risk of neonatal EPS is increased with in utero exposure to FGAs, with effects in the infant lasting for 3 to 12 months after birth.121 In February 2011, the FDA issued a safety announcement informing healthcare professionals that the pregnancy section of drug labels had been updated for the entire class of antipsychotics, highlighting the potential risk for EPS and withdrawal symptoms in newborns whose mothers were treated with antipsychotics during their third trimester.121 Symptoms of neonatal withdrawal reported to the FDA included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.

The risk of antipsychotic use must be weighed against the benefits of pharmacotherapy in pregnant women experiencing disorganized thoughts, delusions about change in body image or pregnancy, or who are unable to provide adequate prenatal care.114,121

Antipsychotics appear in breast milk with milk-to-plasma ratios of 0.5:1. However, 1 week after delivery, clozapine milk concentrations were found to be as much as 279% of serum concentrations. Its use during breast-feeding is not recommended.122 Overall, little is known about breast-feeding and the potential effects of antipsychotics on the neonate. Although not contraindicated, the lowest dosage should be used in the mother, and the infant carefully monitored.

Drug Interactions

Most drug interactions occur because of pharmacodynamic or pharmacokinetic interactions. Common examples of pharmacodynamic interactions resulting in enhanced effect include the excess sedation that can occur when antipsychotics are used concomitantly with other medications that have sedative side effects. Additive antimuscarinic effects of antipsychotics used with other medications with antimuscarinic effects can result in urinary retention, constipation, blurred vision, or other anticholinergic side effects.33,123 Both combined sedative and anticholinergic effects from multiple medications can result in impaired cognition, particularly in the elderly and other patients predisposed to such problems.123 Patients are more likely to experience symptomatic orthostatic hypotension when an antipsychotic is used with other medications that cause orthostasis. Although metoclopramide is prescribed for treating esophageal reflux, it is a DA antagonist, and patients are more likely to experience akathisia and other EPS if it is used concomitantly with antipsychotics.124 Although some SSRIs can interact with antipsychotics through enzyme inhibition, they can also interact through pharmacodynamic mechanisms. 5-HT2receptors are present on the presynaptic dopaminergic neuron, and their activation leads to decreased DA release from the presynaptic terminal. Increased availability of 5-HT through SSRI effect can activate these receptors, decrease DA release, and add to the dopaminolytic effects of antipsychotics.124 In the absence of enzyme inhibition, SSRIs can still precipitate akathisia or EPS when added to a patient stabilized on an antipsychotic. A potentially more dangerous interaction can occur when medications that slow myocardial conduction and thus prolong the QTc are used in combination with antipsychotics that significantly prolong the QTc.124 Medications that prolong the QTc should be monitored carefully in patients taking concomitant diuretics.124 These effects can all increase the risk of clinically significant adverse effects.

Asenapine inhibits CYP2D6, and is the only SGA that has been shown to significantly affect the pharmacokinetics of other medications.60 Table 50-6 lists the known major pathways involved in the metabolism of SGAs. Risperidone is metabolized primarily by CYP2D6 to its active metabolite, 9-OH-risperidone (paliperidone), which is thought to have a similar pharmacodynamic profile.124 Although paliperidone is primarily eliminated renally unchanged, potent inducers of CYP3A4 can cause a potential need for dosage adjustment.63,125 CYP1A2 is the primary isoenzyme for metabolism of asenapine with CYP3A4 also being a significant pathway.63

Based on current information, inhibitors of CYP1A2 have the greatest potential for causing interactions with clozapine and olanzapine.126 Examples include cimetidine, fluvoxamine, and fluoroquinolone antibiotics (e.g., ciprofloxacin) to varying degrees. To date, however, no serious inhibition interactions have been reported with olanzapine, which may be a result of olanzapine’s wide therapeutic index. Carbamazepine has been reported to increase olanzapine elimination by as much as 50%.126 Cigarette smoking is a potent inducer of CYP1A2, and one would expect lower mean olanzapine serum concentrations in smokers compared with those in nonsmokers.

Because of the risk of seizures with higher clozapine tissue concentrations, interactions that inhibit clozapine’s metabolism are potentially significant. In particular, fluvoxamine increases clozapine serum concentrations by an average of twofold to threefold and up to fivefold.126,127 Fluoxetine and erythromycin can increase clozapine serum concentrations to a lesser degree.126,127 Mean clozapine serum concentrations are reported to be 32% lower in smokers compared with those in nonsmokers.126 If a patient taking clozapine stops smoking, the resulting increase in clozapine serum concentration could be associated with seizures.63 Carbamazepine can induce clozapine metabolism and lead to lower serum concentrations.110

A study with the potent CYP3A4 inhibitor ketoconazole showed minimal effects on ziprasidone single-dose pharmacokinetics, with only a 33% mean increase in the ziprasidone area under the time-versus-concentration curve.124These results are consistent with data suggesting that aldehyde oxidase is the major metabolic pathway for ziprasidone, with only 30% to 35% being metabolized by CYP3A4.128

Modest elevations of aripiprazole serum concentration occur in the presence of ketoconazole or quinidine, which inhibit CYP3A4 and 2D6, respectively. Carbamazepine has been reported to decrease aripiprazole serum concentrations.58,127

Since iloperidone is metabolized through CYP2D6 and 3A4, its clearance can be impaired by inhibitors of these pathways. Since iloperidone prolongs the QTc interval, these types of interactions have the potential to be clinically significant. For example, it is recommended that the iloperidone dose be decreased by 50% when used with CYP2D6 inhibitors such as fluoxetine or paroxetine.59

Table 50-9 summarizes potential antipsychotic drug interactions.

TABLE 50-9 Common Potential Drug Interactions with Antipsychotic Medications






Personalized Pharmacotherapy

Pharmacotherapy must be individualized for each person with schizophrenia. With the possible exception of iloperidone, no laboratory tests are generally available that will predict a patient’s response to treatment. Past response to treatment, potential adverse effects, patient personal preference, and medication price are the primary variables that should be used in selecting an antipsychotic for a patient being treated at stages 1 or 2 of the treatment algorithm. In the CATIE study, the number one reason for drug discontinuation was the patient not wanting to take that medication any more, and the second most common reason was adverse effects.29 These two factors should be carefully considered in antipsychotic selection. Medication dosage must also be individualized within the usual dose ranges. Careful consideration must also be given to concomitant medications that may interact with the antipsychotic and necessitate a change in dosage.

Preliminary data suggest a relationship between different genetic markers and clinical improvement as well as QTc prolongation in patients treated with iloperidone. Another study showed some of these markers to be associated with response to risperidone.34,87 It is too early to conclude whether these or other genetic markers will have a clinically useful role to play in the treatment of persons with schizophrenia.

Given that no antipsychotic has proven superiority with regard to efficacy in the treatment of schizophrenia (with the exception of clozapine in treatment resistance), cost should be a factor in antipsychotic selection. Olanzapine, quetiapine, risperidone, and all FGAs have generic equivalents available, and this should be a factor in selecting an antipsychotic at stage 1 of the treatment algorithm.


Assessment of response has traditionally been done subjectively or empirically (a relative sense of how the clinician feels the patient is doing). A formal MSE is used to structure the patient interview and focus on items related to appearance, mood, sensorium, intellectual functioning, and thought processes. However, the MSE is neither specific nor quantitative for the measurement of drug response. Images Clinicians should be trained to use simple, standardized psychiatric rating scales to assist in objectively rating patient drug responses.130 The Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Symptom Scale (PANSS) were developed for use in clinical trials as research tools to quantify symptom improvement seen with antipsychotic treatment.130 Objectively, the use of a numeric indicator (e.g., 20%, 30%, or 40% reduction in BPRS score) has been used to quantify overall symptom reduction and classify patients according to different degrees of response. However, these types of rating scales are too long and unwieldy to be routinely used within the time constraints of most clinical practices. Symptom scales used in clinical practice must be sufficiently brief to be used during an ordinary clinic visit (e.g., 15 to 30 minutes) while measuring both positive and negative symptoms, and being sufficiently representative of overall symptomatology. The four-item Positive Symptom Rating Scale (PSRS) and the Brief Negative Symptom Assessment are brief scales that meet such criteria (Table 50-10).131 A brief rating scale of positive symptoms, such as the PSRS, should be used at baseline before starting pharmacotherapy, and at each time response to pharmacotherapy is assessed.

TABLE 50-10 Brief Clinical Assessments for Monitoring Antipsychotic Response in Schizophrenia


Clinical Controversy

Psychiatry is one of the few specialties in medicine in which measurement is not a routine component of patient care. Although biologic measures do not currently exist in psychiatry, symptoms associated with a patient’s illness can be measured and quantified. Although increasing evidence attests to the benefits of quantifying symptom severity, the use of symptom rating scales remains uncommon in clinical practice.

Similarly, the pharmacotherapeutic plan should include specific monitoring parameters for side effects (see Table 50-11). The plan should include how the potential side effect will be evaluated, and the frequency of assessment. Given the risk of weight gain, diabetes, and lipid abnormalities associated with many of the SGAs, a consensus task force led by the American Diabetes Association recommends the following baseline parameters before beginning antipsychotics: family history, weight, height, body mass index, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.82 They also recommend followup monitoring of these parameters after beginning or changing SGAs. Weight should be monitored monthly for the first 3 months, and quarterly thereafter. The other parameters should be assessed at the end of 3 months and then annually. Self-assessments can be a useful adjunct in treating the patient. Although the patient with schizophrenia may not always be accurate in evaluating symptom severity, the use of patient self-assessments increases patient engagement in care, enhances therapeutic alliance, and gives the clinician an opportunity to identify misconceptions the patient may have regarding symptoms associated with the illness, medication side effects, and the like.130,132 Traditionally, clinicians have often accepted partial symptom response in schizophrenia as success, and have not been aggressive in attempting to achieve greater symptomatic remission. The advent of multiple different SGAs with varying side effect profiles should encourage clinicians to be more assertive in attempting to achieve symptom remission. This is consistent with an increasing focus on remission as a goal of treatment and evolving recovery movements with an emphasis on consumerism in the care of the severely mentally ill.25 A recent study showing how the Internet can be used to aid relapse prevention efforts gives us a glimpse of how consumerism may enhance and influence the care for schizophrenia in the future.133

TABLE 50-11 Antipsychotic Adverse Effects and Monitoring Parameters






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