Viral encephalitis

should also be aggressively treated. Additionally, psychosocial treatments should be used concomitantly to improve patient outcomes.

Nonpharmacologic Therapy

® Psychosocial support is needed to help improve functional outcomes. Only 30% of patients respond robustly to antipsychotics, another 30% respond partially, and another 30% have a minimal response. Patients who do respond often continue to have residual symptoms such as amotivation, isolation, and impaired social functioning, thus limiting their participation in social, vocational, and educational endeavors. Psychosocial interventions are based on the premise that increased psychosocial functioning will lead to improvements in subjective feelings of self-esteem and life satisfaction. A few of the best-supported and most promising approaches to psychosocial rehabilitation are social skills training (SST), cognitive-behavioral therapy (CBT), and cognitive remediation (CR). These treatments are mainly utilized as targeted treatments for social and cognitive impairments and as adjuncts to pharmacotherapy for psychotic symptoms.13 Most psychosocial studies have been carried out in the United Kingdom, and findings are not yet widely utilized in the United States. Nonetheless, there are substantial data to support that family education and vocational support help to improve long-term functional outcomes.

Pharmacologic Therapy

Generally, all people with schizophrenia should be treated with antipsychotics, and adjunctive medications should be used when necessary to treat specific symptoms or comorbid diagnoses. Medications specifically targeting negative symptoms and cognitive deficits are actively being investigated. Because each schizophrenic patient presents differently, each treatment regimen should be individually tailored. After a period of nearly 20 years during which only first-generation antipsychotics (FGAs; typical antipsychotics) were available, nine new antipsychotics have been marketed in the United States since 1990. These agents, known as SGAs (atypical antipsychotics), include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon; Zeldox), aripiprazole (Abilify), paliperidone (Invega), iloperidone (Fanapt), asenapine (Saphris), and clozapine (Clozaril). Clozapine, the prototype of this class of medications, is reserved as second-line therapy due to its unusual side-effect profile (see below). Compared to the older FGAs, the more recently developed SGAs are associated with a lower risk of motor side effects (tremor, stiffness, restlessness, and dyskinesia); may offer greater benefits for affective, negative, and cognitive symptoms; and may prolong the time to psychotic relapse.

Since the introduction of SGAs the use of FGAs has been progressively decreasing, and the current market share for these agents in treatment of schizophrenia is less than 10%. This occurred due to the touted lower side-effect profile and other benefits of SGAs in several domains of the illness. Early comparative studies used high dose, high-potency FGAs such as haloperidol and concluded that SGAs were more effective in some domains. More recently, a large multisite clinical trial (N = greater than 1,400 patients) was designed to examine the effectiveness of SGAs relative to a mid-potency FGA, perphenazine (the Clinical Antipsychotics Trials of Intervention Effectiveness; CATIE trial). This study demonstrated that FGAs may be as effective as SGAs when using the primary endpoint of time to discontinuation of medication.14 Thus, while these results suggest that midpotency FGAs may be similar in efficacy to SGAs, the CATIE trial had several limitations, and other evidence suggests SGAs may be more effective in some illness domains, such as relapse prevention, affective and negative symptoms, and cognitive function. The SGAs have historically been much more expensive than the FGAs, however risperidone and clozapine are now available in lower cost generic formulations, and other SGAs will lose patent protection in the next 5 years. In conclusion, when selecting among the various agents, the risk benefit profile becomes fundamental, as all the antipsychotics are associated with somewhat different side-effect profiles.

Second-Generation (Atypical) Antipsychotics

While FGAs exert most of their effect through dopamine-receptor blockade at the dopamine2 (D2) receptor, the SGAs may work through a more complicated mechanism, as SGAs have greater affinity for serotonin receptors than for dopamine receptors (Fig. 37-1). Despite being very heterogeneous with regard to receptor binding, the overall efficacy among the SGAs is similar.14 Recently new comparative data among SGAs and FGAs (lower doses) have reported that overall efficacy is similar between groups, which suggests a reevaluation of the place of FGAs in therapy is needed.14 Only clozapine, however, has demonstrated superior efficacy for some patients (see the section on treatment-resistant patients). An important distinction of the SGAs as a class is their lower propensity to cause extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). The annual risk of TD is considered to be less than 1.5% per year in adults (less than 54 years old) taking SGAs compared to approximately a 5% per year risk in those taking FGAs.1 Pharmacologic profiles and side-effect profiles, however, are very different among the agents. SGAs as a class are heterogeneous with regard to side-effect profiles. Many SGAs carry an increased risk for weight gain and for the development of glucose and lipid abnormalities; therefore, careful monitoring is essential. Table 37-3 lists the SGA agents, recommended dosing, and dosage forms available. Table 37-4 lists the side-effect profiles of the SGAs and haloperidol. Clozapine is discussed in the section on treatment-resistant patients.

Aripprazois' Clozapine Hak)pofi(tol Oiafiiapino Queliapine Risperidone" Zipfasi<*jne

FIGURE 37-1. Profiles for receptor binding of second-generation antipsychotics and haloperidol.a Partial agonist activity at D2 receptors, whereas all others are D2 antagonists.bPaliperidone data are unavailable, but would be expected to be similar to risperidone. Iloperidone and asenapine are not shown here due to recency of approval. (D, dopamine receptor; H1, histamine receptor; 5-HT, serotonin receptor; Musc, muscarinic receptor; a1 and a2, receptors.) Adapted from The Journal of Clinical Psychiatry and Physicians Post Graduate Press. Collaborative Working Group on Clinical Trial Evaluations. J Clin Psychiatry 1998; 59[Suppl 12]:7, and Pharmacologic Treatment of Schizophrenia. Caddo, OK. Professional Communications, Inc, 2003:52, with permission.

FIGURE 37-1. Profiles for receptor binding of second-generation antipsychotics and haloperidol.a Partial agonist activity at D2 receptors, whereas all others are D2 antagonists.bPaliperidone data are unavailable, but would be expected to be similar to risperidone. Iloperidone and asenapine are not shown here due to recency of approval. (D, dopamine receptor; H1, histamine receptor; 5-HT, serotonin receptor; Musc, muscarinic receptor; a1 and a2, receptors.) Adapted from The Journal of Clinical Psychiatry and Physicians Post Graduate Press. Collaborative Working Group on Clinical Trial Evaluations. J Clin Psychiatry 1998; 59[Suppl 12]:7, and Pharmacologic Treatment of Schizophrenia. Caddo, OK. Professional Communications, Inc, 2003:52, with permission.

Table 37-3 Second-Generation (Atypical) Antipsychotics


Usual Terg*t Du»

Minimal Doie Ijlcrly to Be Etiitfkl* I tiVi j.'diWl


D&iftgfr F

Aripipasole (Ability) li-30

Asenapine (Saplvls) 10 ClOäOyiiwIPMiiiLiliOi^ildtle 400 genially)

Ibptjrticine (Fanipft 12-ifl

Olanzapine (Zyprexa) 15-30

I nitj/rriL Miluliixl

10 Jiyj 15 my diiirtielt Orally tJiynKgr.jSi*j

Ciblw iMftfS ntg/lJ mL b and 10 ring sublingual ;jlik*li Iii, 25 50. «KU jnd WOmrJHWitS fezaCto (srs^rdlsimieflraifcig rat«?iiJ 12.^ ?5. and lOOmg

/yprrXii /ydi^ (orally di"*"IO(|f."1in<J BMeli}

5,10, 15, and M mg it.-1- mg (aiwi recofBimTbrt

kJyrlc Ihnw.'tiíil

O-ietiapIre (Seroquell 30O-B0Ú

Pfcpe1 "done (Riipeitfai. also 3-6

available Qpfln k jllyi

■ Imega lusienna J&, 73, 117, IS6, JA4 nro pffruttl iyi ingti

■ Sito Hh'l SiH ji-xtifxk'íí H-II'.IM■ I .ibkf.; ífl iffl. XA 30Q and 400 ring

■ FlüpeT'dal M rf) (orafcdiitníBgfalíng lab'ets) Q-í. I, ír 1 4 mg

- RlípcfdalCarrila long-actlngtnjettabte I2.Í. 2S. orid SO rng ™l/ly I


Risperidone, a benzisoxazole derivative, was the first SGA to be marketed following the release of clozapine. Risperidone is the only SGA available for administration as a long-acting injection in the United States, and is also the only first-line oral SGA to become available generically. It has high binding affinity to both serotonin 2a (5-HT2A) and D2 receptors and binds to ai and a2 receptors, with very little blockade of cholinergic receptors.16 Multicenter registry trials found 6 to 16 mg of risperidone at least as equally efficacious as M^riM (20 mg), while 6 mg of risperidone produced EPS at a rate no different than placebo. Risperidone is also approved for relapse prevention and is associated with significantly lower relapse rates than long-term haloperidol treatment.18 At clinically effective doses (less than or equal to 6 mg/ day), EPSs are low, although higher doses are clearly associated with a greater incidence of EPS. Risperidone is associated with serum prolactin elevations that are similar to or greater than those seen with the FGAs. Elevated prolactin levels can, but do not always, lead to clinical symptoms such as hormonal problems (e.g., amenorrhea, galactorrhea, and gynecomastia) or sexual dysfunction. Risperidone is associated with mild to moderate weight gain, and mild elevations in lipid and glucose may occur. However, patients chronically treated with other antipsychotics such as olanza-pine may experience a decline in cholesterol and triglyceride levels when changed to risperidone monotherapy.14

Table 37-4 Comparative Side Effects Among the SGAs and Haloperidol"

SWa Eff tct






Ariplprazole Haloperidol

Anlfcjhulinr.Kjic stdi tiffiili (tjb y



+ + (higher



mcullv, eonn option. khaiied

vision, minaiy tiesilarvr^

Fl^ar dinlfaldos«







Dose-dependent EPS


+ +





+ + +



+ +


+ 4












QTc prolongal ion












+ +









Weiçfcl gain


+ +

+ 4 +

+ +


Nuov.f' < lyMt-rt.jl.iriijn








Lipid abnormalities




+ +



0. .ifcivnl; i.; +. miici;n Inw n^: -(-+. moiWVilCr +++. v/iii* I PS.^vlupyi.imKliI \KlrHfi\ M^conrl iyriif .icinn .inh|:vyi I . ' .

"IkjptiidtjrK; ¿nd jurTuuric jrtL not ¡"cfcidixJtlui; (rurcm^y or approval. •Mi (dkb sii^ildi to

0. .ifcivnl; i.; +. miici;n Inw n^: -(-+. moiWVilCr +++. v/iii* I PS.^vlupyi.imKliI \KlrHfi\ M^conrl iyriif .icinn .inh|:vyi I . ' .

"IkjptiidtjrK; ¿nd jurTuuric jrtL not ¡"cfcidixJtlui; (rurcm^y or approval. •Mi (dkb sii^ildi to


Olanzapine has greater affinity for 5-HT2A than for D2 receptors. In addition, the compound has affinity at the binding sites of D4, D3, 5-HT3, 5-HT6, ai-adrenergic, mus-carinici-5 (Mi-5), and histaminei (Hi) receptors.19 Multicenter clinical trials have reported that the effectiveness of olanzapine is at least equal to that of haloperidol for the treatment of positive symptoms20, 1 and equal or superior to haloperidol for the treatment of negative symptoms. The premarketing clinical trials reported no significant differences in efficacy among dosage groups. However, the higher dose range appeared to offer the greatest benefits for both positive and negative symptoms when compared to haloperidol (20 mg). In one study, olanzapine (16.3 mg/day mean modal dose) was superior to haloperidol (16.4 mg/day) for the treatment of negative symp-

toms, while another study found that 13.2 mg olanzapine was superior for both pos-

itive and negative symptoms compared to 11.8 mg haloperidol. Among the firstline antipsychotic agents, olanzapine is associated with the longest time to treatment discontinuation,14 a finding that suggests that olanzapine may somewhat differ from the other SGAs in effectiveness. Olanzapine has a low rate of EPS and causes slight, transient prolactin elevations. However, clinically significant weight gain occurs with olanzapine across the dosage range. The degree of weight gain is similar to that seen with clozapine and greater than that observed with the other SGAs. Olanzapine is also associated with hypertriglyceridemia, increased fasting glucose, and new-onset type 2 diabetes (i.e., metabolic syndrome), and among the first-line SGAs, it is associated with the greatest elevations in these metabolic parameters.14


Structurally quetiapine is related to clozapine and olanzapine. Quetiapine has high affinity for 5-HT2A receptors and lower affinity for D2 and D1 receptors. This drug has some affinity for a1, a2, and H1 receptors, and very little for muscarinic receptors. The efficacy of quetiapine for psychosis was established in two controlled trials, which

22 23

found that maximum benefits occurred at 300 mg per day or greater. ' The most effective doses of quetiapine may be higher than 500 mg/day. Quetiapine may have beneficial effects for anxious and depressive symptoms. Because of its low D2 occupancy, motor side effects and prolactin elevations are usually not seen with quetiapine. Orthostasis occurred in 4% of subjects in clinical trials. Sedation may occur but is generally transient. Mild weight gain and minor elevations in triglycerides can occur.


Ziprasidone was developed specifically to be a compound that blocks D2 receptors, but also binds with even greater affinity to central 5-HT2A receptors. As a result, ziprasidone has a binding affinity ratio of 11:1 for 5-HT2A:D2 receptors. Ziprasidone also has a relatively high affinity for 5-HT2C, 5-HT, oj1-adrenergic, and D1 recept-

ors. Several short-term, placebo-controlled, premarketing clinical trials led to the recommended dose range of 40 to 160 mg daily with food.25,26 Current dosing suggests that efficacy may be greater at doses over 200 mg/day. Liability for EPS, weight gain, and lipid elevations were very low in the clinical trials. Ziprasidone is associated with some prolongation of the QT interval corrected for heartrate (QTc) interval in adults. However, drug overdose data and studies of pharmacokinetic interactions have thus far shown little evidence that significant QTc prolongation may occur. It is advised to utilize caution, however, when using medications that may affect ziprasidone metabolism and when it is prescribed along with other medications known to prolong QTc. Please see the Pharmacokinetics section of this chapter for further discussion of this topic. Caution should also be used when prescribing ziprasidone in situations that have increased risk for prolongation of QTc including comorbid diabetes, electrolyte disturbances (e.g., low serum sodium and potassium concentrations), heavy alcohol consumption, female gender, and congenital QTc disorder.


Aripiprazole was formulated in the early 1980s to function as a potential dopamine modulator, with both antagonist and agonist activity at the D2 receptor. It is the first D2 partial agonist available for the treatment of schizophrenia and is sometimes referred to as a third-generation antipsychotic. This novel mechanism is termed a "dopamine system stabilizer," functioning as an antagonist in a hyperdopaminergic state and as an agonist when in a hypodopaminergic state. Aripiprazole is also a partial agonist at 5-HTia receptors, an antagonist at 5-HT2A receptors, and also has affinity for D3 receptors. Additionally, it has a moderate affinity for ai and H1 receptors with no ap-

preciable affinity for the Mi receptor. The recommended starting dose is 10 to 15 mg daily given without regard to meals. No titration is required, as the starting dose is an effective dose. The recommended dosing range is 10 to 30 mg/day; doses greater than 30 mg have not been systematically evaluated. Side effects are low with sedation and nausea and vomiting occurring most frequently. Elevations in weight, lipids, and glucose are generally negligible, and due to its partial dopamine receptor agonism, it does not usually cause elevations in prolactin. In fact, patients switched to aripiprazole from other antipsychotic agents may experience decreases in prolactin levels.


Paliperidone is the separately marketed 9-hydroxy metabolite of risperidone. The effects of risperidone and paliperidone in the body are expected to be similar, as the effects of risperidone are thought to be a result of both the parent drug and the 9-hydroxy metabolite. The neurotransmitter receptor binding affinity is also similar between the two agents, with paliperidone having a greater affinity at 5-HT2A compared to D2 receptors. Unlike many other antipsychotic medications, the majority of paliperidone is excreted unchanged. Paliperidone is available as an extended release tablet, given once daily. Patients may be told to expect to see the shell of the tablet in the stool, as it does not dissolve in the digestive tract. For adults with schizophrenia, the recommended dose is 6 mg every morning. No dose titration is required; however if needed, the dose can be adjusted at five day intervals to doses of 3 to 12 mg once daily. Side effects of paliperidone are expected to be similar to those of risperidone, including the

potential for dose related EPS and prolactin elevation. A long-acting injectible form of paliperidone has been recently approved.

Patient Encounter, Part 3

Soon after his discharge from the hospital, AC stopped taking his olanzapine. He had gained a lot of weight, and he didn't believe the medication was helping. He continued to have difficulties maintaining employment and being involved socially. With encouragement from his girlfriend, AC sought treatment again and was started on risperidone 2.5 mg a day. He continued to experience paranoia, still feeling unable to function up to his potential at work, and still tending to be reclusive. A new therapist supported his involvement in Alcoholics Anonymous, and AC began to question the depression diagnosis. She referred him to a center specializing in schizophrenia where the diagnosis was established to be schizophrenia, paranoid type, continuous with depressive episode, single episode, alcohol dependence, early full remission; and poly-substance abuse, early full remission.

Why was risperidone selected as the next antipsychotic choice for AC?

Describe nonpharmacologic treatment strategies that may be appropriate for AC.

Discuss a risperidone dosing plan, and list side effects AC may experience on this medication.

Iloperidone (Fenapt)

Iloperidone was approved in the United States in 2009 and is indicated for acute treatment of adults with schizophenia. Iloperidone exhibits high affinity for 5HT2a and dopamine D2 and D3 receptors and acts as an antagonist at these receptors, as well as the 5HTia and norepinephrine ai/a2c receptors. Doses must be titrated due to the risk of orthostatic hypotension and starts at 1 mg twice daily, titrating daily up to a close of 24 mg total daily dose (12 mg twice daily). Iloperidone has the potential to prolong the QT interval, so clinicians should consider using other drugs first. Common adverse reactions include dizziness, dry mouth, fatigue, orthostatic hypotension, tachy cardia, and weight gain.

Table 37-5 First-Generation (Typical) Antipsychotics

Duuye Riitgt


Avail able


Agent (Brand Name)


Equivalent! Inuj)

Formula* ioni

Bun yptolHne

Hifcifx.'fkkrf IHJUül)



7, LC, 1


liiiapine (Laxlta ne)





Pimoiide (Orapfl




Molindone I^dLuhV)





Chlort* cmvmne {ihorMii>e)



T, LC. 1, n

f lupt--5nisTi? IPnohxir»



T.U^ir.'iifi/ir''1 \ uil.i'iui



r, 11

ThiofkJazine (Meferi&




Tulkjopaaiirrt? (Sielaiirwf





1 hiofliiijert^ (W^viiiie)




C tiiMuift C-5B. cofmoietl- susri:'i«irel«isi: L iniecdoft L ifciuKJ wiutkxn eliair, oruApensfortLC i*iukJ eerceritwn H. i«riJ suwosioiy; LtaMer.

Low-poientyaniipsyChorci iritL-ds Thioridazine, meuiridaiirvi, iivd thJoipiömarine. Hlghvpctercy Ahiiptyfluiitt Int kfdi hslepertdoLfluphtnaiiw, (mothlwrie, aivi pihyijici!*.

C tiiMuift C-5B. cofmoietl- susri:'i«irel«isi: L iniecdoft L ifciuKJ wiutkxn eliair, oruApensfortLC i*iukJ eerceritwn H. i«riJ suwosioiy; LtaMer.

Low-poientyaniipsyChorci iritL-ds Thioridazine, meuiridaiirvi, iivd thJoipiömarine. Hlghvpctercy Ahiiptyfluiitt Int kfdi hslepertdoLfluphtnaiiw, (mothlwrie, aivi pihyijici!*.

Asenapine (Saphris)

Asenapine was approved in the United States in 2009 and is indicated for the acute treatment of schizophrenia in adults. Asenapine's mechanism of action is thought to be associated with antagonistic activity at 5HT2a and D2 receptors. Asenapine also exhibits a high affinity for other serotonerigic and dopaminergic receptors, as well as a1 and a2 adrenergic receptors and H1 receptors. The recommended starting and target dose for the treatment of symptoms of schizophrenia is 5 mg sublingually twice a day. Tablets must be placed under the tongue and allowed to be dissolved completely; the tablets should not be chewed or swallowed. Patients should refrain from drinking or eating for 10 minutes post administration. In controlled trials no added benefit was seen with doses above 10 mg twice daily, but there was an increase in adverse effects. Adverse effects commonly seen with asenapine may include somnolence, dizziness, and akathisia.

First-Generation (Typical) Antipsychotics

FGAs are high-affinity D2 receptor antagonists. During chronic treatment, these agents block 65% to 80% of D2 receptors in the striatum and block dopamine receptors in the other dopamine tracts in the brain as well.29 Clinical response is generally associated with 60% D2-receptor blockade, while 70% and 80% are associated with hyperprolactinemia and EPS, respectively. This group of antipsychotics was widely used from the 1950s to the 1990s, when the SGAs began to replace these agents as first-line therapy.

Dosages for these agents are frequently given as chlorpromazine equivalent dosages, which are defined as the dosage of any of the FGAs equipotent with 100 mg of chlorpromazine. The target dose recommendation for acute psychosis is 400 to 600 chlorpromazine equivalents, unless the patient's history indicates that this dose may result in intolerable side effects. Generally maintenance therapy should provide a dose of 300 to 600 chlorpromazine equivalents for maximum efficacy. Information on dosing and available dosage forms is provided in Table 37-5. All FGAs are equally efficacious in groups of patients when used in equipotent doses. However, individual variation does occur, such that a patient may not respond equally to each antipsychot-ic. Selection of a particular antipsychotic should be based on patient variables, such as the need to avoid certain side effects or interactions with concomitant medications. Previous patient or family history of response is also helpful in the selection of a particular agent.


Long-acting, depot preparations are available for two FGAs (fluphenazine decanoate and haloperidol decanoate) in the United States. These compounds are esterified antipsychotics formulated in sesame seed oil for deep intramuscular (IM) injection. Because these are long-acting preparations, patients should be exposed to the oral form of the drug first to ensure tolerability. With initial dosing of haloperidol decanoate, oral supplementation may temporarily be necessary, as the drug accumulates over many weeks, not reaching steady state until 4 to 5 dosing intervals have elapsed. The pharmacokinetic profiles of the depot agents are useful parameters for strategic dosing. Patients may be dosed with fluphenazine decanoate on a 1- to 3-week interval, while haloperidol decanoate is usually dosed once a month. Conversion from oral to depot and maintenance dosing recommendations are shown in Table 37-6. Based on these recommendations, a reasonable estimate is that 12.5 mg (0.5 mL) of fluphenazine decanoate given every 2 weeks is approximately equivalent to 10 mg/day of fluphenazine orally. A maintenance haloperidol decanoate dose of 150 mg every 4 weeks is approximately equivalent to 10 mg/day of oral haloperidol. Initial decanoate injections should be preceded by a small test dose.

Table 37-6 Antipsychotic Dosing of Long-Acting Preparations

Sterling Dam

Mninlvnanre fJ'aiit

Comments l-lalopeddol jo xoral halufwiiiildrdy dose;

decanoale in the elderlyuse 10—IS x oral lulopwiilol djily diw Generally 1OCMS0 ring/month initial dose should not exceed 100 ifiii rttjJrdli.'H el [HL'vkjuft doseiequiremeftis (if gneaier than IQG ing gfcie 3-? day^ epar!) FlLipiwsiirie ljKtiiifluphiniiiinetiaiij'dose.

detanoale generally IJ week-i

1Q-IS v. oral halCfOfriitiil daily dose, generaty 50-300 mg/ month lissed on star tiro dose and clrtral response Generally I ¿5-25 mg dosed at 1-4 Inreivals (iruy be-up to ti in somo- cases)

'sV l! i initial dosing, oral supplemenialon may lempoiai ily lv rwii'sviiy: ilfiii IM inji v linn gennally wiih 71-gauge needle maximum volume per injeclioo silr.' ■nhoukf nor L'SiCT.'d i hlL Available in M iyhjiViiI aid IDD nig/ mL (i-mL vials and 1-rol ampules) Cafi l)t? adminr;iei«l IM i>f v.:

il-gauge needle, must he dry 5houW not exceed 100 rig: when dosing alwvp M) nig, dsauld increase in incremeiils of mg AttMblttl 15 mtVrrt. (S-mL vijli)

Side Effects of FGAs

The FGAs are associated with a host of side effects that largely differ between high-and low-potency agents. In general, the low-potency agents are less likely to cause EPS than the high-potency agents. Of note, lower doses and midpotency agents may be associated with less EPS than once believed and similar to SGAs in clinical trials.14

FGAs are associated with EPS, which includes akathisia (motor and/or subjective restlessness), dystonia (muscle spasm), and pseudoparkinsonism (akinesia, tremor, and rigidity). These fairly common motor side effects are caused by dopamine antagonism in the nigrostriatal pathways. Akathisia is the most frequently occurring motor side effect, with approximately 20% to 40% of people treated with FGA drugs experiencing an objective or subjective feeling of restlessness. Roughly half of the cases of akathisia present within one month of antipsychotic initiation although the onset of akathisia many times may be within 5 to 10 days after the first dose or increase in dosage. Younger people and those taking high doses of high-potency antipsychotics are at greater risk for the development of akathisia. Acute dystonic reactions are abrupt in onset and are usually seen within 24 to 96 hours after a first dose or increase in dosage. Characteristic signs and symptoms include abnormal positioning or spasm of the muscles of the head, neck, limbs, or trunk. Dystonia may occur in 10% to 20% of patients. There is higher risk for dystonia in young male patients and those taking high-potency FGAs. Pseudoparkinsonism resembles idiopathic Parkinson's disease, and features may be present in up to 30% to 60% of people treated with FGAs. The onset of symptoms is usually seen within 1 to 2 weeks following initiation of dosing or a dose increase. Risk factors include older age, female gender, high doses, and pos-

sibly those with depressive symptoms.

TD is a movement disorder characterized by abnormal choreiform (rapid, objectively purposeless, irregular, and spontaneous movement) and athetoid (slow and irregular) movements occurring late in onset in relation to initiation of antipsychotic therapy. This adverse effect usually develops over several months or after at least 3 months of cumulative exposure to neuroleptic medications. Severity of TD can range from mild and barely noticeable to severe. In some cases TD may be severe enough to interfere with ambulation, and may stigmatize persons taking antipsychotics if symptoms are visible to others. The estimated average prevalence of TD is 20% with a range of 13% to 36%. The incidence of new cases per treatment year with FGAs is

approximately 5%. TD is reversible in one-third to one-half of cases with the cessa-

tion of the antipsychotic. When the antipsychotic is tapered or discontinued, there is typically initial worsening of abnormal movements. Risk factors for TD include older age, longer duration of antipsychotic treatment, and presence of EPS, substance abuse, and mood disorders. SGAs carry a lower risk of TD than FGAs. A pooled analysis of studies indicated that new onset TD incidence was 0.8% with SGA treatment versus 5.4% for FGAs.15 A more recent review of studies published from 2004 to 2008 reported a smaller difference in incidence of TD between agents, at 3.9% for SGAs and 5.5% for FGAs.33

Table 37-7 Side Effects of FGAs



AiitiihoHDihjlf Side Effects

fitdiovtuulii Side Effect?

btaiit Eificti.' QTc Prolongation









+ + + +




+ 44






++ +

+ +

+ +














+ ++■

+ 4-





+ 4




1 lü'ow dol

+ + *+




+, ■.fry low; 4+, ft™* + + +, rtttdii^M1; 4 + 44, hnjhi; HPS, ialr.'ii'jyTAh^lal ikJi> elftv IV KiA(, UrSl-JtPeMllOn inl^VdHUn

+, ■.fry low; 4+, ft™* + + +, rtttdii^M1; 4 + 44, hnjhi; HPS, ialr.'ii'jyTAh^lal ikJi> elftv IV KiA(, UrSl-JtPeMllOn inl^VdHUn

Neuroleptic malignant syndrome (NMS), a life-threatening emergency characterized by severe muscular rigidity, autonomic instability, and altered consciousness, can occur uncommonly with all the FGAs, and may also occur with SGAs. Rapid dose escalation, the use of high-potency FGAs at higher doses, and younger patients are associated with a higher risk of NMS. When NMS is diagnosed or suspected, antipsychotics should be discontinued and supportive and symptomatic treatment begun (e.g., antipyretics, cooling blanket, IV fluids, oxygen, monitoring of liver enzymes, and complete blood cell count). Dopamine agonists (e.g., bromocriptine) should be considered in moderate to severe cases.

Additionally, dermatologic side effects, photosensitivity, and cataracts may occur with the phenothiazine agents. Sedation is caused from H1-receptor antagonism; an-ticholinergic side effects (constipation, blurred vision, dry mouth, and urinary retention) are caused from M1-receptor antagonism; and a1-receptor blockade is associated with orthostatic hypotension and tachycardia (Table 37-7). QTc prolongation may occur with lower-potency FGAs, and thioridazine has a black box warning for QTc prolongation.

Treatment Guidelines and Algorithms

Due to the plethora of choices and the rising costs of SGAs, algorithms and treatment/ consensus guidelines have been developed for the treatment of schizophrenia. The most widely accepted algorithm in the United States was developed as part of the Texas Implementation of Medication Algorithms (TIMA). A national panel of experts developed this algorithm, most recently updated in 2006.34 Algorithms go beyond guidelines, providing a framework for clinical decision making at critical decision points. According to the TIMA schizophrenia algorithm, SGAs (except clozapine) should be utilized as first-line treatment. The choice of SGA is guided by consideration of the side-effect profiles and the clinical characteristics of the patient. Treatment with a given drug should be continued for 4 to 6 weeks in order to assess response. If only partial response or nonresponse is noted, a trial of a second SGA should be initiated (Fig. 37-2). Other similar guidelines include the American Psychiatric Association Practice Guidelines for schizophrenia,11 The Expert Consensus Guideline Series,12 and the Schizophrenia Patient Outcomes Research Team (PORT) Treatment Recommendations.35 In contrast to the TIMA guidelines, the PORT recommends either the use of FGAs or SGAs as first-line therapy.

Treatment Adherence

Medication nonadherence in schizophrenia is common and often associated with symptom relapse.36 Estimates of nonadherence to antipsychotics range from approximately 24% to 88% with a mean of approximately 50%. Subjects who are nonad-herent have approximately a fourfold greater risk of a relapse than those who are adherent. Adherence to antipsychotic regimens is problematic for many reasons. Neuro-cognitive deficits and paranoid symptoms may hamper adherence to the therapeutic regimen, and identification of nonadherence by caretakers and providers can be chal lenging. Frequently, there is no obvious connection between nonadherence and symptom exacerbation, as there may be no immediate consequences of missing a dose, and patients may relapse suddenly after only several weeks or months of nonadherence. Antipsychotic side effects such as EPS, weight gain, and sexual dysfunction are also a major contributing factor to treatment nonadherence, with 25% to 66% of subjects

citing adverse effects as the primary reason for nonadherence. Several other factors are associated with nonadherence, including younger age, delusions, substance abuse, and deficit symptoms. For patients who have relapsed several times due to nonadher-ence, have a history of dangerous behavior, or risk a significant loss of social/vocational gains when relapsed, treatment with long-acting formulations should be encouraged. Risperidone is currently the only SGA with a long-acting formulation available. It uses a microsphere technology that maintains stable blood levels for about 2 weeks. Dosing is generally 25 to 50 mg every 2 weeks with oral supplementation in the first 3 weeks.

Trial of Single SGA |Afl f-|f"fiA2ÜLb ÜLANZAP NE, ÜUEflAPlNE, n iPERIDCJME, ür 7IPRrt5.|DON5)

Parl>al or nonresponse

Sis&e! Trial of single BOA or FGA [not i'idl tried n E-iaga 1}

Purlin I Or npnrfi5pvns.11


PaiiiBl M ftonrtsponse'1*



5t*e*£ Thai single agem FÜAor $ÜA (not S&A 1ried inSlaget i or?)

Slags 6 CambinaHion Ifierapy t<f; SGA * FGA; tombinoiion (il SGAs t ECT; FGA or SGA * (Hher agent {e.g.. mood stabilizer]

1 paiicnl ¿5 rtöflürihirsm M . ilinitifin may USi riSfindonfr KflJ-itajng irtiftCtJÖrt. Or harOpftrkSöl (UlluptienaiiiH*

decanoats any ilage. bul should carahilly assess side aflecli. "May ¿a- sidi; Mrl>- in. il 4P (loiapine il htlvyolHCVW juitdaliiy, viiirtci ¿amofbiil jubilance aliusfe. ir £-srs sifrrii pöthive symptoms less ihan 2 years II porsiS»rvi positive syrtiptoms iss dün £ yiNi-'s. clozapine tiiial I ndependsnl number ol pr»;»ding Hialt.

"Evaiiata patent for oBisr undeitymg of concDminan! faints-: «nsito SKKIII-IQ «gniiive behaivioui ih$rapy and oiher psychMKiai ¡merveninin.

FIGURE 37-2. TIMA algorithm for antipsychotic treatment in schizophrenia. Choice of antipsychotic should be guided by considering the clinical characteristics of the patient and the efficacy and side-effect profiles of the medication. Any stage may be skipped depending on the clinical picture or history of antipsychotic failures. (ECT, electroconvulsive therapy; FGA, first-generation antipsychotic; SGA, second-generation antipsychotic.) (Adapted from the Texas Department of State Health Services.)

Table 37-8 Suggestions for First-Line Antipsychotic Therapy in Specific Patients

Clinical condition

Flrst-Ll ne Tr tal ment

Other Optloni

UiJbel« of family liistury OÍ diabetes

to ippUZOle, Qutliipine. ivi jüdünt


Hyper pkietflii or ikjnifScjnr family history of

Arip^HiMk;, iipUiktii*;

RisojikJ&ne. queiiaeiine


HypffiriglyretiifcYnlsof sgnilUant family Iwtoryof

Aripprarole, Jipfasktine

Rifwidone, t)iie<lapine

ulevalpd Iriglytwkfes

ÓvBrWétgM Oi Obti*, Of {onoLim about weight

toiptnaiok:, ¿¡(HaikJOne

RiSpcrkJum.*. quMlapku'

Gjrn.nH h.™jI djrtf untlion Of itXTXrna at>ou( mlwJI

AriOpiaiOk-, Oudiapine, ClQHpine

OlaniiijjirH:. iipuytJiinc


Amenorrhea of problems vnih menstrual penod

Anppfarole, queliapine, clozapine

Ülan;anine, ilpiaMlone

Cardiac arrhylhmlais of current antiarrhythmic

■Utoif npt astdone of clozapine


( i:Lil [ii-.|i:ry of I'1 <| -i il ■>. Ik I = 1 ■ - dllempts


tuirirtTo* oaii antkhctaerQk effects

R.-,| Y'l i: h inrqutftlipifl^ lipf asldcme

Olí niiflim; flow doit)

FPSor ievefe FPS In the pasT

Quetlapine. arlplprazole, clozapine


üuirent tardive dyskinesia

Ckuapine, quaiaprne

Risperidone, olanzapine, rlprasidone

History of nonadherenoe

Long-acting i isperidone

Ciffkulíy SA-allowing lablets/capsules

R-tp-endone c aripipf»rc>l= >qu>d. oraliydivniegrarrig tablets frispendone, olanzapine, clozapine!

long acting risperidone

EPS. extrapyramidal symptoms., J2.35.B.

EPS. extrapyramidal symptoms., J2.35.B.

Patient-Specific Antipsychotic Selection

Patient-specific characteristics may help guide the selection of antipsychotic treatment. Based on expert consensus guidelines, Table 37-8 provides evidence-based suggestions for SGA selection to aid the clinician in individualizing treatment. FGAs continue to have a place in therapy for patients who cannot afford the SGAs or for those who have responded favorably to these agents in the past. However, in the next few years several of the SGAs will be available generically, and cost may become less of an advantage for FGAs. New data suggest that the efficacy of FGAs is comparable to SGAs,14 however clinicians must evaluate the risk to benefit profile on an individualized basis.

Special Populations


Epidemiologic data show that 10% to 30% of patients with schizophrenia develop their first psychotic symptoms prior to their 18th birthday. The diagnosis of schizophrenia in children and adolescents is often difficult to make, and the differential diagnosis includes pervasive developmental disorders, attention-deficit/hyperactivity disorder, and language or communication disorders. The existence of prominent hallucinations or delusions, however, helps make the diagnosis, as they are not a prominent part of the other disorders. Fifty-four percent to 90% of patients developing schizo phrenia before age 18 have premorbid abnormalities such as withdrawal, odd traits,

and isolation.

Treatment for psychotic children and adolescents ideally involves an intensive and comprehensive program with a highly structured environment that includes special education and psychoeducation. Day treatment, hospitalization, or long-term residential treatment may be necessary. Pharmacologic treatment is indicated if psychotic symptoms cause significant impairments or interfere with other interventions. Children and adolescents are more vulnerable to EPS, particularly dystonias, than are adults. Due to concerns about EPS and TD, it has been recommended that pharmaco-therapy in children and adolescents should be initiated with SGAs. Aripiprazole and risperidone are both FDA-indicated for the treatment of schizophrenia in adolescents aged 13 to 17. Recommended initiation and target dosing is lower for adolescents than adults.

Agents with significant sedation and anticholinergic side effects are not preferred, as they can cause attention difficulties and cognitive dulling that may interfere with optimal school performance. Compared to adults, children and adolescents tend to gain more weight on these agents. Young patients should be started on lower doses than adults and should be titrated at a slower rate. Side effects should be monitored closely during initiation and throughout maintenance therapy. Informed consent, addressing the rationale for treatment, and potential risks and benefits of therapy, should be obtained from the parents or guardians prior to treatment with any antipsychotic medication, and assent should be obtained from the child as well.


Psychotic symptoms in late life (greater than 65 years of age) are generally a result of an ongoing chronic illness carried over from younger life; however, a small percentage of patients develop psychotic symptoms de novo, defined as late-life schizophrenia. However, other illnesses presenting with psychotic symptoms are common in this population, as approximately one-third of patients with Alzheimer's disease, Parkinson's disease, and vascular dementia experience psychotic symptoms. The majority of data for antipsychotic use in the elderly comes from experience treating these other disease states.

Antipsychotics can be safe and effective for the treatment of psychosis in the elderly, if used at lower doses than those commonly used in younger adults. Older adults are particularly vulnerable to the side effects of FGAs. Parkinsonian symptoms re portedly occur in over 50% of all elderly patients receiving these agents, and the cumulative annual incidence of TD in middle-aged and elderly patients is over 25%. With the SGAs, the risk appears to be approximately 4%. However, these data are based on a limited number of studies, and future investigations are likely to yield

more specific information regarding TD risk with the SGAs. The likelihood of reversing this potentially debilitating condition diminishes with age. Orthostasis, estimated to occur in 5% to 30% of geriatric patients, is a major contributing factor to the occurrence of falls that often leads to fractures, injuries, and loss of independence. Low-potency antipsychotics and clozapine are more likely to cause significant drops in orthostatic blood pressure. Antipsychotics may cause or worsen anticholinergic effects including constipation, dry mouth, urinary retention, and cognitive impairment. Cognitive impairment may lead to decreased independence, and a more rapid decline in cognitive functioning may occur in the elderly treated with antipsychotics than the younger adult population. As a result of data showing a statistically significant increase in mortality rate in elderly dementia patients who are treated with SGAs, all SGAs now carry a warning, and patients and families should be informed of this risk prior to treatment with these agents. Dosing in the elderly is initiated lower and titration is slower than in adults. Maximum doses are often one-half of adult doses.

Dually Diagnosed

The prevalence of substance dependence and abuse among persons with schizophrenia is significantly higher than in the general population. Conservative estimates of the proportion of schizophrenic patients abusing alcohol and/or illicit drugs range from one-third to as many as one-half.40 The most common drugs of abuse are cannabis and cocaine and alcohol abuse. Unfortunately, substance use often worsens the course and complicates the treatment of schizophrenia. Dually-diagnosed patients are more likely to be nonadherent with treatment. Characteristically, they have a poorer response rate to FGAs, have more severe psychosis, and have higher rates of relapse and rehospital-ization compared to patients who are not abusing substances. Some studies have found that EPS may occur more frequently in substance-abusing patients, and alcohol use is a risk factor for developing TD. There is a growing body of literature indicating that SGAs are effective in this population, and some studies have shown a reduction in the use of drugs and alcohol with SGAs.41

Treatment-Resistant Patients

For approximately 20% to 30% of people with schizophrenia, drug treatment is ineffective. A standard definition of treatment resistance is persistent positive symptoms despite treatment with at least two different antipsychotics given at adequate doses (at least 600 chlorpromazine equivalents) for an adequate duration (4-6 weeks). In addition, patients must have a moderately severe illness as defined by rating instruments,

and have a persistence of illness for at least 5 years. These patients are often highly symptomatic and require extensive periods of hospital care.


To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the FDA approval for the treatment of suicidal behavior in people with psychosis.43

A great deal of interest has been generated in understanding what pharmacologic properties of clozapine contribute to its superior efficacy, but to date this has not been clearly elucidated. Clozapine has a low affinity for D2 receptors, also blocks D1 receptors, and is a 5-HT2A antagonist. Its unsurpassed efficacy suggests that there is a neuropharmacology effect associated with clozapine that is to date unique to this agent.

Clozapine's use is limited by its association with the rare but life-threatening risk of agranulocytosis. Other side effects include seizures, as well as common unpleasant side effects including sedation, enuresis, anticholinergic effects, weight gain, and hypersalivation. The long-term hematologic monitoring (see monitoring section) required for prevention of agranulocytosis can represent a barrier to both patients and care providers. The optimal plasma level of clozapine is a minimum trough level of 300 to 350 ng/mL (300-350 mcg/L or 0.92 to 1.07 ^mol/L or 918-1,071 nmol/ L), usually corresponding to a daily dose of 200 to 400 mg, although dosage must be individualized. According to published guidelines and recommendations, cloza-pine should be considered after two failed antipsychotic trials, but may be considered sooner if the individual patient situation warrants.34

Other Strategies

Approximately 30% of patients treated with clozapine will not respond, and another 30% will have only a partial response to the drug. Treatment options with other medications are limited after clozapine nonresponse. For these patients, the best evidence points to augmentation using an FGA, SGA, or electroconvulsive therapy (ECT). The only available data support the combination of clozapine with risperidone; however, controlled trial results are mixed. Other potential strategies include combining antipsychotics with mood stabilizers (e.g., lithium, lamotrigine, valproate, and topiramate).34

Acutely Psychotic Patients

Psychiatric emergencies occur in a variety of settings, including emergency departments, psychiatric units, medical facilities, and outpatient settings. Although verbal interventions are recommended as initial interventions, most psychiatric emergencies require both pharmacologic and psychological interventions. Often, the psychiatrist must make decisions based on limited information and history. IM formulations are available for a number of FGAs and three SGAs (aripipra-zole, ziprasidone, and olan-zapine). These formulations are safe and effective in treating acute psychosis. These SGAs are now recommended as first-line therapy in agitated schizophrenia patients; however, IM lorazepam with or without concomitant oral (tablets, liquid, or disintegrating tablets) SGAs are also used. Concomitant olanzapine and benzodiazepines may cause orthostasis. High dosing of FGAs, termed rapid neuroleptization, is no longer recommended.

Pregnancy and Lactation

When to use antipsychotics in pregnancy and during lactation remains a complicated decision based on a careful analysis of risks and benefits. Women with schizophrenia, even those who are unmedicated have a significantly greater risk for stillbirth, infant death, preterm delivery, low infant birth weight, and infants that are small for gest-ational age. Furthermore, women who experience a relapse in psychotic symptoms during pregnancy are at the greatest risk for birth complications.4 Because risks related to psychotic relapse may be more detrimental than antipsychotic treatment to both mother and baby, antipsychotics are often continued during this period.

Essentially all antipsychotic medications pass through the placenta. High-potency FGAs are associated with a low risk for congenital abnormalities; however, limb defects and dyskinesias have been reported.45 Low-potency phenothiazine antipsychot-

ics may increase the risk of congenital abnormalities when used in the first trimester. According to the relevant literature published to date, there appears to be little risk associated with the first-line SGAs.4 Long-term neurobehavioral studies of children exposed to SGA in utero have not yet been done, however. On the basis of available data, generalization is impossible, and each case and specific antipsychotic should be weighed on an individual basis. While SGAs are excreted in breast milk, most case reports have reported a low frequency of deleterious effects on the infant. Women taking SGAs may have enhanced fertility compared to women taking FGAs, as SGAs (except risperidone and paliperidone) are less likely to cause prolactin elevations leading to anovulation. Therefore, careful discussion with patients, including education about birth control, must occur.

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