Three Types of Symptoms
Symptoms of schizophrenia can be divided into three groups: positive symptoms, negative symptoms, and cognitive symptoms. Positive and negative symptoms are shown in Table 24.1.
TABLE 24.1
Positive and Negative Symptoms of Schizophrenia
| Positive Symptoms | |
| Negative Symptoms |
Positive Symptoms and Negative Symptoms
Positive symptoms can be viewed as an exaggeration or distortion of normal function, whereas negative symptoms can be viewed as a loss or diminution of normal function. Positive symptoms include hallucinations, delusions, agitation, tension, and paranoia. Negative symptoms include lack of motivation, poverty of speech, blunted affect, poor self-care, and social withdrawal. Positive and negative symptoms respond equally to FGAs and SGAs.
Cognitive Symptoms
Cognitive symptoms include disordered thinking, reduced ability to focus attention, and prominent learning and memory difficulties. Subtle changes may appear years before symptoms become florid, when thinking and speech may be completely incomprehensible to others. Cognitive symptoms may respond equally to FGAs and SGAs.
Acute Episodes
During an acute schizophrenic episode, delusions (fixed false beliefs) and hallucinations are frequently prominent. Delusions are typically religious, grandiose, or persecutory. Auditory hallucinations, which are more common than visual hallucinations, may consist of voices arguing or commenting on one’s behavior. The patient may feel controlled by external influences. Disordered thinking and loose association may render rational conversation impossible. Affect may be blunted or labile. Misperception of reality may result in hostility and lack of cooperation. Impaired self-care skills may leave the patient disheveled and dirty. Patterns of sleeping and eating are usually disrupted.
Residual Symptoms
After florid symptoms (e.g., hallucinations, delusions) of an acute episode remit, less vivid symptoms may remain. These include suspiciousness, poor anxiety management, and diminished judgment, insight, motivation, and capacity for self-care. As a result, patients frequently find it difficult to establish close relationships, maintain employment, and function independently in society. Suspiciousness and poor anxiety management contribute to social withdrawal. Inability to appreciate the need for continued drug therapy may cause nonadherence, resulting in relapse and perhaps hospital readmission.
Long-Term Course
The long-term course of schizophrenia is characterized by episodic acute exacerbations separated by intervals of partial remission. As the years pass, some patients experience progressive decline in mental status and social functioning. However, many others stabilize, or even improve. Maintenance therapy with antipsychotic drugs reduces the risk for acute relapse but may fail to prevent long-term deterioration.
Etiology
Although there is strong evidence that schizophrenia has a biologic basis, the exact etiology is unknown. Genetic, perinatal, neurodevelopmental, and neuroanatomic factors may all be involved. Possible primary defects include excessive activation of CNS receptors for dopamine and insufficient activation of CNS receptors for glutamate. Although psychosocial stressors can precipitate acute exacerbations in susceptible patients, they are not considered causative.
First-Generation (Conventional) Antipsychotics
The FGAs have been in use for decades, and their pharmacology is well understood. Accordingly, it seems appropriate to begin with these drugs, even though their use has greatly declined. Because the pharmacology of the FGAs and SGAs is very similar, when you understand the FGAs, you will know a great deal about the SGAs as well.
Group Properties
In this section we discuss pharmacologic properties shared by all FGAs. Much of our attention focuses on adverse effects. Of these, extrapyramidal side effects are of particular concern. Because of these neurologic side effects, the FGAs are also known as neuroleptics.
Classification
The FGAs can be classified by potency or chemical structure. From a clinical viewpoint, classification by potency is more helpful.
Classification by Potency
First-generation antipsychotics can be classified as low potency, medium potency, or high potency (Table 24.2). The low-potency drugs, represented by chlorpromazine, and the high-potency drugs, represented by haloperidol, are of particular interest.
TABLE 24.2
Antipsychotic Drugs: Relative Potency and Incidence of Selected Side Effects
| Incidence of Side Effects | ||||||||||
| Drug | Trade Name | Equivalent Oral Dose (mg)* | Extrapyramidal Effects† | Sedation | Orthostatic Hypotension | Anticholinergic Effects | Metabolic Effects: Weight Gain, Diabetes Risk, Dyslipidemia | Significant QT Prolongation | Prolactin Elevation | Metabolized by CYP3A4 |
| FIRST-GENERATION (CONVENTIONAL) ANTIPSYCHOTICS | ||||||||||
| Low Potency | ||||||||||
| Chlorpromazine | generic only | 100 | Moderate | High | High | Moderate | Moderate | Yes | Low | — |
| Thioridazine | generic only | 100 | Low | High | High | High | Moderate | Yes | Low | — |
| Medium Potency | ||||||||||
| Loxapine | Loxitane | 13 | Moderate | Moderate | Low | Low | Low | No | Moderate | — |
| Perphenazine | generic only | 8 | Moderate | Moderate | Low | Low | — | No | Low | — |
| High Potency | ||||||||||
| Fluphenazine | generic only | 1 | Very high | Low | Low | Low | — | No | Moderate | — |
| Haloperidol | Haldol | 2 | Very high | Low | Low | Low | Moderate | Yes | Moderate | — |
| Pimozide | Orap | 1 | High | Moderate | Low | Moderate | — | Yes | Moderate | — |
| Thiothixene | Navane | 2 | High | Low | Moderate | Low | Moderate | No | Moderate | — |
| Trifluoperazine | generic only | 1 | High | Low | Low | Low | — | No | Moderate | — |
| SECOND-GENERATION (ATYPICAL) ANTIPSYCHOTICS | ||||||||||
| Aripiprazole | Abilify | 2 | Very low | Low | Low | None | None/low | No | Low | Yes |
| Asenapine | Saphris | 4 | Moderate | Moderate | Moderate | Low | Low | Yes | Low | Slightly |
| Brexpiprazole | Rexulti | 2 | Very low | Very low | Low | None | Low | No | Low | Yes |
| Cariprazine | Vraylar | 1.5 | Very low | Moderate | Low | Low | Moderate | No | No | Yes |
| Clozapine | Clozaril, FazaClo, Versacloz | 75 | Very low | High | Moderate | High | High | No | Low | Yes |
| Iloperidone | Fanapt | 4 | Very low | Moderate | Moderate | Moderate | Moderate | Yes | Low | Yes |
| Lurasidone | Latuda | 10 | Moderate | Moderate | Low | None | None/low | No | Low | Yes |
| Olanzapine | Zyprexa | 3 | Low | Moderate | Moderate | Moderate | High | No | Low | No |
| Paliperidone | Invega | 2 | Moderate | Low | Low | None | Moderate | Yes | High | Slightly |
| Quetiapine | Seroquel | 95 | Very low | Moderate | Moderate | None | Moderate/high | Yes | Low | Yes |
| Risperidone | Risperdal | 1 | Moderate | Low | Low | None | Moderate | No | High | No |
| Ziprasidone | Geodon, Zeldox  |
20 | Low | Moderate | Moderate | None | None/low | Yes | Low | Yes |
It is important to note that, although the FGAs differ from one another in potency, they all have the same ability to relieve symptoms of psychosis. Recall that the term potency refers only to the size of the dose needed to elicit a given response; potency implies nothing about the maximal effect a drug can produce. Hence, when we say that haloperidol is more potent than chlorpromazine, we only mean that the dose of haloperidol required to relieve psychotic symptoms is smaller than the required dose of chlorpromazine. We do not mean that haloperidol can produce greater effects. When administered in therapeutically equivalent doses, both drugs elicit an equivalent antipsychotic response.
If low-potency and high-potency neuroleptics are equally effective, why distinguish between them? The answer is that, although these agents produce identical antipsychotic effects, they differ significantly in side effects. Hence, by knowing the potency category to which a particular neuroleptic belongs, we can better predict its undesired responses. This knowledge is useful in drug selection and providing patient care and education.
Chemical Classification
The FGAs fall into four major chemical categories (Table 24.3). One of these categories, the phenothiazines, has three subgroups. Drugs in all groups are equivalent with respect to antipsychotic actions, and hence chemical classification is not emphasized in this chapter.
TABLE 24.3
Antipsychotic Drugs: Routes and Dosages
| Chemical Group and Generic Name | Trade Name | Availability | Usual Total Daily Dose for Schizophrenia (mg)* |
| Chlorpromazine | generic only | 10-, 25-, 50-, 100-, 200-mg tablets | 300–1000 |
| Thioridazine | generic only | 10-, 15-, 25-, 50-, 100-, 150-, 200-mg tablets | 300–800 |
| Fluphenazine | generic only |
1-, 2.5-, 5-, 10-mg tablets 2.5-mg/mL elixir 5-mg/mL oral concentrate |
5–20 |
| Perphenazine | generic only | 2-, 4-, 8-, 16-mg tablets | 12–64 |
| Trifluoperazine | generic only | 1-, 2-, 5-, 10-mg tablets | 15–50 |
| Thiothixene | generic only | 1-, 2-, 5-, 10-, 20-mg capsules | 15–50 |
| Haloperidol | Haldol |
0.5-, 1-, 2-, 5-, 10-, 20-mg tablets 2-mg/mL liquid |
6–40 |
| Loxapine | Loxitane | 5-, 10-, 25-, 50-mg capsules | 30–100 |
| Aripiprazole | Abilify |
2-, 5-, 10-, 15-, 20-, 30-mg tablets 1-mg/mL oral solution 10-, 15-mg orally disintegrating tablets |
10–30 |
| Asenapine | Saphris | 5-, 10-mg sublingual tablets | 10–20 |
| Brexpiprazole | Rexulti | 0.25-, 0.5-, 1-, 2-, 3-, 4-mg tablets | 2–4 |
| Cariprazine | Vraylar | 1.5-, 3-, 4.5-, 6-mg capsules | 1.5–6 |
| Clozapine | Clozaril, FazaClo, Versacloz |
12.5-, 25-, 50-, 100-, 200-mg tablets 50-mg/mL oral suspension 12.5-, 25-, 100-, 150-, 200-mg orally disintegrating tablets |
150–600 |
| Iloperidone | Fanapt | 1-, 2-, 4-, 6-, 8-, 10-, 12-mg tablets | 12–24 |
| Lurasidone | Latuda | 20-, 40-, 60-, 80-, 120-mg tablets | 40–160 |
| Olanzapine | Zyprexa |
2.5-, 5-, 7.5-, 10-, 15-, 20-mg tablets 5-, 10-, 15- ,20-mg orally disintegrating tablets |
5–30 |
| Paliperidone | Invega | 1.5-, 3-, 6-, 9-mg extended release tablets | 3–12 |
| Quetiapine | Seroquel |
25-, 50-, 100-, 200-, 300-, 400-mg immediate release tablets 50-, 100-, 200-, 300-, 400- mg extended-release tablets |
300–750 |
| Risperidone | Risperdal |
0.25-, 0.5-, 1-, 2-, 3-, 4-mg film-coated tablets 1-mg/mL oral solution 0.5-, 1-, 2-, 3-, 4-mg orally disintegrating tablets |
2–8 |
| Ziprasidone | Geodon, Zeldox  |
20-, 40-, 60-, 80-mg capsules | 8–160 |
Two chemical categories—phenothiazines and butyrophenones—deserve attention. The phenothiazines were the first modern antipsychotic agents. Chlorpromazine, our prototype of the low-potency neuroleptics, belongs to this family. The butyrophenones stand out because they are the family to which haloperidol belongs. Haloperidol is the prototype of the high-potency FGAs.
Mechanism of Action
The FGAs block a variety of receptors within and outside the CNS. To varying degrees, they block receptors for dopamine, acetylcholine, histamine, and norepinephrine. There is little question that blockade at these receptors is responsible for the major adverse effects of the antipsychotics. However, because the etiology of psychotic illness is unclear, the relationship of receptor blockade to therapeutic effects can only be guessed. The current dominant theory suggests that FGA drugs suppress symptoms of psychosis by blocking dopamine2 (D2) receptors in the mesolimbic area of the brain. In support of this theory is the observation that all of the FGAs produce D2 receptor blockade. Furthermore, there is a close correlation between the clinical potency of these drugs and their potency as D2 receptor antagonists.
Therapeutic Use: Schizophrenia
Schizophrenia is the primary indication for antipsychotic drugs. These agents effectively suppress symptoms during acute psychotic episodes and, when taken chronically, can greatly reduce the risk for relapse. Initial effects may be seen in 1 to 2 days, but substantial improvement usually takes 2 to 4 weeks, and full effects may not develop for several months. Positive symptoms may respond somewhat better than negative symptoms or cognitive dysfunction. All of the FGA agents are equally effective, although individual patients may respond better to one FGA than to another. Consequently, selection among these drugs is based primarily on their side effect profiles, rather than on therapeutic effects. It must be noted that antipsychotic drugs do not alter the underlying pathology of schizophrenia. Hence, treatment is not curative—it offers only symptomatic relief. Management of schizophrenia is discussed later in the chapter.
Neuroleptics may be employed acutely to help manage patients with bipolar disorder going through a severe manic phase. Neuroleptic medications are also used to treat Tourette syndrome, a rare inherited disorder characterized by severe motor tics, barking cries, grunts, and outbursts of obscene language. Additional applications include suppression of emesis through dopamine receptor blockade, relief of symptoms caused by Huntington chorea, and treatment of organic mental syndromes.
Adverse Effects
The antipsychotic drugs block several kinds of receptors and produce an array of side effects, including a variety of undesired effects. However, these drugs are generally very safe; death from overdose is practically unheard of. Among the many side effects FGAs can produce, the most troubling are the extrapyramidal reactions—especially tardive dyskinesia (TD).
Extrapyramidal Symptoms
EPSs are movement disorders resulting from effects of antipsychotic drugs on the extrapyramidal motor system. The extrapyramidal system is the same neuronal network whose malfunction is responsible for the movement disorders of Parkinson disease (PD). Although the exact cause of EPSs is unclear, blockade of D2 receptors is strongly suspected.
Four types of EPS occur. They differ with respect to time of onset and management. Three of these reactions—acute dystonia, parkinsonism, and akathisia—occur early in therapy and can be managed with a variety of drugs. The fourth reaction—TD—occurs late in therapy and has no satisfactory treatment. Characteristics of EPSs are shown in Table 24.4.
TABLE 24.4
Extrapyramidal Side Effects of Antipsychotic Drugs
| Type of Reaction | Time of Onset | Features | Management |
| EARLY REACTIONS | |||
| Acute dystonia | A few hours to 5 days | Spasm of muscles of tongue, face, neck, and back; opisthotonus | Anticholinergic drugs (e.g., benztropine) IM or IV |
| Parkinsonism | 5–30 days | Bradykinesia, mask-like facies, tremor, rigidity, shuffling gait, drooling, cogwheeling, stooped posture | Anticholinergics (e.g., benztropine, diphenhydramine), amantadine, or both. For severe symptoms, switch to a second-generation antipsychotic. |
| Akathisia | 5–60 days | Compulsive, restless movement; symptoms of anxiety, agitation | Reduce dosage or switch to a low-potency antipsychotic. Treat with a benzodiazepine, beta blocker, or anticholinergic drug. |
| LATE REACTION | |||
| Tardive dyskinesia | Months to years | Oral-facial dyskinesias, choreoathetoid movements | Best approach is prevention; no reliable treatment. Discontinue all anticholinergic drugs. Give benzodiazepines. Reduce antipsychotic dosage. For severe TD, switch to a second-generation antipsychotic. |
The early reactions occur less frequently with low-potency agents (e.g., chlorpromazine) than with high-potency agents (e.g., haloperidol). In contrast, the risk for TD is equal with all FGAs.
For many patients, EPSs are uncomfortable, disturbing, and sometimes dangerous. Some manifestations of EPSs, such as TD, are irreversible. It is crucial to monitor patients treated with antipsychotic medications for evidence of EPSs.
Acute Dystonia
Acute dystonia can be both disturbing and dangerous. The reaction develops within the first few days of therapy and frequently within hours of the first dose. Typically, the patient develops severe spasm of the muscles of the tongue, face, neck, or back. Oculogyric crisis (involuntary upward deviation of the eyes) and opisthotonus (tetanic spasm of the back muscles causing the trunk to arch forward while the head and lower limbs are thrust backward) may also occur. Severe cramping can cause joint dislocation. Laryngeal dystonia can impair respiration.
Intense dystonia is a crisis that requires rapid intervention. Initial treatment consists of an anticholinergic medication (e.g., benztropine, diphenhydramine) administered by the intramuscular (IM) or intravenous (IV) route. As a rule, symptoms resolve within 5 minutes of IV dosing and within 15 to 20 minutes of IM dosing.
It is important to differentiate between acute dystonia and psychotic hysteria. Misdiagnosis of acute dystonia as hysteria could result in giving bigger antipsychotic doses, thereby causing the acute dystonia to become even worse.
Parkinsonism
Antipsychotic-induced parkinsonism is characterized by bradykinesia, mask-like facies, drooling, tremor, rigidity, shuffling gait, cogwheeling, and stooped posture. Symptoms develop within the first month of therapy and are indistinguishable from those of idiopathic PD.
Neuroleptics cause parkinsonism by blocking dopamine receptors in the striatum. Because idiopathic PD is also due to reduced activation of striatal dopamine receptors (see Chapter 21), it is no wonder that PD and neuroleptic-induced parkinsonism share the same symptoms.
Neuroleptic-induced parkinsonism is treated with some of the drugs used for idiopathic PD. Specifically, centrally acting anticholinergic drugs (e.g., benztropine, diphenhydramine) and amantadine [Symmetrel] may be employed. Levodopa and direct dopamine agonists (e.g., bromocriptine) should be avoided because these drugs activate dopamine receptors and might thereby counteract the beneficial effects of antipsychotic treatment.
Use of antiparkinsonism drugs should not continue indefinitely. Antipsychotic-induced parkinsonism tends to resolve spontaneously, usually within months of its onset. Accordingly, antiparkinsonism drugs should be withdrawn after a few months to determine whether they are still needed.
If parkinsonism is severe, switching to an SGA is likely to help. As discussed later, the risk for parkinsonism with SGAs is much lower than with FGAs.
Akathisia
Akathisia is characterized by pacing and squirming brought on by an uncontrollable need to be in motion. This profound sense of restlessness can be very disturbing. The syndrome usually develops within the first 2 months of treatment. Like other early EPSs, akathisia occurs most frequently with high-potency FGAs.
Three types of drugs have been used to suppress symptoms: beta blockers, benzodiazepines, and anticholinergic drugs. Although these drugs can help, reducing antipsychotic dosage or switching to a low-potency FGA may be more effective.
It is important to differentiate between akathisia and exacerbation of psychosis. If akathisia were to be confused with anxiety or psychotic agitation, it is likely that antipsychotic dosage would be increased, thereby making akathisia more intense.
Tardive Dyskinesia
TD, the most troubling EPS, develops in 15% to 20% of patients during long-term therapy with FGAs. The risk is related to duration of treatment and dosage size. For many patients, symptoms are irreversible.
TD is characterized by involuntary choreoathetoid (twisting, writhing, worm-like) movements of the tongue and face. Patients may also present with lip-smacking movements, and their tongues may flick out in a “fly catching” motion. One of the earliest manifestations of TD is slow, worm-like movement of the tongue. Involuntary movements that involve the tongue and mouth can interfere with chewing, swallowing, and speaking. Eating difficulties can result in malnutrition and weight loss. Over time, TD produces involuntary movements of the limbs, toes, fingers, and trunk. For some patients, symptoms decline after a dosage reduction or drug withdrawal. For others, TD is irreversible.
The cause of TD is complex and incompletely understood. One theory suggests that symptoms result from excessive activation of dopamine receptors. It is postulated that, in response to chronic receptor blockade, dopamine receptors of the extrapyramidal system undergo a functional change such that their sensitivity to activation is increased. Stimulation of these “supersensitive” receptors produces an imbalance in favor of dopamine and thereby produces abnormal movement. In support of this theory is the observation that symptoms of TD can be reduced (temporarily) by increasing antipsychotic dosage, which increases dopamine receptor blockade. (Because symptoms eventually return even though antipsychotic dosage is kept high, dosage elevation cannot be used to treat TD.)
There is no reliable management for TD. Measures that may be tried include gradually withdrawing anticholinergic drugs, giving benzodiazepines, and reducing the dosage of the offending FGA. For patients with severe TD, switching to an SGA may help because SGAs are less likely to promote TD.
Because TD has no reliable means of treatment, prevention is the best approach. Antipsychotic drugs should be used in the lowest effective dosage for the shortest time required. After 12 months, the need for continued therapy should be assessed. If drug use must continue, a neurologic evaluation should be done at least every 3 months to detect early signs of TD. For patients with chronic schizophrenia, dosage should be tapered periodically (at least annually) to determine the need for continued treatment.
Other Adverse Effects
Neuroleptic Malignant Syndrome.
Neuroleptic malignant syndrome (NMS) is a rare but serious reaction that carries a 4% risk for mortality—down from 30% in the past, thanks to early diagnosis and intervention. Primary symptoms are “lead pipe” rigidity, sudden high fever (temperature may exceed 41°C), sweating, and autonomic instability, manifested as dysrhythmias and fluctuations in blood pressure. Level of consciousness may rise and fall, the patient may appear confused or mute, and seizures or coma may develop. Death can result from respiratory failure, cardiovascular collapse, dysrhythmias, and other causes. NMS is more likely with high-potency FGAs than with low-potency FGAs.
Treatment consists of supportive measures, drug therapy, and immediate withdrawal of antipsychotic medication. Hyperthermia should be controlled with cooling blankets and antipyretics (e.g., aspirin, acetaminophen). Hydration should be maintained with fluids. Benzodiazepines may relieve anxiety and help reduce blood pressure and tachycardia. Two drugs—dantrolene and bromocriptine—may be especially helpful. Dantrolene is a direct-acting muscle relaxant (see Chapter 20). In patients with NMS, this drug reduces rigidity and hyperthermia. Bromocriptine is a dopamine receptor agonist (see Chapter 17) that may relieve CNS toxicity.
Resumption of antipsychotic therapy carries a small risk for NMS recurrence. The risk can be minimized by (1) waiting at least 2 weeks before resuming antipsychotic treatment, (2) using the lowest effective dosage, and (3) avoiding high-potency agents. If a second episode occurs, switching to an SGA may help.
Anticholinergic Effects.
First-generation agents produce varying degrees of muscarinic cholinergic blockade (see Table 24.2) and can elicit the full spectrum of anticholinergic responses (dry mouth, blurred vision, photophobia, urinary hesitancy, constipation, tachycardia). Patients should be informed about these responses and taught how to minimize danger and discomfort. As indicated in Table 24.2, anticholinergic effects are more likely with low-potency FGAs than with high-potency FGAs. Anticholinergic effects and their management are discussed in detail in Chapter 14.
Orthostatic Hypotension.
Antipsychotic drugs promote orthostatic hypotension by blocking alpha1-adrenergic receptors on blood vessels. Alpha-adrenergic blockade prevents compensatory vasoconstriction when the patient stands, thereby causing blood pressure to fall. Hypotension is more likely with low-potency FGAs than with the high-potency FGAs (see Table 24.2). Tolerance to hypotension develops in 2 to 3 months.
Sedation.
Sedation is common during the early days of treatment but subsides within a week or so. Neuroleptic-induced sedation is thought to result from blockade of histamine-1 (H1) receptors in the CNS. Daytime sedation can be minimized by giving the entire daily dose at bedtime.
Neuroendocrine Effects.
Antipsychotics increase levels of circulating prolactin by blocking the inhibitory action of dopamine on prolactin release. Elevation of prolactin levels promotes gynecomastia (breast growth) and galactorrhea in up to 57% of women. Up to 97% of women experience menstrual irregularities. Gynecomastia and galactorrhea can also occur in males. Because prolactin can promote growth of prolactin-dependent carcinoma of the breast, neuroleptics should be avoided in patients with this form of cancer. (It should be noted that, although FGAs can promote the growth of cancers that already exist, there is no evidence that FGAs actually cause cancer.)
