Positive Symptoms	Negative Symptoms
Hallucinations	Social withdrawal
Delusions	Emotional withdrawal
Disordered thinking	Lack of motivation
Disorganized speech	Poverty of speech
Combativeness	Blunted affect
Agitation	Poor insight
Paranoia	Poor judgment
	Poor self-care

First-generation (conventional) antipsychotics

The FGAs have been in use for over 50 years, and their pharmacology is well understood. Accordingly, it seems appropriate to begin with these drugs, even though their use has greatly declined. Besides, since the pharmacology of the FGAs and SGAs is very similar, once 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 31–3). The low-potency drugs, represented by chlorpromazine, and the high-potency drugs, represented by haloperidol, are of particular interest.

Table 31–3

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
Clozapine	Clozaril, FazaClo	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

^*Doses listed are the therapeutic equivalent of 100 mg of oral chlorpromazine.

^†Incidence here refers to early extrapyramidal reactions (acute dystonia, parkinsonism, akathisia). The incidence of late reactions (tardive dyskinesia) is the same for all traditional antipsychotics.

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.

The FGAs fall into five major chemical categories (Table 31–4). 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 31–4

Antipsychotic Drugs: Routes and Dosages

Chemical Group and Generic Name	Trade Name	Route	Usual Total Daily Dose for Schizophrenia (mg)
Chemical Group and Generic Name	Trade Name	Route	Short Term	Maintenance
FIRST-GENERATION (CONVENTIONAL) ANTIPSYCHOTICS
Phenothiazine: Aliphatic
Chlorpromazine	generic only	PO, IM, IV	200–1000	50–400
Phenothiazine: Piperidine
Thioridazine	generic only	PO	200–800	50–400
Phenothiazine: Piperazine
Fluphenazine	generic only	PO, IM	5–30	1–15
Perphenazine	generic only	PO	12–64	8–24
Trifluoperazine	generic only	PO, IM	10–60	4–30
Thioxanthene
Thiothixene	Navane	PO	10–60	6–30
Butyrophenone
Haloperidol	Haldol	PO, IM	5–50	1–5
Dibenzoxazepine
Loxapine	Loxitane	PO	20–160	20–60
Diphenylbutylpiperidine
Pimozide	Orap	PO	1–2*	10*
SECOND-GENERATION (ATYPICAL) ANTIPSYCHOTICS
Aripiprazole	Abilify	PO	10–15	10–15
Asenapine	Saphris	Sublingual	10	10
Clozapine	Clozaril, FazaClo	PO	300–900	300–600
Iloperidone	Fanapt	PO	12–24	12–24
Lurasidone	Latuda	PO	40–80	40–80
Olanzapine	Zyprexa	PO, IM	5–10	10–20
Paliperidone	Invega	PO	6	6
Quetiapine	Seroquel	PO	50	300–400
Risperidone	Risperdal	PO, IM	2–4	4–6
Ziprasidone	Geodon, Zeldox	PO, IM	40	80–120

^*Dosage for Tourette’s syndrome.

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, since 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 uses

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 of 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 (eg, delusions, hallucinations) may respond somewhat better than negative symptoms (eg, social and emotional withdrawal, blunted affect, poverty of speech) or cognitive dysfunction (eg, disordered thinking, learning and memory difficulties). 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 in depth later in the chapter.

Bipolar disorder (manic-depressive illness).

Most patients with bipolar disorder are managed with a mood-stabilizing agent (eg, lithium, valproic acid). Neuroleptics may be employed acutely, usually in combination with lithium or valproic acid, to help manage patients going through a severe manic phase. Bipolar disorder and its treatment are the subject of Chapter 33.

Tourette’s syndrome.

This rare inherited disorder is characterized by severe motor tics, barking cries, grunts, and outbursts of obscene language, all of which are spontaneous and beyond control of the patient. In addition to these core symptoms, patients frequently have symptoms resembling those of obsessive-compulsive disorder (OCD) or attention-deficit/hyperactivity disorder (ADHD). Neuroleptic drugs (eg, pimozide, fluphenazine, haloperidol) are the most effective agents for managing core symptoms. When core symptoms are mild, clonidine is the drug of choice. Symptoms of OCD can be managed with a selective serotonin reuptake inhibitor (eg, fluoxetine [Prozac]). Symptoms of ADHD can be controlled with a CNS stimulant (eg, methylphenidate [Ritalin]).

Prevention of emesis.

Neuroleptics suppress emesis by blocking dopamine receptors in the chemoreceptor trigger zone of the medulla. These drugs can be employed to suppress vomiting associated with cancer chemotherapy, gastroenteritis, uremia, and other conditions.

Other applications.

Neuroleptics can be used for delusional disorders, schizoaffective disorder, and dementia and other organic mental syndromes (ie, psychiatric syndromes resulting from organic causes, such as infection, metabolic disorders, poisoning, and structural injury to the brain). In addition, neuroleptics can relieve symptoms of Huntingtons chorea.

Adverse effects

The antipsychotic drugs block several kinds of receptors, and hence produce an array of side effects. Side effects associated with blockade of specific receptors are summarized in Table 31–5.

Table 31–5

Receptor Blockade and Side Effects of Antipsychotic Drugs

Receptor Type	Consequence of Blockade
D₂ dopaminergic	EPS; prolactin release
H₁ histaminergic	Weight gain, sedation
Muscarinic cholinergic	Dry mouth, blurred vision, urinary retention, constipation, tachycardia
Alpha₁-adrenergic	Orthostatic hypotension; reflex tachycardia

EPS = extrapyramidal symptoms.

Although antipsychotic agents produce a variety of undesired effects, these drugs are, on the whole, 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

Extrapyramidal symptoms (EPS) 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’s disease (PD). Although the exact cause of EPS 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—tardive dyskinesia—occurs late in therapy and has no satisfactory treatment. Characteristics of EPS are summarized in Table 31–6.

Table 31–6

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 (eg, benztropine) IM or IV.
Parkinsonism	5–30 days	Bradykinesia, mask-like facies, tremor, rigidity, shuffling gait, drooling, cogwheeling, stooped posture	Anticholinergics (eg, 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 (eg, chlorpromazine) than with high-potency agents (eg, haloperidol). In contrast, the risk of TD is equal with all FGAs.

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 (eg, benztropine, diphenhydramine) administered IM or IV. 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. Why? Because 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. Since 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 (eg, benztropine, diphenhydramine) and amantadine [Symmetrel] may be employed. Levodopa and direct dopamine agonists (eg, bromocriptine) should be avoided. Why? 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 if they are still needed.

If parkinsonism is severe, switching to an SGA is likely to help. As discussed below, the risk of parkinsonism with the 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 EPS, 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.

Tardive dyskinesia, 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.

Tardive dyskinesia 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 following 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. (Since 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 agent may help. Why? Because SGAs are less likely to promote TD.

Since 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 of 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 (eg, 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 25). In patients with NMS, this drug reduces rigidity and hyperthermia. Bromocriptine is a dopamine receptor agonist (see Chapter 21) that may relieve CNS toxicity.

Resumption of antipsychotic therapy carries a small risk of 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 31–3), 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 31–3, 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. Patients should be informed about signs of hypotension (lightheadedness, dizziness) and advised to sit or lie down if these occur. In addition, patients should be informed that hypotension can be minimized by moving slowly when assuming an erect posture. With hospitalized patients, blood pressure and pulses should be checked before dosing and 1 hour after. Measurements should be made while the patient is lying down and again after the patient has been sitting or standing for 1 to 2 minutes. If blood pressure is low, or if pulse rate is high, the dose should be withheld and the prescriber consulted. Hypotension is more likely with low-potency FGAs than with the high-potency FGAs (see Table 31–3). 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 histamine₁ receptors in the CNS. Daytime sedation can be minimized by giving the entire daily dose at bedtime. Patients should be warned against participating in hazardous activities (eg, driving) until sedative effects diminish.

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. Since 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.)

Seizures.

First-generation agents can reduce seizure threshold, thereby increasing the risk of seizure activity. The risk of seizures is greatest in patients with epilepsy and other seizure disorders. These patients should be monitored, and, if loss of seizure control occurs, the dosage of their antiseizure medication must be increased.

Sexual dysfunction.

First-generation agents can cause sexual dysfunction in women and men. In women, these drugs can suppress libido and impair the ability to achieve orgasm. In men, FGAs can suppress libido and cause erectile and ejaculatory dysfunction; the incidence is 25% to 60%. Drug-induced sexual dysfunction can make treatment unacceptable to sexually active patients, thereby leading to poor compliance. A reduction in dosage or switching to a high-potency FGA may reduce adverse sexual effects. Patients should be counseled about possible sexual dysfunction and encouraged to report any problems.

Agranulocytosis.

Agranulocytosis is a rare but serious reaction. Among the FGAs, the risk is highest with chlorpromazine and certain other phenothiazines. Since agranulocytosis severely compromises the ability to fight infection, a white blood cell (WBC) count should be done whenever signs of infection (eg, fever, sore throat) appear. If agranulocytosis is diagnosed, the neuroleptic should be withdrawn. Agranulocytosis will then reverse.

Severe dysrhythmias.

Four FGAs—chlorpromazine, haloperidol, thioridazine, and pimozide—pose a risk of fatal cardiac dysrhythmias. The mechanism is prolongation of the QT interval, an index of cardiac function that can be measured with an electrocardiogram (ECG). As discussed in Chapter 7 (Adverse Drug Reactions and Medication Errors), drugs that prolong the QT interval increase the risk of torsades de pointes, a dysrhythmia than can progress to fatal ventricular fibrillation. To reduce the risk of dysrhythmias, patients should undergo an ECG and serum potassium determination prior to treatment and periodically thereafter. In addition, they should avoid other drugs that cause QT prolongation (see Chapter 7, Table 7–2), as well as drugs that can increase levels of the drugs under consideration.