These include the first-generation (typical) neuroleptics, which act by blocking dopamine D2 receptors, and the second-generation (atypical) neuroleptics, which act on dopamine, serotonin, and other neurotransmitter systems. Some antipsychotic effect may occur within hours or days of initiating treatment, but full effects usually require 6 weeks to several months of daily, therapeutic dosing.
Useful to group into high-, mid-, and low-potency neuroleptics (Table 197-3). High-potency neuroleptics are least sedating, have almost no anticholinergic side effects, and have a strong tendency to induce extrapyramidal side effects (EPSEs). The EPSEs occur within several hours to several weeks of beginning treatment and include acute dystonias, akathisia, and pseudo-parkinsonism. Extrapyramidal symptoms respond well to trihexyphenidyl, 2 mg twice daily, or benztropine mesylate, 1–2 mg twice daily. Akathisia may respond to beta blockers. Low-potency neuroleptics are very sedating, may cause orthostatic hypotension, are anticholinergic, and tend not to induce EPSEs frequently.
TABLE 197-3ANTIPSYCHOTIC AGENTS ||Download (.pdf) TABLE 197-3ANTIPSYCHOTIC AGENTS
|Name ||Usual PO Daily Dose, mg ||Side Effects ||Sedation ||Comments |
|First-Generation Antipsychotics |
|Low potency |
|Anticholinergic effects, orthostasis, photosensitivity, cholestasis, QT prolongation ||+++ ||EPSEs usually not prominent; can cause anticholinergic delirium in elderly pts |
| Trifluoperazine (Stelazine) ||2–50 ||Fewer anticholinergic side effects ||++ ||Well tolerated by most pts |
| Perphenazine (Trilafon) ||4–64 ||Fewer EPSEs than with higher potency agents ||++ || |
| Loxapine (Loxitane) ||30–100 ||Frequent EPSEs ||++ || |
| Molindone (Moban) ||30–100 ||Frequent EPSEs ||0 ||Little weight gain |
|High potency |
| Haloperidol (Haldol) ||5–20 ||No anticholinergic side effects; EPSEs often prominent ||0/+ ||Often prescribed in doses that are too high; long-acting injectable forms of haloperidol and fluphenazine available |
| Fluphenazine (Prolixin) ||1–20 ||Frequent EPSEs ||0/+ || |
| Thiothixene (Navane) ||2–50 ||Frequent EPSEs ||0/+ || |
|Second-Generation Antipsychotics |
|Clozapine (Clozaril) ||150–600 ||Agranulocytosis (1%), weight gain, seizures, drooling, hyperthermia ||+ + ||Requires weekly WBC count for first 6 months, then biweekly if stable |
|Risperidone (Risperdal) ||2–8 ||Orthostasis ||+ ||Requires slow titration; EPSEs observed with doses >6 mg qd |
|Olanzapine (Zyprexa) ||10–30 ||Weight gain ||++ ||Mild prolactin elevation |
|Quetiapine (Seroquel) ||350–800 ||Sedation, weight gain, anxiety ||+++ ||Bid dosing |
|Ziprasidone (Geodon) ||120–200 ||Orthostatic hypotension ||+/++ ||Minimal weight gain, increases QT interval |
|Aripiprazole (Abilify) ||10–30 ||Nausea, anxiety, insomnia ||0/+ ||Mixed agonist/antagonist |
|Paliperidone (Invega) ||3–12 ||Restlessness, EPSEs, increased prolactin, headache ||+ ||Active metabolite of risperidone |
|Iloperidone (Fanapt) ||12–24 ||Dizziness, hypotension ||0/+ ||Requires dose titration, long-acting injectable available |
|Asenapine (Saphris) ||10–20 ||Dizziness, anxiety, EPSEs, minimal weight gain ||++ ||Sublingual tablets; bid dosing |
|Lurasidone (Latuda) ||40–80 ||Nausea, EPSEs ||++ ||Uses CYP3A4 |
Up to 20% of pts treated with conventional antipsychotic agents for >1 year develop tardive dyskinesia (probably due to dopamine receptor supersensitivity), an abnormal involuntary movement disorder most often observed in the face and distal extremities. Treatment includes gradual withdrawal of the neuroleptic, with possible switch to a novel neuroleptic; anticholinergic agents can worsen the disorder.
Rarely, pts exposed to neuroleptics develop neuroleptic malignant syndrome (NMS), a life-threatening complication with a mortality rate as high as 25%; hyperpyrexia, autonomic hyperactivity, muscle rigidity, obtundation, and agitation are characteristics associated with increased WBC, increased creatine phosphokinase, and myoglobinuria. Treatment involves immediate discontinuation of neuroleptics, supportive care, and use of dantrolene and bromocriptine.
A class of agents that has become the first line of treatment (Table 197-3); efficacious in treatment-resistant pts, tend not to induce EPSEs or tardive dyskinesia, and appear to have uniquely beneficial properties on negative symptoms and cognitive dysfunction. Main problem is side effect of weight gain (most prominent with clozapine and in olanzapine; can induce diabetes). The CATIE study, a large-scale investigation of antipsychotic agents in the “real world,” revealed a high rate of discontinuation of all medications over 18 months; olanzapine was modestly more effective than other agents but with a higher discontinuation rate due to side effects.
Four mood stabilizers in common use: lithium, valproic acid, carbamazepine/oxcarbazepine, and lamotrigine (Table 197-4). Lithium is the gold standard and the best studied, and along with carbamazepine and valproic acid, is used for treatment of acute manic episodes; 1–2 weeks to reach full effect. As prophylaxis, the mood stabilizers reduce frequency and severity of both manic and depressed episodes in cyclical mood disorders. In refractory bipolar disorder, combinations of mood stabilizers may be beneficial.
TABLE 197-4CLINICAL PHARMACOLOGY OF MOOD STABILIZERS ||Download (.pdf) TABLE 197-4CLINICAL PHARMACOLOGY OF MOOD STABILIZERS
|Agent and Dosing ||Side Effects and Other Effects |
|Lithium ||Common side effects |
Starting dose: 300 mg bid or tid
Therapeutic blood level: 0.8–1.2 meq/L
Nausea/anorexia/diarrhea, fine tremor, thirst, polyuria, fatigue, weight gain, acne, folliculitis, neutrophilia, hypothyroidism
Blood level is increased by thiazides, tetracyclines, and NSAIDs
Blood level is decreased by bronchodilators, verapamil, and carbonic anhydrase inhibitors
Rare side effects: Neurotoxicity, renal toxicity, hypercalcemia, ECG changes
|Valproic acid ||Common side effects |
Starting dose: 250 mg tid
Therapeutic blood level: 50–125 μg/mL
Nausea/anorexia, weight gain, sedation, tremor, rash, alopecia
Inhibits hepatic metabolism of other medications
Rare side effects: Pancreatitis, hepatotoxicity, Stevens-Johnson syndrome
|Carbamazepine/Oxcarbazepine ||Common side effects |
|Starting dose: 200 mg bid for carbamazepine, 150 mg bid for oxcarbazepine ||Nausea/anorexia, sedation, rash, dizziness/ataxia |
|Therapeutic blood level: 4–12 μg/mL for carbamazepine || |
Carbamazepine, but not oxcarbazepine, induces hepatic metabolism of other medications
Rare side effects: Hyponatremia, agranulocytosis, Stevens-Johnson syndrome
|Lamotrigine ||Common side effects |
|Starting dose: 25 mg/d || |
Rash, dizziness, headache, tremor, sedation, nausea
Rare side effect: Stevens-Johnson syndrome
For a more detailed discussion, see Reus VI: Mental Disorders, Chap. 466, p. 2708, in HPIM-19.