Serotonin–Dopamine Antagonists and Similarly Acting Drugs (Second Generation or Atypical Antipsychotics)

For a more detailed discussion of this topic, see Second Generation Antipsychotics, Sec. 31.28, p. 3206, in Comprehensive Textbook of Psychiatry, 9th Edition.

The serotonin–dopamine antagonists (SDAs), also known as second-generation or atypical antipsychotic drugs, have truly justified the numerous terminologies that define their role as psychotropic agents. The term atypical signifies their major difference from typical or conventional antipsychotics because they have a wider application than first-generation dopamine receptor antagonists (DRAs). Since the last edition, all second-generation antipsychotic drugs have received approval to be used as monotherapy or adjunctive therapy in the treatment of bipolar disorder, some have also been approved for major depression, and some are used in generalized anxiety disorder (GAD). Based on multiple indications for each, a section under each medicine specifying its U.S. Food and Drug Administration (FDA)–approved indications has been added.

The second-generation antipsychotic drugs include risperidone (Risperdal), risperdal Consta (long acting), olanzapine, olanzapine for extended-release injectable suspension (Zyprexa Relprevv), quetiapine (Seroquel), quetiapine XR (Seroquel XR), ziprasidone (Geodon), aripiprazole (Abilify), paliperidone (Invega), paliperidone palmitate (Invega Sustenna), asenapine (Saphris), lurasidone (Latuda) and clozapine (Clozaril) iloperidone (Fanapt).

Mechanisms of Action

The term SDA defines their neuroreceptor profile with a higher ratio of serotonin type 2 (5-HT₂) to D₂ dopamine receptor blockades than the typical, or conventional, DRAs that previously were the mainstay of treatment. All have different chemical structures, receptor affinities, and side effect profiles. No SDA is identical in its combination of receptor affinities, and the relative contribution of each receptor interaction to the clinical effects is unknown.

The SDAs also appear to be more specific for the mesolimbic than striatal dopamine system, and in some cases, they are associated with rapid dissociation from the D₂ receptor. It is hypothesized that these properties account for the improved tolerability associated with the SDAs. Second-generation drugs have largely replaced the DRAs because they are considered to have a lower risk of extrapyramidal side effects (EPS) and thereby eliminate the need for anticholinergic drugs. Second-generation drugs are also effective for the treatment of bipolar disorder and mood disorders with psychotic or manic or depressive features. A few are also approved
for the treatment of major depressive disorder (MDD) and also have an indication in GAD.

Weight Gain Risk

Although associated with a lowered but not absent risk of EPS, some of the drugs in this group often produce substantial weight gain, which in turn increases the potential for development of diabetes mellitus. Although olanzapine and clozapine appear to account for most cases of drug-induced diabetes mellitus but ziprasidone and aripiprazole have not been found to pose a risk, the FDA has requested that all SDAs carry a warning label that patients taking the drugs be monitored closely and has recommended the following guidelines for all second-generation antipsychotics.

Personal and family history of obesity, diabetes, dyslipidemia, hypertension, and cardiovascular disease
Weight and height (so that body mass index can be calculated)
Waist circumference (at the level of the umbilicus)
Blood pressure
Fasting plasma glucose level
Fasting lipid profile

Patients with preexisting diabetes should have regular monitoring, including HgA1C and in some cases insulin levels. Among these drugs, clozapine sits apart. It is not considered a first-line agent because of side effects and need for weekly blood tests. Although highly effective in treating both mania and depression, clozapine does not have an FDA indication for these conditions.

Therapeutic Indications

Although initially approved for the treatment of schizophrenia and acute mania, some of these drugs have also been approved as adjunctive therapy in treatment-resistant depression and as adjunctive therapy in MDD. They are also useful in posttraumatic stress disorder and anxiety disorders, and although clinicians tend to use them in behavioral disturbances associated with dementia, all SDAs carry a FDA boxed warning regarding adverse effects when used in elderly persons with dementia-related psychoses because elderly patients with dementia related psychoses are at an increased risk (1.6 to 1.7 times) of death compared with placebo. All of these agents are considered first-line drugs for schizophrenia except clozapine, may cause adverse hematologic effects that require weekly blood sampling.

Schizophrenia and Schizoaffective Disorder

The SDAs are effective for treating acute and chronic psychoses such as schizophrenia and schizoaffective disorder, in both adults and adolescents. SDAs are as good as or better than typical antipsychotics (DRAs) for the treatment of positive symptoms in schizophrenia and superior to DRAs for the treatment of negative symptoms. Compared with persons treated with DRAs, persons treated with SDAs have fewer relapses and require less frequent hospitalization, fewer emergency department visits, less phone contact with mental health professionals, and less treatment in day programs.

Because clozapine has potentially life-threatening adverse effects, it is appropriate only for patients with schizophrenia who are resistant to all other antipsychotics. Other indications for clozapine include treatment of persons with severe tardive dyskinesia—which can be reversed with high dosages in some cases—and those with a low threshold for EPS. Persons who tolerate clozapine have done well on long-term therapy. The effectiveness of clozapine may be increased by augmentation with risperidone, which raises clozapine concentrations and sometimes results in dramatic clinical improvement.

Mood Disorders

All of the SDAs are FDA approved for treatment of acute mania. Some of these agents, including aripiprazole, olanzapine, quetiapine, and quetiapine XR, are also approved for the maintenance treatment in bipolar disorder as monotherapy or adjunctive therapy The SDAs improve depressive symptoms in schizophrenia, and both clinical experience and clinical trials show that all of the SDAs augment antidepressants in the acute management of major depression. At this time, olanzapine in combination with fluoxetine has been approved for treatment-resistant depression, and aripiprazole and Seroquel XR are indicated for adjunctive therapy to antidepressants in MDDs. Quetiapine and quetiapine XR are also approved in bipolar depression, and a fixed combination of olanzapine and fluoxetine (Symbyax) is approved by the FDA as a treatment for acute bipolar depression.

Other Indications

About 10 percent of schizophrenic patients exhibit outwardly aggressive or violent behavior. The SDAs are effective for treatment of such aggression. Other off-label indications include AIDS dementia, autistic spectrum disorders, Tourette’s disorder, Huntington’s disease, and Lesch-Nyhan syndrome. Risperidone and olanzapine have been used to control aggression and self-injury in children. These drugs have also been coadministered with sympathomimetics, such as methylphenidate (Ritalin) or dextroamphetamine (Dexedrine), to children with attention-deficit/hyperactivity disorder who are comorbid for either opposition-defiant disorder or conduct disorder. SDAs—especially olanzapine, quetiapine, and clozapine—are useful in persons who have severe tardive dyskinesia. The SDAs are also effective for treating psychotic depression and for psychosis secondary to head trauma, dementia, or treatment drugs.

Treatment with SDAs decreases the risk of suicide and water intoxication in patients with schizophrenia. Patients with treatment-resistant obsessive-compulsive disorder (OCD) have responded to the SDAs; however, a few persons treated with the SDAs have been noted to develop treatment-emergent symptoms of OCD. Some patients with borderline personality disorder may improve with the SDAs.

Some data suggest that treatment with conventional DRAs has protective effects against the progression of schizophrenia when used during the first episode of psychosis. Ongoing studies are looking at whether the use of SDAs in at-risk patients with early evidence of disease prevents deterioration, thus improving long-term outcome.

Adverse Effects

The SDAs share a similar spectrum of adverse reactions but differ considerably in terms of frequency or severity of their occurrence. Specific side effects that are more common with an individual SDA are emphasized in the discussion of each drug.

Table 28-1 Comparison of Usual Dosing^a for Some Available Second-Generation Antipsychotics in Schizophrenia

Antipsychotic	Typical Starting Dosage	Maintenance Therapy Dose Range	Titration	Maximum Recommended Dosage
Aripiprazole (tablets)	10–15 mg once a day	10–30 mg per day	Dosage increases should not be made before 2 wk	30 mg/day
Asenapine (Saphirs)	5 mg twice a day	10 mg twice a day	Titration not necessary	20 mg/a day
Clozapine (tablets)	12.5 mg once or twice a day	150–300 mg/day in divided doses or 200 mg as a single dose in the evening	The dosage should be increased to 25–50 mg on the second day. Further increases may be made in daily increments of 25–50 mg to a target dosage of 300–450 mg per day. Subsequent dosage increases should be made no more than once or twice weekly in increments of no more than 100 mg.	900 mg/day
Iloperidone (Fanapt)	1 mg twice a day	12–24 mg a day in divided dose	Start at 1 mg twice a day than move to 2-, 4-, 6-, 8- and 12-mg twice a day. Do this over the course of 7 days	24 mg/day
Lurasidone (Latuda)	40 mg/day	40–80 mg/day	Titration not necessary	120 mg/day
Olanzapine (tablets and orally disintegrating tablets)	5–10 mg/day	10–20 mg/day	Dosage increments of 5 mg once a day are recommended when required at intervals of not less than 1 wk.	20 mg/day
Paliperidone (extended-release tablets)	3–9 mg once a day	3–6 mg per day	Plasma concentration rises to a peak approximately 24 hr after dosing	12 mg/day
Quetiapine (tablets)	25 mg twice a day	Lowest dose needed to maintain remission	Increase in increments of 25–50 mg two or three times a day on the second and third day, as tolerated, to a target dosage of 500 mg daily by the fourth day (given in two or three doses/day). Further dosage adjustments, if required, should be of 25–50 mg twice a day and occur at intervals of not fewer than 2 days.	800 mg/day
Risperidone IM long acting	25–50 mg every 2 wk	Start with oral risperidone for 3 wk	Starting dose: 25 mg every 2 wk	50 mg for 2 wk
Risperidone (tablets and oral solution)	1 mg once a day	2–6 mg once a day	Increase to 2 mg once a day on the second day and 4 mg once a day on the third day. In some patients, a slower titration may be appropriate. When dosage adjustments are necessary, further dosage increments of 1–2 mg/day at intervals of not less than 1 wk are recommended.	1 6 mg/day
Ziprasidone (capsules)	20 mg twice a day with food	20–80 mg twice a day	Dosage adjustments based on individual clinical status may be made at intervals of not fewer than 2 days.	80 mg twice a day
Ziprasidone (IM)	For acute agitation: 10–20 mg, as required, up to a maximum of 40 mg/day	Not applicable	For acute agitation: Doses of 10 mg may be administered every 2 hr, and doses of 20 mg may be administered every 4 hr up to a maximum of 40 mg/day.	For acute agitation: 40 mg/day, for not more than 3 consecutive days
Note: Information taken from U.S. Prescribing Information for individual agents.
^aDosage adjustments may be required in special populations.
IM, intramuscular.

Indications

Risperidone is indicated for the acute and maintenance treatment of schizophrenia in adults and for the treatment of schizophrenia in adolescents age 13 to 17 years. Risperidone is also indicated for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder in adults and in children and adolescents age 10 to 17 years. The combination of risperidone with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder.

Risperidone is also indicated for the treatment of irritability associated with autistic disorder in children and adolescents age 5 to 16 years, including symptoms of aggression toward others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.

Pharmacology

Risperidone is a benzisoxazole. Risperidone undergoes extensive first-pass hepatic metabolism to 9-hydroxyrisperidone, a metabolite with equivalent antipsychotic activity. Peak plasma levels of the parent compound occur within 1 hour for the parent compound and 3 hours for the metabolite. Risperidone has a bioactivity of 70 percent. The combined half-life of risperidone and 9-hydroxyrisperidone averages 20 hours, so it is effective in once-daily dosing. Risperidone is an antagonist of the serotonin 5-HT_2A, dopamine D₂, α₁– and α₂-adrenergic, and histamine H₁ receptors. It has a low affinity for α-adrenergic and muscarinic cholinergic receptors. Although it is as potent an antagonist of D₂ receptors as is haloperidol (Haldol), risperidone is much less likely than haloperidol to cause EPS in humans when the dose of risperidol is below 6 mg/day.

Dosages

The recommended dose range and frequency of risperidone dosing has changed since the drug first came into clinical use. Risperidone is available in 0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets and a 1-mg/mL oral solution. The initial dosage is usually 1 to 2 mg at night, which can then be increased to 4 mg per day. Positron emission tomography (PET) studies have shown that dosages of 1 to 4 mg per day provide the required D₂ blockade needed for a therapeutic effect. At first it was believed that because of its short elimination half-life, risperidone should be given twice a day, but studies have shown equal efficacy with once-a-day dosing. Dosages above 6 mg a day are associated with a higher incidence of adverse effects, particularly EPS. There is no correlation between plasma concentrations and therapeutic effect. Dosing guidelines for adolescents and children are different from those for adults,
requiring lower starting dosages; higher dosages are associated with more adverse effects.

Side Effects

The EPS of risperidone are largely dosage dependent, and there has been a trend to using lower doses than initially recommended. Weight gain, anxiety, nausea and vomiting, rhinitis, erectile dysfunction, orgasmic dysfunction, and increased pigmentation are associated with risperidone use. The most common drug-related reasons for discontinuation of risperidone use are EPS, dizziness, hyperkinesias, somnolence, and nausea. Marked elevation of prolactin may occur. Weight gain occurs more commonly with risperidone use in children than in adults.

Risperidone is also available as an orally disintegrating tablet (Risperdal M-Tab), which is available in 0.5-, 1-, and 2-mg strengths, and in a depot formulation (Risperdal Consta), which is given as an intramuscular (IM) injection formulation every 2 weeks. The dose may be 25, 50, or 75 mg. Oral risperidone should be coadministered with Risperdal Consta for the first 3 weeks before being discontinued.

Paliperidone (INVEGA)

Pharmacology

Paliperidone is a benzisoxazole derivative and is the major active metabolite of risperidone. It is approved by the FDA for the treatment of schizophrenia. Peak plasma concentrations (C_max) are achieved approximately 24 hours after dosing, and steady-state concentrations of paliperidone are attained within 4 or 5 days. The hepatic isoenzymes CYP 2D6 and CYP 3A4 play a limited role in the metabolism
and elimination of paliperidone, so no dose adjustment is required in patients with mild or moderate hepatic impairment.

Dosage

Only gold members can continue reading. Log In or Register to continue