Second-Generation Antipsychotics

Second-generation antipsychotics represented a great advance in the treatment of psychosis and agitation. Generally these medications have much milder side effect profiles than first generation antipsychotics and, in fact, were initially called 'atypical' because of their lack of extrapyramidal effects (i.e., they were not neuroleptics). As knowledge has expanded, the characteristics of second-generation antipsychotics can be defined pharmacologically as being serotonin/dopamine antagonists, D2 antagonists with rapid dissociation, D2 partial agonists, or serotonin partial agonists at 5HT1A receptors.

In the context of medical psychiatry, second generation antipsychotics have a variety of uses.As reviewed in other sections, second-generation antipsychotics can be used to treat mania, agitation, delirium, etc. Because a second-generation antipsychotics have largely similar efficacy, and this section we will focus on the differing side effect profiles, which are also reviewed in this article. Side effect profiles can play a great role in determining the choice of antipsychotic as well as its dosage titration in a medically ill patient.

Extrapyramidal symptoms

Although the first-generation antipsychotics are known for their tendency to produce extrapyramidal symptoms (more so for higher potency antipsychotics), second-generation antipsychotics can also be associated with extra.pyramidal symptoms, although the incidence is not as great. The risk of extrapyramidal symptoms with second-generation as shown in the table of side effects. ★Essentially, except for risperidone, and to some extent aripiprazole, extrapyramidal side effects tend to be minimal among the second generation antipsychotics and are of little practical concern. Interestingly, clozapine can be used to treat tardive dyskinesia and torticollis.

Metabolic syndrome

Metabolic syndrome, the constellation of weight gain, hypertriglyceridemia, and glucose dysregulation, is associated with second generation antipsychotics as a class. The exact mechanism through which antipsychotics,especially second generation antipsychotics, lead to metabolic abnormalities is not thoroughly understood. If one considers the general receptor profile of such agents, it is possible that antagonism of H1 histamine receptors and 5HT 1A/5HT2C serotonergic receptors initially contributes to increased appetite. The role of 5HT 2C antagonism may be questionable, however, because clozapine and ziprasidone are strong 5HT 2C antagonists, but ziprasidone is associated with little if any weight gain (in contrast to the significant weight gain associated with clozapine). Metabolic syndrome can be especially problematic for older adults.

The relative associations between second generation antipsychotics and elements of metabolic syndrome are provided in the following figure, from Brooks et al. Although weight is often used as an easily obtained measure, waist circumference is superior in many ways. For example, waist circumference is not subject to minor fluctuations or proximity to meals or occasional high sodium intake. Moreover, waist circumference has a very high positive predictive value for metabolic syndrome. Patients on second generation antipsychotics should be monitored, and one such monitoring schedule is provided here. There is evidence that altering one's lifestyle can reduce the likelihood of metabolic syndrome.

sga metabolic

Sedation

Sedation is a side effect common to many second generation antipsychotics, with the exception of aripiprazole. The most sedating second generation antipsychotics are clozapine (by far), followed by quetiapine, olanzapine, risperidone, and ziprasidone. Most of the time, the biggest problem with sedation occurs early in therapy and then tolerance develops over time. This isn't always they case and sometimes people just need a different medication.

Neuroleptic malignant syndrome

NMS is uncommon with second-generation antipsychotics, but it is still a possibility that should be included on an appropriate differential diagnosis.

Dosing

Rather than review usual doses here, some exceptions are covered. Dosing of second-generation antipsychotics in the treatment of delirium is covered here.

The FDA approved dosage of most second generation antipsychotics is sometimes low for patients with serious and chronic illness. Consequently, sometimes one chooses to deviate from the package insert. For example, even though it exceeds the maximum recommended dose, there are case series reports of essentially 'loading' acutely agitated patients with oral olanzapine. In this arrangement, termed HI-DOS, patients are started on 40 mg/day and then reduced to 20 mg/day over a few days. In some refractory patients, olanzapine has been continued at 40-60 mg/day. Quetiapine can be used in very high doses (2,000 mg/day or more) in refractory illness if a patient is not excessively sedated. Anecdotal reports are that if patient is not excessively sedated at 500 mg/day, then he/she can tolerate much more quetiapine. Off-label dosing is usually only described anecdotally because there is little or no incentive for industry to fund such studies and the paucity of federal funds does not lead to funding either.

The availability of intramuscular forms of second-generation antipsychotics allows for better emergent management and some medications, such as olanzapine, have a reported efficacy of as little as 15 minutes. (There is a warning with intramuscular olanzapine that it should not be paired with intramuscular benzodiazepines because of the risk of respiratory depression. This is more of an issue in patients with COPD).

Care should be taken when dosing second-generation antipsychotics in geriatric populations, as they are more sensitive to sedation and orthostasis. They are also more likely to be on medications with P450 interactions

Clozapine must be titrated and if a patient has not taken his/her clozapine dose for 3 or more days, DO NOT resume clozapine at the previous dose. Clozapine must be titrated from the bottom again.

Special considerations

★Some second-generation antipsychotics have special considerations. For example,

As a class, second-generation antipsychotics have an FDA-provided black box warning regarding a possible increase in the risk of death when the drugs are used to treat dementia-related psychosis. Although many people still use second-generation antipsychotics fro this purpose, one should be very clear in explaining the risks to caretakers and family.