Dosages and sedation. Not all FGAs have the same sedative effect, nor do all SGAs (Table 1).9 In general, the high-milligram, low-potency FGAs—such as chlorpromazine—produce more sedation than the low-milligram, high-potency FGAs—such as haloperidol and fluphenazine.9 This principle tends to hold true for the SGAs as well. For example, the high-potency, low-dose SGA risperidone is less sedating than the lower-potency, high-dose SGAs quetiapine and clozapine.
Dose does not always determine sedation, however. Olanzapine, which is commonly dosed at 15 to 30 mg/d, is more sedating than ziprasidone, for which the usual range is 80 to 160 mg/d.3,10-12
Table 1
Antipsychotics’ potency, dosages, and sedative properties
| Medication | Relative potency (mg)* | Common dosage (mg/d) | Sedation |
|---|---|---|---|
| First-generation antipsychotics | |||
| Chlorpromazine | 100.0 | 300 to 600 | Moderate |
| Fluphenazine | 1.0 to 2.0 | 4 to 20 | Mild |
| Haloperidol | 2.0 | 5 to 20 | Mild |
| Second-generation antipsychotics | |||
| Aripiprazole | 7.5 | 15 to 30 | Mild |
| Clozapine | 50.0 | 250 to 500 | Marked |
| Olanzapine | 4.0 | 15 to 30 | Moderate |
| Quetiapine | 80.0 | 300 to 800 | Moderate |
| Risperidone | 1.0 | 2 to 6 | Mild |
| Ziprasidone | 20.0 | 80 to 160 | Mild |
| * Approximate dose equivalent to 100 mg of chlorpromazine | |||
| Source: Data from reference 9. | |||
Mechanism and sedation
The mechanisms of antipsychotics’ therapeutic and sedative properties appear to be different.13 The degree of sedation shows little relationship with the various antipsychotics’ potency at the dopamine D2 receptor, which suggests that dopamine D2 receptor antagonism is not involved in causing sedation.
Instead, the degree of sedation may be associated with each antipsychotic’s affinity for the histamine H1 receptor, which is highly variable (Table 2).1,14,15 In general:
- agents that are more potent histamine H1 antagonists—such as olanzapine and clozapine14—produce more sedation
- agents that are weaker H1 antagonists—such as risperidone, ziprasidone, and aripiprazole—produce less sedation.
Although dosage and affinity for histamine H1 receptors play important roles in the sedative effect of a medication, what ultimately determines sedative effect is the combination of histamine H1 affinity and the amount of drug reaching the histamine H1 receptors in the CNS.
For example, the SGA quetiapine—which has moderate affinity for histamine H1 receptors14—also has relatively low affinity for dopamine D2 receptors. Higher dosages of quetiapine are therefore required to produce antipsychotic effects compared with other SGAs—such as risperidone, ziprasidone, and aripiprazole—that have higher affinities for the dopamine D2 receptors.
Because of higher dosing, higher amounts of quetiapine are assumed to be reaching the histamine H1 receptors in the CNS. This is why quetiapine causes more sedation in clinical use than does risperidone, even though risperidone has greater affinity for the histamine H1 receptor.
Table 2
Antipsychotics’ sedative effects by the numbers: Equilibrium dissociation constants at brain receptors*
| Receptors | |||
|---|---|---|---|
| Dopamine D2 | Serotonin 5-HT2A | Histamine H1 | |
| FGA | |||
| Haloperidol | 2.60 | 61.00 | 260.0 |
| SGAs | |||
| Aripiprazole | 0.34 | 3.40 | 61.00 |
| Clozapine | 210.00 | 2.60 | 3.10 |
| Olanzapine | 20.00 | 1.50 | 0.10 |
| Risperidone | 3.80 | 0.15 | 5.20 |
| Quetiapine | 770.00 | 31.00 | 19.00 |
| Ziprasidone | 2.60 | 0.12 | 4.60 |
| * Lower numbers are equivalent to higher receptor binding affinity. Each antipsychotic’s sedative effect is determined by histamine H1 affinity and the amount of drug that reaches H1 receptors in the CNS—which in turn is affected by the agent’s dosage and dopamine D2 receptor affinity. | |||
| FGA: first-generation antipsychotic; SGAs: second-generation antipsychotics | |||
| Source: References 1,14,15 | |||
Sleep patterns in mental illness
Sleep disturbances—including changes in sleep patterns, insomnia, and excessive sleeping—occur frequently in patients with psychiatric disorders. The sleep process itself (Table 3) is disrupted in patients with schizophrenia.
A study that examined sleep patterns in 40 patients with schizophrenia found longer sleep latency, more frequent arousals, and increased periods of wakefulness after sleep onset compared with controls without a psychiatric disorder. Ratings of sleep efficiency—ratio of sleep time to time in bed—were:
- 95% in the control group
- 78% in antipsychotic-naïve patients with schizophrenia
- 72% in patients with chronic schizophrenia.15
A study of sleep in 19 patients with schizophrenia and 13 nonpsychiatric controls16 found individuals with schizophrenia had:
- increased duration of stage 1 sleep
- decreased duration of stages 3 and 4 (slow-wave) sleep
- 83% total sleep efficiency, compared with 95% in nonpsychiatric controls.
Because of these differences in sleep patterns, patients with schizophrenia often experience inadequate sleep.
Antipsychotic effects on sleep patterns. Your choice of an antipsychotic also can affect the patient’s sleep. In a study of sleep measures in patients with schizophrenia treated with risperidone or haloperidol, Yamashita et al17 reported a significant difference in the time each group spent in slow-wave sleep (27% with risperidone vs 20% with haloperidol). The authors suggested that risperidone might lengthen the amount of slow-wave sleep because of its higher affinity for serotonin 5-HT2 receptors compared with haloperidol.
Salin-Pascual et al18 found that olanzapine improved total sleep time and sleep efficacy, reduced stage 1 sleep, and significantly enhanced stage 2 and slow-wave (delta) sleep.
Serotonin 5-HT2 receptors have been reported to be involved in controlling sleep quality.19 Similar to risperidone and olanzapine, the other SGAs also have a higher affinity than haloperidol for serotonin 5-HT2 receptors (Table 2). Thus, although antipsychotics’ sedative effects may adversely affect patients, SGAs may have the potential to improve sleep quality in individuals with schizophrenia. SGAs increase slow-wave sleep, and patients feel more rested after awakening.