Managing first-episode psychosis: An early stage of schizophrenia with distinct treatment needs

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.