Pharmacotherapy management of schizophrenia for family physicians

Case description: part 1

K.W. is a 25-year-old woman who presents to your medical office with a family member. She describes visual hallucinations of snakes coming out of a lake. She also has a delusion that “someone put an aneurysm in her head by laying hands on her at her workplace.” K.W. has had these symptoms for the past month. Your electronic medical record tells you that 6 months ago, another physician in your clinic started K.W. on 15 mg of oral olanzapine once daily and referred her to a psychiatrist after she presented with suspected first-episode psychosis. K.W. states that the olanzapine caused excess sedation, so she stopped taking it. She did not follow up with the psychiatrist. She has no additional medical history and denies substance use. Collateral information from her family confirms that K.W. has never used substances.

Adherence to antipsychotic medications

More than half of patients with schizophrenia are non-adherent to their psychotropic medications, and this increases their risk of hospitalization, disease progression, and death.^3-6 In a retrospective study of patients with schizophrenia, 35% of nonadherent patients had a psychiatric hospitalization compared with 14% of adherent patients (number needed to harm of 4 over 3 years).⁴

One way to reduce the risk of antipsychotic medication nonadherence is to maximize tolerability. Most antipsychotic adverse effects are dose related; thus, avoiding overly rapid or premature dose escalations can improve tolerability.⁷ This can be achieved by starting at low initial doses, such as those listed in Table 1,^8-16 and then increasing in increments equivalent to the initial dose.⁷ To allow for assessment of tolerability and to avoid rapid dose escalations, the frequency of dose increases should depend on the duration of time a given antipsychotic takes to reach steady state.⁷ For example, the initial suggested dose of aripiprazole for schizophrenia is 10 mg, and it takes 14 days of consecutive treatment for aripiprazole to reach steady state. Thus, an approach to aripiprazole initiation would be to start at 10 mg once daily for 2 weeks and then, if necessary, increase the dose by 10 mg at a time.

Most patients with first-episode psychosis respond well to approximately half the labeled maximum dose of an antipsychotic medication and dosing above the labeled maximum dose should only be done after specialist consultation.⁷ This is important because the toxic range of antipsychotic medication is very close to the therapeutic range.¹⁷ If patients do not demonstrate improvement while taking doses at or above the labeled maximum dose, the dose should be reduced and alternative antipsychotic therapy should be considered.⁷ It might take as long as 2 to 4 weeks at a therapeutic antipsychotic dose for initial improvement in positive schizophrenia symptoms, such as delusions and hallucinations. An adequate antipsychotic medication trial is defined as 6 weeks of treatment with at least 80% of the labeled maximum dose.⁷ Primary negative schizophrenia symptoms, such as avolition and anhedonia, are more challenging to treat and generally do not respond well to antipsychotic therapy.¹⁷

Back to the case

K.W. was initially started on 15 mg of olanzapine once daily but did not tolerate it. An initial regimen of 5 mg of olanzapine once daily might have increased the likelihood of tolerability. After 1 week the dose could then have been increased to half the labeled maximum dose (10 mg daily) and response assessed after 2 to 4 weeks.

Antipsychotic medication selection

As all antipsychotic medications have comparable efficacy (except for clozapine, which is the most effective antipsychotic medication for schizophrenia treatment), choosing initial therapy based on the adverse effect profile is another strategy to promote adherence.^18-20 For this reason, first-generation antipsychotic medications are not usually recommended as first-line therapy, as they have higher discontinuation rates compared with second-generation antipsychotic medications (SGAs) owing to increased rates of extrapyramidal symptoms (EPS).^20,21 For example, in a 6-week study of patients after their first episode of psychosis, 8% of patients treated with risperidone withdrew due to adverse effects compared with 26% of patients treated with haloperidol.²²

Antipsychotic medications differ substantially in their relative rates of EPS, weight gain, hyperprolactinemia, sedation, orthostatic hypotension, sexual dysfunction, and anticholinergic effects.^8,18 Clinicians might consider using a shared decision-making approach to select an antipsychotic medication that has the most acceptable adverse effect profile for each patient.⁷

Table 2 describes suggested management of SGA adverse effects.^7,8,18,23-25 In general, options for managing adverse effects include lowering the antipsychotic dose, changing administration times, using adjunctive medications, or switching to an alternate antipsychotic medication.⁷

Back to the case

From your assessment of K.W.’s current clinical presentation, you deem it appropriate for her to be admitted to an acute care facility for inpatient psychiatry treatment. On the inpatient psychiatry ward, she is diagnosed with schizophrenia and receives inpatient treatment for 1 month. She is discharged, taking 3 mg of risperidone orally at night and 150 mg of paliperidone intramuscularly every 4 weeks.

Long-acting injectable antipsychotic medications (LAIAs)

Long-acting injectable antipsychotic medications should be considered early in the course of schizophrenia to attempt to improve adherence.²⁶ For example, in the PRIDE (Paliperidone Palmitate Research in Demonstrating Effectiveness) study, 450 patients with schizophrenia were randomized to oral antipsychotic medications or a once-monthly paliperidone injection. After 15 months, treatment failure was 39.8% in the paliperidone injection group and 53.7% in the oral antipsychotic group (number needed to treat of 7).²⁷ Additionally, observational data of LAIA use in schizophrenia demonstrate a 20% to 30% reduction in risk of rehospitalization compared with oral antipsychotic medications.²⁸

Unfortunately, LAIAs are typically much more expensive than oral agents are (eg, around $40 per month for oral risperidone vs around $400 per month for injectable risperidone) and drug coverage can be a challenge. Further, injection site reactions occur in up to 10% of patients.¹⁵ However, the cost savings of reduced hospitalizations with LAIAs might offset the overall cost to the health care system.²⁹ If possible, patients should be involved in a shared decision-making process regarding the use of oral versus injectable antipsychotic treatment.

Before initiation of a LAIA, tolerability with the oral equivalent must be established.⁸ Table 1 describes the overlap time required between oral antipsychotic medications and LAIAs.^8-16

Case description: part 2

Four months after her discharge from the hospital, K.W. presents back to your office. She has been adherent to the risperidone and paliperidone prescribed in hospital. She has had no hallucinations, delusions, or paranoid thoughts since being discharged from hospital and she is managing well at home. She denies sexual dysfunction, anticholinergic adverse effects, or sedation. You assess her for EPS using the Simpson Angus Scale. On the Simpson Angus Scale, she scores a 2 on the gait criterion owing to noticeably decreased left arm swing with obvious rigidity.

Management of EPS

Extrapyramidal symptoms are a constellation of movement disorders that occur secondary to the use of dopamine receptor blocking agents such as antipsychotic medications.⁸ One strategy to reduce the risk of EPS is to use the lowest effective antipsychotic dose (Table 1).^8-16

The 4 main types of EPS, in order of typical onset, are as follows:

• acute dystonic reactions (usually occur within the first 2 weeks of treatment),⁸

• akathisia (usually begins within 2 to 4 weeks of treatment),⁸

• pseudoparkinsonism (usually seen within 3 to 6 weeks of treatment initiation but might also occur any time after),⁸ and

• tardive dyskinesia (usually not seen until 3 months after treatment initiation).⁸

The goals of EPS treatment include resolution of symptoms and prevention of tardive dyskinesia. Although EPS occurs less frequently with SGAs compared with first-generation agents (aside from the higher incidence of akathisia with aripiprazole), EPS is still a concern with SGA use.^30,31 For example, it is reported that 7.2% of patients who receive a long-acting risperidone injection will develop an acute dystonic reaction.³² Risk factors for EPS include the type of antipsychotic medication, high doses of antipsychotic medication, and history of previous EPS.^30,31 Table 2 presents strategies to treat EPS.^7,8,18,23-25

Case resolution

K.W. appears to have pseudoparkinsonism secondary to her antipsychotic regimen. She is currently taking 2 antipsychotic medications. Dual antipsychotic therapy can be appropriate when starting a long-acting injection to provide a temporary bridge until LAIA onset; however, long-acting injectable paliperidone is unique in that it is the only LAIA that does not require oral overlap on initiation. Additionally, long-acting injectable paliperidone achieves steady state in 4 to 5 months; thus, K.W. would now be at steady state levels. You recognize that she is taking the labeled maximum dose of long-acting injectable paliperidone despite this being her first time taking an antipsychotic consistently. She is responding well but the EPS she is experiencing are concerning. In consultation with her psychiatrist, you stop the risperidone, as it was unintentionally continued on hospital discharge, and decrease her dose of paliperidone to 100 mg every 4 weeks. Two months later you check in with K.W. and find that her EPS have resolved, and her schizophrenia remains controlled.

Switching antipsychotic medications

If K.W.’s pseudoparkinsonism had not improved, she might have needed to switch antipsychotic medications. Caution is required when switching antipsychotic medications to minimize the risk of a relapse and withdrawal symptoms. A crossover rotation approach is usually recommended, wherein the first medication is tapered down while the second medication is simultaneously titrated up. This process usually occurs over a minimum of 2 to 4 weeks for oral antipsychotic therapy. Switching LAIAs is more complex and the product monograph for the specific antipsychotic agents should be reviewed. A useful resource for cross-tapering can be found at www.switchrx.com. When considering switching, it is important to first consider confounding factors for nonresponse including nonadherence, substance use, and interactions between medications and substances (eg, cigarette smoking) that might alter antipsychotic pharmacokinetics.⁸