Phases of Treatment in Schizophrenia

Treatment of Acute Psychosis

Acute psychotic symptoms require immediate attention. Treatment during the

acute phase focuses on alleviating the most severe psychotic symptoms. This phase

usually lasts from 4 to 8 weeks. Acute schizophrenia is typically associated with severe

agitation, which can result from such symptoms as frightening delusions, hallucinations,

or suspiciousness, or from other causes, including stimulant abuse. Patients with akathisia

can appear agitated when they experience a subjective feeling of motor restlessness.

Differentiating akathisia from psychotic agitation can be difficult, particularly when

patients are incapable of describing their internal experience. If patients are receiving an

agent associated with extrapyramidal side effects, usually a first-generation antipsychotic,

a trial with an anticholinergic anti- Parkinson medication, benzodiazepine, or propranolol

(Inderal) may be helpful in making the discrimination.

Clinicians have a number of options for managing agitation that results from

psychosis. Antipsychotics and benzodiazepines can result in relatively rapid calming of

patients. With highly agitated patients, intramuscular administration of antipsychotics

produces a more rapid effect. An advantage of an antipsychotic is that a single

intramuscular injection of haloperidol (Haldol), fluphenazine (Prolixin, Permitil),

olanzapine (Zyprexa), or ziprasidone (Geodon) will often result in calming without an

excess of sedation. Low-potency antipsychotics are often associated with sedation and

postural hypotension, particularly when they are administered intramuscularly.

Intramuscular ziprasidone and olanzapine are similar to their oral counterparts in not

causing substantial extrapyramidal side effects during acute treatment. This can be an

important advantage over haloperidol or fluphenazine, which can cause frightening

dystonias or akathisia in some patients. A rapidly dissolving oral formulation of

olanzapine (Zydis) may also be helpful as an alternative to an intramuscular injection.

Benzodiazepines are also effective for agitation during acute psychosis.

Lorazepam (Ativan) has the advantage of reliable absorption when it is administered

either orally or intramuscularly. The use of benzodiazepines may also reduce the amount

of antipsychotic that is needed to control psychotic patients.

Some studies suggest that a longer time between the first onset of psychosis and

the initiation of treatment is related to a worse outcome. As a result, clinicians must

consider the possibility that delayed treatment may worsen the patient's prognosis.

However, these data do not mean that all patients need to be treated immediately. A brief

delay may permit clinicians to develop a more thorough diagnostic evaluation and rule

out causes of abnormal behavior, such as substance abuse, extreme stress, medical

illnesses, and other psychiatric illnesses.

Treatment During Stabilization and Maintenance Phase

In the stable or maintenance phase, the illness is in a relative stage of remission.

The goals during this phase are to prevent psychotic relapse and to assist patients in

improving their level of functioning. As newer medications have been introduced with a

substantively reduced risk of tardive dyskinesia, one of the major concerns about long-

term treatment has been diminished. During this phase, patients are usually in a relative

state of remission with only minimal psychotic symptoms. Stable patients who are

maintained on an antipsychotic have a much lower relapse rate than patients who have

their medications discontinued. Data suggest that 16 to 23 percent of patients receiving

treatment will experience a relapse within a year and 53 to 72 percent will relapse

without medications. Even patients who have had only one episode have a four in five

chance of relapsing at least once over the following 5 years. Stopping medication

increases this risk fivefold. Although published guidelines do not make definitive

recommendations about the duration of maintenance treatment after the first episode,

recent data suggest that 1 or 2 years might not be adequate. This is a particular concern

when patients have achieved good employment status or are involved in educational

programs because they have a lot to lose if they experience another psychotic

decompensation.

It is generally recommended that multiepisode patients receive maintenance

treatment for at least 5 years, and many experts recommend pharmacotherapy on an

indefinite basis.

Noncompliance

Noncompliance with long-term antipsychotic treatment is very high. An estimated

40 to 50 percent of patients become noncompliant within 1 or 2 years. Compliance

increases when long-acting medication is used instead of oral medication.

When beginning long-acting drugs, some oral supplementation is necessary while peak

plasma levels are being achieved. Fluphenazine and haloperidol have been formulated as

long-acting injectables. A long-acting form of risperidone is also available.

There are a number of advantages to using long-acting injectable medication. Clinicians

know immediately when noncompliance occurs and have some time to initiate

appropriate interventions before the medication effect dissipates; there is less day-to-day

variability in blood levels, making it easier to establish a minimum effective dose; and

finally, many patients prefer it to having to remember dosage schedules of daily oral

preparations.

Dosing

The clinically effective dose for treatment depends on the characteristics of the

drug and patient factors, such as inherited sensitivity and ability to metabolize a drug,

concurrent medical disorders, use of concurrent medications, and history of exposure to

previous medications.

Plasma concentrations of many psychotropics can vary up to tenfold. Thus, to

some extent, the optimal dose for an individual is ultimately determined by trial and

error, guided by the empirical evidence of the usual dose range for that drug. Some drugs

demonstrate a clear relationship between increases in dose and clinical response. This

dose- response curve plots the drug concentration against the effects of the drug.

The potency of a drug refers to the relative dose required to achieve certain

effects, not to its efficacy. Haloperidol, for example, is more potent than chlorpromazine,

because approximately 5 mg of haloperidol is required to achieve the same therapeutic

effect as 100 mg of chlorpromazine. These drugs, however, are equal in their clinical

efficacy—that is, the maximal clinical response achievable by administration of a drug.

Drugs must be used in effective dosages for sufficient periods. Although drug

tolerability and safety are always a consideration, subtherapeutic doses and incomplete

therapeutic trials should be avoided. The use of inadequate doses merely exposes the

patient to the risk of side effects, without providing the probability of therapeutic benefit.

In view of the wide margin of safety associated with most currently prescribed

medications, more risk exists in underdosing than in overshooting the recommended dose

range.

Time of dosing is usually based on the plasma half-life of a drug and its side

effect profile. Sedating drugs are given all at night or with disproportionate daily doses at

night. The opposite is true with activating drugs. The frequency of dosing is less clear

cut. Most dosing regimens of psychotropic drugs, such as once-a-day versus divided

doses, are based on measurements of plasma concentrations rather than receptor

occupancy in the brain. Evidence suggests a significant dissociation exists between brain

and plasma kinetics. Reliance on plasma kinetics as the basis for dosing regimens leads to

misunderstanding of necessary schedules.

As a rule, psychotropic drugs should be used continuously. Exceptions are the use

of drugs for insomnia, acute agitation, and severe situational anxiety. A common mistake

is the use of high-potency benzodiazepines, such as alprazolam (Xanax) and clonazepam

(Klonopin), only after an attack has begun. These drugs should be used as part of a

regular schedule to prevent attacks.

Some patients who experience sexual dysfunction while being treated with SSRIs

take a drug holiday, that is, they skip a daily dose from time to time to facilitate sexual

performance.

Intermittent dosing regimens of SSRIs have been found to be effective as a

treatment for premenstrual dysphoric disorder. The drugs are taken daily during the 2-

week luteal phase of the menstrual cycle.

Duration of Treatment

A common question from a patient: “How long do I need to take the medication?”

The answer depends on multiple variables, including the nature of the disorder, the

duration of symptoms, the family history, and the extent to which the patient tolerates and

benefits from the medication. Patients can be given a reasonable explanation of the

probabilities but should be told that it is first best to see if the medication works for him

or her and whether the side effects are acceptable. Any more definitive discussion of

treatment duration can be held once the degree of success is clear. Even patients with a

philosophical aversion to the use of psychotropic drugs may elect to stay on medication

indefinitely if the magnitude of improvement is great. Most psychiatric disorders have

high rates of chronicity and relapse. Because of this, long-term treatment is often needed

to prevent recurrence. Nevertheless, the fact remains that psychotropic drugs are not said

to cure the disorders they treat, but rather to help control the symptoms.

Treatment is conceptually broken down into three phases: the initial therapeutic

trial, the continuation, and the maintenance phase. The initial period of treatment should

last at least several weeks because of the delay in therapeutic effects that characterizes

most classes of psychotropic drugs. The required duration of a therapeutic trial of a drug

should be discussed at the outset of treatment, so that the patient does not have unrealistic

expectations of an immediate improvement in symptoms. Patients are more likely to

experience side effects early in the course of pharmacotherapy than any relief from their

disorder. In some cases, medication may even exacerbate some symptoms. Patients

should be counseled that a poor initial reaction to medication is not an indicator of the

ultimate outcome of treatment. For instance, many patients with panic disorder develop

jitteriness or an increase in panic attacks after starting on tricyclic or SSRI treatment.

Benzodiazepine agonists are an exception to the rule that clinical onset is delayed. In

most cases, their hypnotic and antianxiety effects are evident immediately.

Ongoing use of medication, however, does not provide absolute protection against

relapse. Continuation therapy provides clinically and statistically significant protective

effects against relapse. The optimal duration of continuation or maintenance therapy is

variable and dependent on the clinical history of the patient. Early-onset chronic major

depression, for example, has a more severe course and greater comorbidity than late-

onset chronic major depression. In addition to early onset, a history of multiple past

episodes, and severity and length of current episode would make longer, even indefinite,

treatment appropriate.

Risperidone

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-HT2A,

dopamine D2, α1- and α2- adrenergic, and histamine H1 receptors. It has a low affinity

forα- adrenergic and muscarinic cholinergic receptors. Although it is as potent an

antagonist of D2 receptors as is haloperidol (Haldol), risperidone is much less likely

(except in high doses) than haloperidol to cause extrapyramidal symptoms in humans.

Side Effects

Extrapyramidal effects of risperidone are largely dosage dependent, and a trend is

seen 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 extrapyramidal symptoms, dizziness,

hyperkinesias, somnolence, and nausea. Marked elevation of prolactin can occur. Weight

gain occurs more commonly with risperidone use in children than in adults.

Dosages

The recommended dose range and frequency of risperidone dosing has changed

since the drug first came into clinical use. Risperidone is available in 1-, 2-, 3-, and 4-mg

tablets, and a 1-mg/mL oral solution and in M-tab form (rapidly dissolving). The initial

dosage is usually 1 to 2 mg at night, which can then be raised 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 extrapyramidal

symptoms. No correlation has been found between plasma concentrations and therapeutic

effect.

Risperidone (Risperdal Consta) is the only SDA currently available in a depot

formulation. It 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.