Pharmacological approaches to the management of schizophrenia

The introduction of chlorpromazine in 1952 heralded a new era of pharmacotherapy for people with schizophrenia.1 Since then, numerous antipsychotic agents have become available. All block postsynaptic dopamine D2 receptors, and, more variably, a variety of other receptors. The propensity of these drugs to block D2 receptors in the mesolimbic projections is thought to underlie their therapeutic effects on positive symptoms. (For definitions of "positive" and "negative" symptoms, see Box 1.) Antipsychotic agents acting on D2 receptors in the basal ganglia and hypothalamus typically cause extrapyramidal side effects (EPS) (Box 2) and neurohormonal changes. As these side effects are an almost constant accompaniment to the therapeutic effects of these older agents, they are colloquially known as "typical" antipsychotics. As a group, these drugs have some major shortcomings:

• 30%–50% of patients with positive symptoms of schizophrenia are either not responsive or only partially responsive to typical antipsychotics;3

• Negative symptoms4 and neurocognitive deficits (Box 1)5 respond poorly to typical antipsychotics or are exacerbated by them6 (see also Pantelis and Lambert (page 62)7);

• Typical antipsychotics can cause a plethora of common side effects, including sedation, cognitive impairment, weight gain, diabetes, hyperprolactinaemia (associated with sexual problems and possibly osteopenia), cardiac conduction problems (which may be fatal), seizures, postural hypotension, and antimuscarinic effects such as dry mouth, constipation and urinary retention.8

For these and other reasons, typical antipsychotics are increasingly being supplanted by the newer, "atypical" antipsychotics.

"Atypical" has had various meanings, which may be classified according to the effects that differentiate these drugs from "typical" agents (Box 3). It should be stressed that the atypicals are not a single class of drugs. Indeed, they differ from each other in terms of receptor binding, efficacy, and side-effect profile. Also, as they are relatively new agents, our clinical experience with them over long periods is not as extensive as for the typicals. However, the overall risk–benefit ratio is more favourable for the atypicals, making them the preferred treatment for most patients.9,10

The atypical agents currently marketed in Australia are clozapine, risperidone, olanzapine, quetiapine and amisulpride. Several other agents are in the final stages of development.

Atypical antipsychotics other than clozapine (which is usually reserved for "treatment-resistant" patients [see Pantelis and Lambert, (page 62)]7) are advocated as first-line treatments for psychotic disorders, especially in patients experiencing their first psychotic episode. If one atypical is either insufficiently effective or produces worrisome side effects, another should be tried. Failure or intolerance of a second atypical should prompt a full review of the patient's status, including assessment of treatment compliance and potential aggravating factors such as illicit drug use (see Lubman and Sundram, (page 71)28). If such factors can be excluded or controlled, some clinicians would advocate the early introduction of clozapine. In its draft guidelines for the treatment of schizophrenia,29 the Royal Australian and New Zealand College of Psychiatrists has advocated such an approach. Typical long-acting "depot" medication (given by slow-release injection) is considered an absolute last resort, owing to the burden of side effects and uncertainties about long-term risks and benefits. However, the use of typical depot antipsychotics in any individual patient should be examined in the light of the potential benefits and disadvantages outlined in Box 5.

After a first psychotic episode, most clinicians would advocate treatment for at least a year, after which a slow decrease in antipsychotic medication could be attempted with careful monitoring of symptoms.30 It should be stressed that this represents an option for a minority of patients. For those who have experienced repeated psychotic episodes, long-term (even life-long) treatment is necessary, at the lowest effective therapeutic dose. A general principle, based on clinical experience, is to titrate the maintenance dose to a level of control of positive symptoms that is satisfactory to the patient, his or her family and the treating clinician, and then slowly lower the dose until optimal negative symptom control is achieved (E4). This process may take weeks to months. Whereas a "one size fits all" approach will work well for a majority of patients (ie, 4 ± 2 mg/day risperidone, 15 ± 7.5 mg/day olanzapine, 400 ± 200 mg/day amisulpride, or 600 ± 400 mg/day quetiapine), patients who receive optimised doses often report improvements in drug tolerance. An individualised treatment plan that includes multidisciplinary collaboration and input from all treating agencies (including general practitioners and non-government organisations providing community rehabilitation services) enhances the therapeutic alliance, leading to improvements in compliance and, ultimately, to improved quality of life. Small perturbations in positive symptom control can be best managed by temporarily increasing the dose of the atypical agent, with a firm commitment to reducing it again as soon as possible. The principle is to use the lowest dose possible to maintain control of the target symptoms (usually positive symptoms, but other domains are equally important). (See Pantelis and Lambert, (page 62),7 for further discussion.)

An important clinical decision is whether and when to switch patients from typical to atypical antipsychotics. Ideally, this should be a joint decision between the patient, the patient's family (if appropriate) and the clinician. Factors strengthening the case for switching medication are presented in Box 6. As switching does carry a small risk of relapse, patients should be fully informed and closely monitored during the changeover, which should follow an established switching protocol, if possible. A number of pitfalls may potentially impair the success of the switching process: 31

• Patients may, in effect, be switching from high equivalent doses to much lower doses (often a consequence of the fact that there are acknowledged reference ranges suggested for the atypicals that were not in evidence with the typicals);

• Published conversion references used to estimate equivalent doses can differ by as much as 500%, leading to erroneous assumptions about appropriate dosage of the new agent;

• Salient pharmacodynamic and pharmacokinetic considerations (eg, very short plasma half-lives, long-acting depot formulations, antipsychotics that are loosely bound to dopamine receptors, anticholinergic and antihistaminergic blocking effects) may not be accounted for;

• Withdrawal effects during switching are often neither recognised nor adequately treated. These include (i) supersensitivity psychosis, a "rebound" psychosis that appears some days or weeks after rapid lowering of previous antipsychotic levels, with subsequent overactivity of mesolimbic dopamine receptors; (ii) cholinergic rebound syndrome, a potentially severe, flu-like syndrome resulting from the rapid unblocking of central cholinergic muscarinic receptors; and (iii) withdrawal EPS, which can mimic any of the acute or persistent extrapyramidal syndromes, especially dyskinesia. (The latter is not a manifestation of "new" EPS caused by the new antipsychotic, but rather an effect similar to supersensitivity psychosis, in which striatal supersensitive dopamine receptors are too rapidly unblocked.)

Switching should usually be performed slowly, with cross-titration of agents (E4).32 In the switching phase, anticholinergic agents such as benztropine mesylate should be used if they were used before, or if the prior antipsychotic was of an anticholinergic type (eg, chlorpromazine, thioridazine, clozapine). This is to avoid the cholinergic rebound syndrome. When switching from a sedating agent to a less-sedating one (eg, chlorpromazine to risperidone), short-term benzodiazepines and/or hypnotics such as zopiclone or zolpidem are commonly prescribed to manage any rebound insomnia. It is important to remember that the ultimate goal of switching is to have the patient receive the smallest effective dose possible of a single antipsychotic.

In patients experiencing a relapse of psychosis, it is important to ascertain whether the medication itself is ineffective or the patient is not complying with the treatment regimen. Physical and social triggers may further contribute to relapse (substance abuse, family expressed emotion [ie, criticism/dissatisfaction and emotional overinvolvement expressed by the family towards the patient], comorbid physical or psychiatric illness, and "stress"). Reasons for non-compliance may include lack of insight, forgetfulness, or intolerance of side effects. Such factors need to be understood and acknowledged, and focused interventions should be offered.2

If the problem appears to be one of drug efficacy, it may be appropriate to increase the dose, while carefully monitoring side effects, or switch to an atypical agent. If the patient is already taking an atypical antipsychotic, switching to a new class may help. If the patient has already had trials of at least two types of antipsychotics, with at least eight weeks' treatment with each drug and adequate compliance, the patient may be considered "treatment resistant". Patients with a more chronic course may require longer medication exposure before it is decided that the treatment is ineffective. However, to our knowledge, there is currently no clear empirical trial evidence to support this notion (see Pantelis and Lambert, (page 62)7).

In the immediate acute phase, behavioural symptoms (including aggression) are often the ones that bring the patient to a doctor's attention. These situations require careful assessment, including an estimation of risk to self or others. The interventions required are multifaceted, but in terms of medication, symptoms may be best managed by adjunctive benzodiazepines (in Australia, diazepam 5–10 mg/day is commonly prescribed). For patients who are unresponsive to benzodiazepines, oral atypical agents have been successfully used (eg, olanzapine wafers [10–20 mg/day] or risperidone liquid [1–2 mg/day]). The use of an atypical antipsychotic in acute psychotic episodes allows patients to receive a single drug (rather than multiple agents), effectively targets behavioural disturbance and starts the process of treating the psychotic illness itself. The risk–benefit ratio with this strategy is better than poorly controlled polypharmacy for most patients.33

Parenteral control of acute behavioural disturbance should be a last resort. Preferred options include the use of benzodiazepines in the short term: intramuscular (IM) lorazepam 1–2 mg (maximum 8 mg/day) is recommended, although it is not always available in Australia and may need to be specially requested; IM clonazepam 1–2 mg (maximum 6–8 mg/day) is in fairly common use; IM diazepam is used to a lesser extent, but, as it has a poor risk–benefit ratio in this form, its parenteral use is not recommended. Intramuscular olanzapine 10 mg (maximum 20 mg/day in this form; to be available soon in Australia) offers good efficacy with few unwanted side effects (E2).34 If such agents are unavailable or have failed, consideration can be given to IM administration of typical antipsychotics such as zuclopenthixol acetate (50–100 mg IM per 48 hours) or low-dose droperidol (5–20 mg; maximum 20 mg/day).

Despite the common belief that intramuscular typical agents are ultimately effective in controlling acute behavioural disturbances, the evidence suggests that these agents may not demonstrate any particular benefit in terms of sedation and behavioural control over standard treatments.35 Furthermore, special caution should be exerted in using these agents, owing to their propensity to produce postural hypotension, EPS, and cardiotoxicity (especially droperidol in larger doses). Intramuscular haloperidol has limited application nowadays in Australia because of the significant adverse behavioural effects (eg, akathisia and other EPS, dysphoria, cognitive problems, decreased sense of wellbeing) associated with its use. Finally, as patients often dislike receiving typical antipsychotics parenterally, their use may adversely affect the therapeutic alliance between clinicians and patients.

For patients who do not reliably or consistently take oral medications, long-acting depot antipsychotics should be considered. Depot injections are widely used in Australia36 and New Zealand.37 While there are advantages and disadvantages of using depot injections (Box 5), one of the major problems with the depot antipsychotics currently available in Australia is that they are all "typical" agents, with the usual burden of side effects. A long-acting depot preparation of the atypical agent risperidone has recently been formulated and appears to be effective and well tolerated (E2).38 It is expected to be released in Australia soon. A long-acting form of olanzapine is also expected within the next two years.