Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL OPTIONS - Psychiatry

February 2010

SWITCHING ANTIPSYCHOTIC THERAPEUTIC STRATEGIES: PRACTICAL CONSIDERATIONS

Editorial Review:

Roger S. McIntyre, MD, FRCPC

Head, Mood Disorders Psychopharmacology Unit, University Health Network, Associate Professor of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario

The therapeutic objectives in the management of psychiatric disorders have become increasingly refined with a greater emphasis on functional recovery. In addition to symptom elimination and functional recovery, clinicians and patients endeavour to engender an improved quality of life and sense of well-being. The absence of psychopathology does not equate with the presence of health. Both efficacy and pragmatic clinical trials are increasingly evaluating quality of life and so-called “humanistic” outcomes. The impetus for this refocus is provided in part by the importance of subjective outcomes as well as objective improvement in mental disorders. Antipsychotic agents form the cornerstone of therapy in schizophrenia and represent valuable treatment alternatives in the acute and maintenance treatment of bipolar disorder. Atypical antipsychotic agents are an advance over conventional agents with respect to acceptability and several domains of tolerability.

Notwithstanding the latest advances, many patients receiving antipsychotic therapy fail to achieve symptomatic, syndromal and/or functional recovery. Moreover, other patients are unable to tolerate the treatments due to adverse events and/or experience serious safety concerns (e.g. metabolic disruption). Taken together, practitioners often find themselves in situations where there is a need to switch antipsychotic treatments. Treating patients can be described as evidence-based and collaborative utilizing measurement-based tactics. To that end, patients, families and caregivers are an integral part of the decision-making process of whether to remain on medication and/or to switch to an alternative strategy.

Rationale for Switch Therapy

Switching therapy is conducted for several reasons. The overarching aim is to improve patient quality of life (QoL). Whether the underlying disorder is schizophrenia or bipolar disorder, most patients switch from one atypical to another. Not only is medication switch a common scenario in the management of schizophrenia and bipolar disorder, frequent switches are the rule rather than the exception.¹ Although inadequate efficacy is among the most prominent reasons to switch therapy, relative efficacy is not limited to control of symptoms. Rather, both schizophrenia and bipolar disorder influence a wide spectrum of psychological and neurological components that affect QoL, such as cognitive function, that may impede recovery even when the most classic symptoms of disorder are reasonably well controlled. Side effects may also adversely affect patient well-being even if they are not an immediate threat to adherence. When the goal is independent living, a return to employment or an improvement in QoL, a switch in therapy may still be attractive for a patient with stable disorder if a switch has the potential to facilitate these goals (Figure 1).

Figure 1.

The Increasing Role of Atypical Antipsychotics

Atypical antipsychotics are categorized together as a single class of agents. Their point of commonality is their indications in schizophrenia and, in some cases, bipolar disorder. Beyond that, these agents are heterogeneous in their profile of pharmacology, tolerability and efficacy. The sequencing and selecting of an atypical antipsychotic in schizophrenia or bipolar disorder is influenced by their evidentiary-based profile, as well as their inherent and relative tolerability and safety profile. Acute extrapyramidal symptoms (EPS), sedation/somnolence, changes in body composition/metabolic parameters, orthostatic hypotension, prolactin elevation, electrocardiographic changes, blood dyscrasias, tardive dyskinesia, and neuroleptic malignant syndrome are warnings and precautions with atypical antipsychotics. It is important to state, however, that each agent’s propensity for these foregoing tolerability and safety concerns is variable with some agents having a greater association and others minimal to no association.

Yet the atypical agent s are not interchangeable. They differ in both clinical and potentially important mechanistic Figure 1. Components of a Treatment Switch for Independent Living as a Goal features, such as relative neurotransmitter receptor occupancy.² The differences in activity are likely to explain the differences in side effect profile and interpatient variability in response. The clinical distinctions between clozapine, the oldest and prototypical atypical agent, and the six other atypical agents—risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone and paliperidone— illustrate the lack of pharmacodynamic similarity. An exemplar of this is clozapine, which is the only agent with unequivocal efficacy in treatment-resistant schizophrenia as well as suicide reduction.

Balancing Benefit and Risk

Benefit from switching has been recorded in multiple studies. In a population-based study specifically designed to confirm a reduction in EPS among patients switched from typical to atypical antipsychotics in practice outside of a clinical trial, antiparkinsonian drug prescribing fell 9.2% (P<0.0001) after such a switch.³ In contrast, antiparkinsonian drug prescribing increased by 12.9% (P<0.0001) when patients were switched from one typical neuroleptic to another typical agent. In combined data from three trials evaluating the benefit of a switch to ziprasidone among patients who were stable on their current therapy, whether a typical or atypical agent, but who still had troublesome symptoms, significant (P<0.05) improvements were reported on all major symptom measures and most subscales by week 6 when compared to baseline.⁴

However, the risks and benefits of switching must be considered carefully against other strategies, particularly when simply modifying the dose of the current therapy may either provide greater symptom control or reduce adverse events. The risks from switching are measurable and include poorer outcomes and higher costs in the absence of the desired response.⁵ In contrast, failure to switch in a timely fashion when response is inadequate is also associated with adverse outcomes and higher costs.⁶ Importantly, inadequate response to one antipsychotic therapy does not preclude response to another.⁷ Similarly, the difference in adverse events among agents within the atypical class and across all antipsychotic agents encourages switching when side effects threaten QoL or the overa
nt.

Figure 2.

<img4032|center>

Lastly, the potential for patients with schizophrenia to require life-long therapy demands a holistic approach to disorder control that includes attention to longterm health risks. This has become a more important concern when it became apparent that some but not all atypical agents can produce a sufficient gain in weight to impose a risk of chronic health disturbances, such as hypertension and hyperglycemia.⁸ While weight gain by itself may be an unacceptable side effect for many patients, the adverse effect of weight on cardiovascular (CV) risk factors may be life-threatening in some cases if left untreated for sustained periods. Such complications of therapy as imposed by suboptimal symptom control or by therapy that imposes asymptomatic health risks, such as diabetes, hyperlipidemia, progressive renal impairment and CV events, may be difficult to justify if there are alternative therapies with the potential to provide comparable efficacy.

Success in Switch Therapy

Several studies confirm that switching can improve patient well-being. This includes numerous studies switching from a typical to an atypical agent, including improvements in QoL among elderly patients who made such a switch to olanzapine or risperidone,⁹ as well as studies demonstrating improvements after switching between atypical agents. Switch studies do not necessarily suggest superiority of one agent over another because of the interindividual responses to any given antipsychotic. By definition, patients enter a switch study because of poor control or unacceptable adverse events on the agent they are discontinuing. However, these studies demonstrate that patients who do not fare well on one treatment may be more succeessful on another. A few examples include an efficacy benefit observed when patients were switched from conventional antipsychotics, olanzapine or risperidone to ziprasidone;⁴ an efficacy advantage when patients were switched from olanzapine, risperidone or quetiapine to aripiprazole;¹⁰ and QoL improvements when patients were switched from haloperidol to olanzapine, risperidone or clozapine.¹¹ Clozapine has demonstrated efficacy in a high proportion of patients with schi
m any other atypical agent.¹²

Figure 3.

<img4033|center>

Similar data can be cited for demonstrating clinical benefits when switches are performed for adverse events. Although there is considerable interpatient variability in susceptibility to specific side effects, relative risk of individual adverse events, unlike efficacy, do tend to be drug-specific. For example, the atypical antipsychotic risperidone has been much more closely related to hyperprolactinemia and the side effects that stem from elevated prolactin levels than quetiapine or aripiprazole. Reductions in prolactin levels have been observed with both of these latter agents in switch strategies.^13,14 Weight gain and associated metabolic disturbances have been mostly associated with olanzapine and clozapine.^15,16

Summary

Switching antipsychotic therapies is an important clinical decision both for its potential benefits, such as a better QoL for the patient, and for its potential risks, which includes trading side effects without any significant clinical gains. The risks and benefits should be considered carefully. However, the risk of inaction may exceed the risk of attempting a switch when patients are not achieving a level of function that may be possible with an adjustment in their treatment regimen. Clinicians and patients should aim to improve symptoms, function and QoL in patients as part of chronic disease management that includes, but is not limited to, the most appropriate atypical antipsychotic.

References

1. Mahmoud et al. Risperidone versus conventional antipsychotics for schizophrenia and schizoaffective disorder: symptoms, quality of life, and resource use under customary care. Clin Drug Investig 2004;24:275-86.

2. Goldstein JM. The new generation of antipsychotic drugs: how atypical are they? Int J Neuropsychopharmacol 2000;3:339-49.

3. Park et al. Effect of switching antipsychotics on antiparkinsonian medication use in schizophrenia: population-based study. Br J Psychiatry 2005;187:137-42.

4. Weiden et al. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J Clin Psychiatry 2003;64:580-8.

5. Faries et al. Clinical and economic ramifications of switching antipsychotics in the treatment of schizophrenia. BMC Psychiatry 2009;9:54.

6. Ascher-Svanum et al. Clinical, functional, and economic ramifications of early nonresponse to antipsychotics in the naturalistic treatment of schizoprenia. Schizophr Bull 2008;34:1163-71.

7. Buckley et al. Strategies for dosing and switching antipsychotics for optimal clinical management. J Clin Psychiatry 2008;69(suppl 1):4-17.

8. Henderson et al. Prolactin-related and metabolic adverse effects of atypical antipsychotic agents. J Clin Psychiatry 2008;69(suppl 1):32-44.

9. Ritchie et al. The impact upon extrapyramidal side effects, clinical symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia. Int J Geriatr Psychiatry 2003;18(5):432-40.

10. Tandon et al. A prospective, multicenter, randomized, parallel-group, open-label study of aripiprazole in the management of patients with schizophrenia or schizoaffective disorder in general psychiatric practice: Broad Effectiveness Trial with Aripiprazole (BETA). Schizophr Res 2006;84:77-89.

11. Aguglia et al. Insight in persons with schizophrenia: effects of switching from conventional neuroleptics to atypical antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 2002;26(7-8):1229-33.

12. McEvoy et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163(4):600-10.

13. Kaneda et al. Impact of a switch from typical to atypical antipsychotic drugs on quality of life and gonadal hormones in male patients with schizophrenia. Neuro Endocrinol Lett 2004;25(1-2):135-40.

14. Hanssens et al. Sexual dysfunction in a naturalistic, open label study of aripiprazole and standard of care of community-treated patients with schizophrenia (The STAR Trial). 159th Annual Meeting of the American Psychiatric Association. Toronto, Canada, May 2006. Poster NR361.

15. McIntyre et al. Antipsychotic-induced weight gain: bipolar disorder and leptin. J Clin Psychopharmacol 2003;23(4):323-7.

16. Weiden et al. Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a roadmap. J Clin Psychiatry 2007;68(suppl 7):1-48.

EXPLORING CHARACTERISTICS OF ATYPICAL ANTIPSYCHOTICS

Editorial Review:

Ric M. Procyshyn, MSc, PharmD, PhD

Clinical Research Psychopharmacologist, BC Mental Health and Addictions Services, Clinical Associate Professor, Department of Psychiatry, Adjunct Professor, Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia

Clinical practice guidelines and treatment algorithms consider the atypical antipsychotics as first-line agents for the treatment of schizophrenia.^1,2,3 These agents have a broad spectrum of activity and apart from being used to treat and mitigate the symptoms of schizophrenia, many of these agents are now considered as first-line options for the treatment of acute mania, acute bipolar I depression, and maintenance of bipolar disorder.⁴ The fact that these agents belong to the same class of antipsychotics (i.e. the atypicals) can unfortunately foster the impression that they are more similar than different in terms of their basic pharmacodynamic and pharmacokinetic properties. This in fact is far from true, as the pharmacodynamic and pharmacokinetic differences between these agents are more remarkable than similar. As examples, both the receptor binding profiles and metabolic pathways vary greatly between these antipsychotics and combine (along with other factors) to generate unique “fingerprints” that are fundamental in helping to explain the relative differences in terms of effectiveness and tolerability between these drugs.

Prior to the introduction of the atypical antipsychotics, extrapyramidal symptoms (EPS) had been a consistent consequence (as well as an indicator) of effective antipsychotic therapy. With the development of the second generation of antipsychotics, the descriptor “atypical” was employed to describe the low relative risk of EPS and tardive dyskinesia that was found to be associated with this new class of antipsychotics.⁵ However, with time several other definitions for atypicality have been coined with varied acceptance, including: 1) reduced elevations in prolactin; 2) higher relative affinity for the 5HT_2A receptor compared to the dopamine 2 (D₂) receptor; and 3) greater clinical effect on negative symptoms.^6,7 For the most part, the reduction of EPS associated with the atypical agents is considered a class effect that differentiates it from the typical agents in general. However, apart from EPS, other pharmacological and clinical differences between the atypical and typical antipsychotics are perhaps more relative than absolute.⁸

Pharmacodynamics (Receptor Binding)

As alluded to above, many of the clinical features that differentiate the atypical antipsychotics from the typical agents (e.g. effectiveness and adverse events) can be explained in part by the receptors to which they bind. It was the observation of D₂ receptor binding by all typical antipsychotics that led to the development of the dopamine hypothesis, which postulates that hyperactive dopaminergic activity in the mesolimbic region of the brain is a fundamental feature in the pathophysiology of schizophrenia.⁹ The pharmacodynamics of atypical agents does not refute this hypothesis since they, too, occupy (as an antagonist or partial agonist) D₂ receptors.¹⁰ However, apart from the D₂ receptor, the atypical agents have considerable effects on other neurotransmitter systems that contribute to their overall clinical profile. Perhaps the serotonin (5-HT) system is the most important of these as antagonism of the 5-HT_2A and 5-HT_2C receptors has been implicated to contribute to antipsychotic efficacy.¹¹ Furthermore, it is postulated that the antagonism of 5-HT_2A receptors in the prefrontal cortex may explain the greate
ical agents in treating cognitive deficits as well as negative symptoms.¹²

Table 1.

<img4034|center>

Similar to explaining efficacy, the relative binding affinities to various receptors also help explain side effects associated with antipsychotics. For example, while the typical antipsychotics derive their effectiveness from D₂ antagonism in the mesolimbic region of the brain, their propensity to simultaneously antagonize D2 receptors in the striatum increases their risk for EPS.¹³ Fortunately, there exist two relatively well defined thresholds for D₂ receptor occupancy that separate these clinical outcomes from one another. In this case, an initial threshold between 65% and 80% D₂ receptor occupancy correlates with antipsychotic effect; more specifically, for lessening positive symptoms. A second threshold of greater than 80% D₂ receptor occupancy correlates significantly with an increased risk for developing EPS.¹⁴ While the relative freedom from EPS associated with the atypical agents may be due to relatively lower affinities for D₂ receptors (compared to the typical agents), it is also likely that affinities for other receptors (particularly serotonin but also muscarinic, histamine and adrenergic receptors) may mitigate some side effects attributed to D₂ receptor antagonism in the striatum.¹⁵

While receptor profiles help differentiate fundamental pharmacological properties between the typical and atypical agents, they also risk perpetuating the impression that atypical agents, as a class, are quite similar to each other. However, the same premise used for differentiating atypical from typical antipsychotics may also be useful for differentiating atypicals from each other. As an example, receptor occupancy between the various atypical agents for dopamine and serotonin receptor subtypes vary significantly (Table 1).⁵ Unquestionably, this accounts for some of the differences observed in effectiveness and adverse effects among these agents. While differences in efficacy among the atypical antipsychotics have not been remarkable in controlled trials, the fact remains that in clinical practice some individuals will respond more favourably to one agent and not to another. In other words, a poor response to one atypical antipsychotic certainly does not preclude a good response if the patient is switched to another atypical agent. Similarly, adverse events associated with a particular atypical antipsychotic do not predict an adverse event for an alternative atypical agent. These individual responses, whether they be related to symptom improvement or adverse events, are related to many variables of which differences in receptor binding profiles is only one.

Pharmacokinetics (Metabolism)

Pharmacokinetics essentially refers to how the body handles a medication. More specifically, pharmacokinetics is the characterization of the time course of drug absorption, distribution, metabolism and excretion and describes the relationship of these processes to the drug’s therapeutic and adverse effects. The distinct pharmacokinetic properties (particularly with respect to how they are metabolized) of each atypical antipsychotic will also determine its liability for drug-drug interactions.

To elaborate, drug metabolism involves a process in which an enzyme or series of enzymes transforms a compound into a more water-soluble form that is more readily eliminated from the body. The two major metabolic processes include phase I (oxidative) and phase II (conjugative) pathways. Phase I metabolism relies on a group of mixed-oxidase enzymes that either expose or add a functional group through various oxidative reactions. Collectively, these enzymes are known as cytochrome P450 enzymes (CYP450). To date, more than 40 CYP450 enzymes have been identified in humans. However, six of these enzymes (1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) are responsible for the oxidative metabolism of the majority of drugs.¹⁶ Although these enzymes are predominantly hepatic, they are also found in significant concentrations in the gut wall (particularly 3A4).¹⁷ As with most psychotropic medications, the atypical antipsychotics are substrates for more than one CYP450 enzyme. However, each atypical is predominantly metabolized via one CYP450 enzyme as follows: clozapine and olanzapine (CYP1A2), risperidone (CYP2D6), paliperidone (minimal phase I metabolism), quetiapine (CYP3A4), ziprasidone (CYP3A4 but also by aldehyde oxidase) and aripiprazole (CYP2D6 and CYP3A4).^18-20

These differences in metabolic pathways determine each agent’s predisposition for drug-drug interactions via induction or inhibition of the CYP450 isozymes. For example, if a patient is being treated with an antipsychotic primarily metabolized by CYP4501A2 (i.e. clozapine or olanzapine) and an inducer of CYP4501A2 is added (e.g. smoking or fluvoxamine), the consequence would be an increase in metabolism and lower serum concentrations of the respective antipsychotic. Since this type of drug interaction (induction) is dependent on the synthesis of new CYP450 enzymes, the clinical consequence (i.e. loss of effectiveness due to decreased serum concentration) may take two to three weeks to manifest.

Conversely, if an inhibitor of a CYP450 enzyme is added to ongoing therapy, the effect is immediate. For example, if a patient is being treated with risperidone or aripiprazole and an inhibitor of CYP2D6 is added (e.g. paroxetine or ritonavir), the inhibitor will render the CYP450 enzyme less effective for metabolizing the substrate (in this case, risperidone or aripiprazole). The consequence of this type of drug interaction may include an increase in the antipsychotic’s serum concentration and pharmacological effect with potential to increase adverse events such as EPS. As for paliperidone and ziprasidone, minimal drugdrug interactions would be expected. In the case of paliperidone, this is because less than 20% of its metabolism is via phase I and II processes with the majority of it being renally eliminated as unchanged drug. Regarding ziprasidone, its major metabolic route (approximately two-thirds) is via aldehyde oxidase, a cytosolic enzyme that does not appear to be easily saturated.

Clinicians must be mindful of the significant differences in metabolism of these agents in order to predict and prevent drugdrug interactions.

A Brief Description of Each Agent

Clozapine, the prototype of the atypical antipsychotics, is a dibenzodiazepine. Although its introduction helped define atypicality due to its association with a low risk of EPS (even over prolonged courses), it is not used as first-line therapy. This is because clozapine is associated with the risk of agranulocytosis (about 1% per year), which is a potentially life-threatening complication.²¹ The risk for developing agranulocytosis appears to be greater in the first three months of therapy; however, all patients treated with clozapine require continuous hematological monitoring. Despite this risk, clozapine remains an important therapeutic option in patients who have responded poorly to other antipsychotic drugs.²² Clozapine has also been associated with the metabolic syndrome, myocarditis and dose-dependent seizures.

Risperidone is a benzisoxazole derivative and is the only atypical antipsychotic to be formulated as a long-acting injectable that can be given every two weeks. Although the risk of EPS with risperidone is minimal at low doses, its high affinity for D₂ receptors does result in EPS at higher doses (greater than 6 mg/day) to rates consistent with some typical agents.²³ In a controlled trial, the incidence rates of EPS for patients treated with risperidone were similar to those observed on haloperidol.²⁴ Similarly, risperidone is also associated with elevated prolactin levels. Both of these outcomes sometimes bring into question of how atypical risperidone really is. On the other hand, risperidone has high affinity for the 5-HT_2A receptor,¹⁴ which may explain, in part, its efficacy for treating negative symptoms.²⁵

Paliperidone is a 9-hydroxy active metabolite of risperidone and is manufactured as a controlled-release formulation allowing once-daily dosing. Paliperidone differs from risperidone in that as much as 60% is cleared renally as unchanged drug. In fact, only about 20% is metabolized via phase I or II processes.²⁶ Although paliperidone may have some safety advantages over risperidone in the way of fewer drug-drug interactions, its receptor binding profile appears quite similar to risperidone.²⁶

Olanzapine is a thienobenzodiazepine and is also associated with a dose-dependent risk of EPS.²⁷ However, if doses are kept within the approved dosage range (5-20 mg/day), EPS are low. Like risperidone, olanzapine also has high affinity for the 5-HT_2A receptor. A significant clinical concern associated with olanzapine has been its propensity to cause metabolic disturbance including weight gain, dyslipidemia and insulin resistance.²⁸ Like clozapine, olanzapine’s metabolism is induced by cigarette smoking (the aromatic hydrocarbons in smoke induce the CYP4501A2 enzyme). This is not inconsequential as the prevalence rate of smoking among individuals with schizophrenia may be as high as 90%. As such, higher doses of olanzapine (and clozapine) may be required for those patients who smoke.²⁹ Clinicians should always be aware of their patient’s smoking status.

Quetiapine is a dibenzothiazepine and has an extremely low potential to cause EPS or elevations in prolactin levels as a result of its transient occupancy (fast off-rate) from the D₂ receptors.³⁰ Quetiapine’s moderate affinity for histamine-1 and alpha-1 adrenergic receptors is believed to be, in part, the mechanism that underlies its association with transient sedation and orthostatic hypotension, respectively.⁷ Quetiapine has an active metabolite (norquetiapine) that, unlike quetiapine, can block the norepinephrine transporter and antagonize the 5HT_2C receptor, both helping to explain quetiapine’s overall efficacy in treating disorders of mood and cognition.

Ziprasidone is a benzisoxazole derivative similar to risperidone; however, it is associated with a lower risk of EPS and hyperprolactinemia.³¹ Although ziprasidone has a high affinity for D₂ receptors relative to other atypical agents, it also has a very high affinity for the 5-HT_2A receptor, which has been proposed as a mechanism explaining its low risk of EPS.³² Although there were initial concerns that ziprasidone was associated with prolonged QTc intervals, extensive research and investigation have shown this to be unjustified.³³ One of the most significant advantages of ziprasidone is a low risk for weight gain. Furthermore, it does not appear to be associated with dyslipidemias or insulin resistance. To ensure its absorption (bioavailability), ziprasidone should be taken with food (a meal equal to or greater than 500 kcal, irrespective of fat content) twice daily.³⁴

Aripiprazole is a dihydrocarbostyril. Similar to ziprasidone, aripiprazole has little propensity to cause weight gain or significant metabolic disturbances. Although aripiprazole has the highest affinity for D₂ receptors, it is only associated with mild EPS. This paradox is explained by the fact that aripiprazole is a partial agonist at the D₂ receptor. Aripiprazole is also a partial agonist at the 5-HT_1A receptor (so, too, is clozapine, quetiapine and ziprasidone). In a 26-week, placebo-controlled prevention of relapse trial, the most frequently reported adverse event associated with aripiprazole was insomnia. Other adverse events reported with a greater incidence compared to placebo were tremor, akathisia, vomiting and nausea.³⁵

Summary

The term atypical is used to characterize a broad variety of antipsychotics used for treatment of schizophrenia and other psychotic disorders. However, the term atypical is not clearly defined and may generate a misleading impression among clinicians that these compounds are very closely related. Rather, these agents possess very different pharmacodynamic and pharmacokinetic profiles. Overall, the atypical antipsychotics are effective for the clinical management of psychoses; however, their employment for other psychiatric illnesses has expanded to include disorders of mood, often with a lower risk of side effects compared to the older agents. Due to the real differences between the atypical agents, clinicians should consider switching to an alternative atypical antipsychotic if the one used currently is associated with less than optimal clinical response and/or tolerability.

References

1. Canadian Psychiatric Association. Clinical practice guidelines: treatment of schizophrenia Can J Psychiatry 2005;50(suppl 1):7S-57S.

2. Lehman et al. American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guidelines for the treatment of patients with schizophrenia. Am J Psychiatry 2004;161(2 suppl):1-56.

3. Argo et al. Texas Medication Algorithm Project Procedural Manual: Schizophrenia Treatment Algorithms. Available at: http://www.dshs.state.tx.us/ mhprograms/pdf/SchizophreniaManual_060608.pdf Accessed November 5, 2009. Texas Department of State Health Services.

4. Yatham et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: Update 2009. Bipolar Disord 2009;11:225-55.

5. Farah A. Atypicality of atypical antipsychotics. Prim Care Companion J Clin Psychiatry 2005;7:268-74.

6. Reynolds GP. What is an atypical antipsychotic? J Psychopharmacol 1997;11(3):195-9.

7. Goldstein JM. The new generation of antipsychotic drugs: how atypical are they? Int J Neuropsychopharmacol 2000;3:339-49.

8. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002;47(1):27-38.

9. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976;192(4238):481-3.

10. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999;156(2):286-93.

11. Richtand et al . Dopamine and s e rotoni n receptor binding and antipsychotic efficacy. Neuropsychopharmacol 2007;32(8):1715-26.

12. Milan MJ. Improving the treatment of schizophrenia: focus on serotonin (5-HT) (1A) receptors. J Pharmacol Exp Ther 2000;295(3):853-61.

13. Tauscher et al. Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. Psychopharmacol 2002;162(1):42-9.

14. Kapur et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000;157(4):514-20.

15. Olijslagers et al. Modulation of midbrain dopamine neurotransmission by serotonin, a versatile interaction between neurotransmitters and significance for antipsychotic drug action. Curr Neuropharmacol 2006;4(1):59-68.

16. Guengerich FP. Role of cytochrome P450 enzymes in drug-drug interactions. Adv Pharmacol 1997;43:7-35.

17. Kolars et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992;90:1871-8.

18. Fuller MA, Sajatovic M. Drug Information Handbook for Psychiatry: A Comprehensive Reference of Psychotropic, Non-Psychotropic and Herbal Agents. 4th ed. Hudson, OH: Lexi-Comp; 2004.

19. Vermeir et al. Absorption, metabolism and excretion of a single oral dose of 14C-paliperidone 1 mg in healthy subjects. Eur Neurophsychopharmacol 2005;15 (suppl 3):S648.

20. Beedham C, Miceli JJ, Obach RS. Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J Clin Psychiatry 2003;23:229-32.

21. Alvir et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 1993;329(3):162-7.

22. Iqbal et al. Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry 2003;15(1):33-48.

23. Kapur et al. The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study. Life Sci 1995;57(10):PL103-7.

24. Rosebush PI, Mazurek MF. Neurologic side effects in neuroleptic-naive patients treated with haloperidol or risperidone. Neurology 1999;52(4):782-5.

25. Curtis et al. Long-acting risperidone improves negative symptoms in stable psychotic patients. Eur Psychiatry 2007;22(suppl 1):S151.

26. Dolder C, Nelson M, Deyo Z. Paliperidone for schizophrenia. Am J Health Syst Pharm 2008;65(5):403-13.

27. Kapur et al. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155(7):921-8.

28. Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry 2001;62(suppl 7):22-31.

29. Green et al. Treatment of schizophrenia and comorbid substance use disorder. Curr Drug Targets CNS Neurol Disord 2002;1(2):129-39.

30. Kapur et al. A positron emission tomography study of quetiapine in schizophrenia. A preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 2000;57:553-9.

31. Tarsy D, Baldessarini RJ, Tarazi FI. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs 2002;16(1):23-45.

32. Mamo et al. A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 2004;161(5):818-25.

33. Harringan et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004;24(1):62-9.

34. Gandelman et al. The impact of calories and fat content of meals on oral ziprasidone absorption: A randomized, open-label, crossover trial. J Clin Psychiatry 2009;70(1):58-62.

35. Pigott et al. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: A placebo-controlled 26-week study. J Clin Psychiatry 2003;654(9):1048-56.

ANTIPSYCHOTIC THERAPY SWITCH STRATEGIES: BUILDING ON REALISTIC GOALS

Editorial Review:

Christoph U. Correll, MD

Medical Director, Recognition and Prevention Program, Director, Adverse Events Assessment and Prevention Unit, Advanced Center for Intervention and Services Research, The Zucker Hillside Hospital, Center for Translational Psychiatry, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Associate Professor of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York

Adherence to treatment is the first step to effective use of antipsychotic agents whether they are employed for schizophrenia or for bipolar disorder. Patients who are not satisfied with their therapy, whether as the result of insufficient efficacy or unacceptable side effects, are very likely to adhere poorly to their treatment regimen. In the CATIE study, 74% of patients discontinued their assigned antipsychotic therapy within 18 months of initiation, a rate attributed to limited efficacy, adverse events and patient decision, likely dissatisfaction.¹ Although reasons other than inadequate efficacy or adverse events may prompt a switch, including more convenient dosing, the broad array of antipsychotic drugs permits clinicians and patients to consider alternative therapies in the quest for improved functioning and quality of life that will be defined by both symptom control and relative freedom from adverse events.

Traditionally, physicians have been reluctant to switch antipsychotic therapies except in cases of obvious therapeutic failure.² Concerns include the risk of a difficult transition and the potential that the next therapy will be no better than the one it is replacing.^3,4 Importantly, no antipsychotic is completely without side effects,⁵ raising the potential for one set of patient dissatisfactions to be replaced by another. However, antipsychotic therapies do differ markedly in their clinical risks and benefits in individual patients, and there is an expanding literature to guide rational decisions regarding treatment switches. This includes more information about the criteria to be considered in making the switch as well as data that define specific steps to improve the transition from one therapy to another. When current therapy is a source of dissatisfaction for any cause, a switch for realistic goals after adequate preparation for a transition may result in improved outcomes, not least because of an improvement in adherence.

Options Before Switching Therapy

Medication cannot be effective if it is not taken and the reasons for poor adherence are many. While some patients may abandon therapy because they have lost confidence in its efficacy, others may find specific side effects unacceptable.⁶ Weight gain, particularly among female patients, is a relevant example of an adverse effect that can potentially lead to poor adherence even when the effects are subtle. Some patients may not even volunteer this adverse event as a source of poor adherence without direct questioning. The same is true for sexual dysfunction. Other patients may be appropriately concerned about the long-term health consequences of excessive weight gain. However, without a clear understanding of the reasons for poor adherence, a logical and rational choice of a replacement agent is unlikely. Although a clinician or a patient may decide to switch therapy due to poor symptom control or adverse events even as he remains compliant with the current agent, the possibility of poor compliance is perhaps the most compelling impetus to continuously gauge patient satisfaction with current therapy and consider an alternative drug when satisfaction is poor.

Individualization of care is a common theme in medicine, but there are few examples in which this concept is more important than in the application of antipsychotic therapies, whether they are employed in schizophrenia or in bipolar disorder. In a patient poorly managed on an otherwise appropriate therapeutic regimen, switching therapy may be the best option, but it is not the only option.³ In particular, there appears to be substantial interpatient variability in dose response to therapies regarding both efficacy and side effects. For those with inadequate symptom control, simply increasing the dose may be a reasonable first step before considering a treatment switch. Conversely, it may be possible to decrease the current dose to eliminate side effects or reduce their intensity. Increasing the dose may result in a greater rate and potentially unacceptable increase in adverse events. The risk of reducing the dose is a loss of symptom control, so dose titration, although simpler than a switch of antipsychotic therapy, should not be performed without first informing patients of these risks and monitoring for these effects.

For adverse effects that threaten patient well-being or adherence, adjunctive therapies may be another alternative to a switch strategy. For example, anticholinergic agents may be useful for extrapyramidal symptoms (EPS), while exercise and diet instruction may be useful for controlling weight gain. Although clinicians need to consider whether such strategies may increase inconvenience or create other barriers to compliance, patients may wish to consider these alternatives compared to a treatment switch when provided with a full explanation of the options for improving subjective well-being and quality of life (QoL). While patients are the best source of information about their satisfaction with treatment, they are also the best guide for selecting an alternative strategy based on their own willingness to consider adjunctive agents, new treatments and lifestyle changes to achieve clinical goals.

Compliance Awareness

Importantly, controlled clinical trials offer relatively limited guidance for efficacy and adherence to specific dose levels in the individual patient. Although controlled trials may provide an outline of the therapeutic window, compliance is generally greater than that outside of a clinical trial. Moreover, clinical trials are often conducted in patients with few or no comorbidities or may be designed to exclude patients with severe or difficult-to-control disorder. Although controlled trials often associate active therapies with high rates of efficacy achieved over prolonged periods, naturalistic studies suggest that the majority of patients discontinue their initial antipsychotic therapy within the first year (Table 1).¹ Sensitivity to the broad array of clinical issues that lead to this high rate of discontinuation, which range from inadequate control of symptoms to the reasons for non-compliance, might help direct a strategy for dose adjustment or a switch in therapy.

Selecting a Replacement Agent

In patients who are not achieving treatment goals on their current therapy, whether due to persistent symptoms or unacceptable adverse events, clinicians should consider a broad array of variables that may be useful in selecting the next therapy. Past experience with antipsychotic therapies, including response and level of tolerability, is very important. Although the benefit of selecting an antipsychotic therapy specifically on the basis of receptor affinity is unproven, it is reasonable to consider an agent with a different receptor affinity profile based on dopamine- or serotonin-related activity when a switch is being made for lack of efficacy. Similarly, if a patient is being considered for a switch largely on the basis of a dominant adverse event, suc
edation, it is appropriate to give particular attention to options that pose a low risk of the adverse event that the patient wishes to avoid.

Table 1.

<img4035|center>

Patient expectations should be monitored. The transition to a new medication may be difficult, and whenever possible, patients need to be participants in the decision to switch and be actively involved in evaluating its success. Environmental issues, such as the patient’s support system, their history of adherence to past medications and their willingness to engage in the process, may be critical for the success of the new therapy. Practical considerations are relevant. For example, twice- or three-times-daily dosing may defeat an otherwise effective therapy in patients who may experience difficulty following a demanding regimen.

Strategies for Switch Therapy

Once the decision has been made to switch, there are a number of methods with varying strengths and weaknesses for moving the patient from one antipsychotic to another.⁷ Selecting one of these methods should be influenced by the specific goals of switching, by the agents being exchanged and by patient characteristics. In general, switching for lack of efficacy is self-evident. Poor symptom control is an absolute indication for altering therapeutic strategy, and there is a reasonable expectation of benefit from alternative therapies. Although controlled trials suggest that none of the approved antipsychotic agents can be definitely differentiated from one another on the basis of efficacy (with the exception of clozapine in refractory patients), these drugs are not homogeneous and the considerable interpatient variability in response suggests lack of response to one agent does not necessarily predict the same to another.

However, when a switch is being contemplated for relative intolerability, the extent of intolerability is a factor because of the expectation that no antipsychotic is completely free of unwanted effects. One group of authors recommended six steps in a process for considering a switch to reduce the risk of adverse events:⁸ establish some degree of confidence that the current therapy is the cause of the unwanted adverse effect; confirm that the side effect is likely to persist with an unacceptable intensity if therapy is continued; consider how the side effect might be managed without a switch; consider the likelihood that a substitute antipsychotic will reduce the risk of the adverse event; consider the risk of new side effects from a switch therapy; and consider the likelihood of efficacy from a switch therapy.

Switch strategies range from the very simple to the relatively complex. The least complex switch is a next-dose substitution. The patient simply stops taking the current therapy and begins taking the switch drug in the absence of any titration or tapering. The switch therapy is initiated at a dose that is in the therapeutic range with the expectation that the new therapy will provide similar or often better activity than the treatment that is being discontinued. This type of abrupt switch may be appropriate in some situations, particularly in urgent cases, but it is not a common practice. In most cases, some period of transition is necessary to control symptoms and minimize risk of adverse events.

In general, it is prudent to taper the drug that is being discontinued while slowly uptitrating the agent that is being introduced, but there are several strategies, such as using similar gradation so that the patient is receiving a full therapeutic dose of the new agent by the time that he or she has been weaned off the index agent.⁷ Conversely, a cross-plateau approach may be more attractive for those at particularly high risk for adverse consequences in the event of poor symptom control. In this strategy, tapering of the pre-switch drug does not begin until the new drug has been uptitrated to full strength, producing a point at which patients are at full therapeutic doses of both drugs before being weaned back to a single agent (Figure 1). This fu
works best when the pre- and post-switch antipsychotics differ in their side effect profiles substantially, so that rebound phenomena are avoided and adverse effects are not additive.

Figure 1.

<img4036|center>

However, each of these strategies is complicated by the interindividual differences in the therapeutic window. Although the goal may be to bring the index agent below therapeutic levels after a new therapy is already providing symptomatic relief, this point may occur at different dose levels in different patients. Consequently, patients must be closely monitored during the transition period to ensure persistent symptom control and to adjust therapy if necessary when side effects are encountered. It may also be appropriate to base titration schedules on half-life. For example, daily dose increases may be well tolerated with drugs that have a relatively short half-life, such as ziprasidone or quetiapine, but greater intervals may be appropriate for longer-acting agents such as aripiprazole to permit time for detection of adverse events, especially after minimally therapeutic dose ranges have been reached.

Perhaps due to the array of antipsychotics, the heterogeneity among these agents and the specific needs of patients, there is no single standard switch strategy that can be recommended regardless of therapy. In a metaanalysis that compared abrupt to gradual discontinuation among atypical agents, there was no clear difference in outcome from a gradual crossover strategy.⁹ However, all trials that this meta-analysis was based on were conducted in inpatients and rescue medications were allowed and available. Thus, it is reasonable to be concerned that the clinical instability generated by an abrupt switch can complicate the transition from one agent to another. The plateau crosstitration strategy, the most conservative approach, poses the least risk of inadequate symptom control and may provide the greatest likelihood of an orderly switch. This is particularly appropriate when switching between two relatively well-tolerated
with dissimilar side effect profiles. When the newly introduced agent is among those that can be rapidly titrated to a therapeutic dose, the period of time in which patients are controlled on two medications will be relatively brief.

Table 2.

<img4037|center>

Summary

Several therapeutic choices exist in the control of schizophrenia and bipolar disorder. Due to substantial differences in how patients respond to these therapies and the relative differences in tolerability, it is important to select treatment strategies that help improve or maintain an acceptable QoL. The options may permit patients to reach a higher level of functioning made possible by broader symptom control, favourable effects on cognitive function and a reduced likelihood of sedation or EPS. Reducing the long-term health risks, such as those posed by weight gain, dyslipidemia or hyperglycemia, should also be considered when making therapeutic choices. To achieve these goals, switching therapies frequently is a necessary exercise in optimal patient management. Although articulated therapeutic goals in mind and with careful attention to the potential benefits and risks, they can be an important avenue for improving outcomes.

References

1. Lieberman et al. Effectiveness of antipsychotic therapy in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.

2. Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes. J Clin Psychiatry 2007;68(suppl 6):10-13.

3. Essock et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry 2006;163(12):2090-5.

4. Faries et al. Clinical and economic ramifications of switching antipsychotics in the treatment of schizophrenia. BMC Psychiatry 2009;9:54.

5. Davis JM, Leucht S. Commentary on strategies for switching antipsychotics. BMC Med 2008;6:18.

6. Liu-Seifert H, Adams DH, Kinon BJ. Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs. BMC Med 2005;3:21.

7. Masand PS, Berry SL. Switching antipsychotic therapies. Ann Pharmacother 2000;34(2):200-7.

8. Weiden PJ, Buckley PF. Reducing the burden of side effects during long-term antipsychotic therapy: the role of switching medications. J Clin Psychiatry 2007;68(suppl 6):14-23.

9. Remington et al. The crossover approach to switching antipsychotics: what is the evidence? Schizophr Res 2005;76:267-72.

OUTPATIENT TREATMENT CONSIDERATIONS DURING THE TRANSITION PERIOD

Editorial Review:

David Bloom, MD, FRCPC

Medical Chief, Intellectual Handicap with Pyschiatric Comorbidity Program, Medical Chief, Psychotic Disorders Program, Douglas Mental Health University Institute, Assistant Professor of Psychiatry, McGill University, Montreal, Quebec

In the best circumstances, patients with schizophrenia or bipolar disorder can anticipate sufficient symptom control to permit a return to function reasonably close to the pre-morbid state. Although most patients experience some side effects, these can be mild and acceptable. The challenge for all patients with imperfect symptom control or residual side effects is whether a change in therapy will provide an additional incremental improvement in quality of life. There are no objective methods of predicting a response from a switch, but an array of therapies with different characteristics, including variability in their mechanisms of action, does support a potential for benefit. Several considerations should guide decisions.

The potential for clinical benefit from a switch can be raised by anyone concerned about the well-being of a patient, including the family, a member of the health care team or the patient. One of the most common reasons to consider a switch in therapy is simply to improve symptom control. However, in the case of schizophrenia, the definition of symptom control can be relative, ranging from suppression of vivid hallucinations to a broader recovery that includes an ability to return to work or otherwise participate in normal daily activities. Similarly, a therapy for bipolar disorder may be declared effective if it prevents frequent mood cycling, but a more comprehensive recovery that also includes full participation in activities of normal living may be a reasonable goal in many individuals. Overall, the goal of a switch may be to find a therapy that permits the patient to move forward in his or her life beyond overt symptom control. For many patients, the quest to derive greater participation and more enjoyment from life is a reasonable expectation of an optimal regimen of currently available therapies.

Tolerability: A Patient’s Perspective

A switch to reduce side effects is another common reason that also has indirect implications for long-term outcome (Table 1). An acceptable balance of efficacy and tolerability is subjective and patient-driven, so that patients are the ultimate authority of which side effects are worth tolerating to gain adequate symptom control. When an acceptable balance is lost, it is reasonable to anticipate diminishing adherence with the predictable consequence of treatment failure. Although it is always appropriate for the physician and patient to agree on a treatment course, sensitivity to the patient’s concerns about side effects may be among the most critical elements of a successful collaboration. Tolerability is relative. While patients may req
he need to accept some unwanted effects of therapy for the benefit gained, a side effect is minor only in the eyes of the patient, providing a justification for considering a switch for any event that has a persistent and substantial negative influence on quality of life (QoL).

Table 1.

<img4038|center>

A View on Long-term Benefit and Risks

Concern about the relative safety of an antipsychotic drug driven by metabolic abnormalities, changes in indicators of liver function or abnormalities on blood monitoring may produce a physician-driven decision to consider a switch in medication. Although patients may express concern about drug-related weight gain, which often precedes such metabolic disturbances as hyperlipidemia and hyperglycemia, adverse laboratory results,¹ even if asymptomatic, are an important reason to consider alternative therapies. Treatment change may not be the only option. For example, increased exercise leading to weight loss may reverse adverse metabolic changes on antipsychotic drugs associated with metabolic disturbances.² However, the long-term risks of persistent hyperlipidemia include cardiovascular disease.³ Similarly, the long-term risks of hyperprolactinemia include osteoporosis and some forms of cancer,⁴ so that alternatives may be warranted even if the symptoms of schizophrenia are otherwise well controlled.

In patients who develop uncontrolled symptoms on their current therapy, particularly when these symptoms pose a risk of harm to the patient or others, deliberation about a switch in therapy is unnecessary. However, in the outpatient care of reasonably stable patients, a switch in therapy should be undertaken within the context of a careful assessment of the potential for benefit and the potential for harm. The discussion should involve the patient and other individuals who will be affected by the switch, particularly those who may be needed to provide support during the period of transition. When involving family members or those with a close relationship to an adult patient such as a roommate, consent from the patient is preferred. However, it may be appropriate to abrogate confidentiality when patients unreasonably refuse consent for those with a need to know about a potential change in the disorder course, including those who live with the patient.

In a discussion about a potential switch, it is important to consider whether expectations are realistic. Clinical trials have generated probabilities of response and quantified differences in relative rates of specific adverse events for the available antipsychotic therapies, but individual response or tolerability is not wholly predictable. The risk not only includes a failure to gain the anticipated advantages but to lose ground in regard to either symptom control or degree of to
s should not discourage patients from seeking a better QoL through a change in medication; however, they do demand a clear articulation of goals (Table 2), and that patients recognize their participation in evaluating benefits in the context of risks and assume an important collaborative role in seeking the best outcome.

Table 2.

<img4039|center>

Preparing for the Transition Period

Patients and caregivers well informed about the period of transition are more likely to weather transient periods of instability. Although it may be possible to perform an abrupt switch in therapy, such as initiating paliperidone in a patient previously taking risperidone, weaning the patient gradually from the index therapy is generally preferable because it will provide some protection against relapse if the new agent proves ineffective. In many cases, it may be appropriate to uptitrate the new agent to a full therapeutic dose before even beginning a gradual elimination of the former agent. Since abrupt withdrawal of some agents, particularly clozapine, can induce rebound, a transition of at least one week may be prudent in most patients. Longer periods of gradual substitution of the new agent may be especially warranted in patients who are discontinuing a therapy that they have been on for an extended period.

The most well tolerated second-generation antipsychotics can generally be rapidly uptitrated, but even when patients arrive at a therapeutic dose, a full appreciation of the benefits and risks may take a month or more as patients become acclimatized to the new therapy. During this time, patients should be followed closely with progressively tighter monitoring for those with a history of severe disorder. A health care professional qualified to evaluate symptom control and adverse events should contact the patient at least every two weeks over the transition period. Patients switching medication and their caregivers should be provided with emergency contact numbers. Again, patients fully informed about the types of side effects they may encounter on the new medication will be better prepared to traverse the transition and evaluate the relative benefits of the change.

The objective of schizophrenia treatment is recovery, which is a concept that can be distinguished from remission. While complete remission from schizophrenia is rare, recovery relates to the relative ability of patients to connect to the individuals they were prior to the onset of their disorder. Current therapies infrequently permit remission but they do permit patients to realize important goals such as independent living or a sense of control over their illness. Physicians, patients or caregivers frequently seek a switch in therapy to get closer to this goal. Over a lifetime, patients may undergo multiple treatment switches, including cycling back to a previous therapy, which can be a viable strategy, in order to improve QoL. Patients should not be discouraged from this quest, although a systematic approach is essential to ensure that the effort is rewarded by the fulfillment of realistic expectations.

Managing Side Effects: Strategies for Successful Switching

For many pharmacologic agents, the period of greatest risk of side effects is often early in the course of therapy with diminishing importance as the patient becomes acclimatized. Although there is no method of predicting which adverse events will persist or worsen with continuing therapy, patients should be reassured during this period of transition and provided with supportive care. For example, it may be helpful to employ an additional agent such as a benzodiazepine or an antiepileptic such as valproic acid to control agitation or aggression during the transition period.⁵ Patients may wish to keep a diary of adverse events so that they can identify more persistent types as well as changes and improvements in these side effects over time. This type of documentation may provide the patient with a sense of control during the transition when adverse events are most common. As no therapy is completely free of side effects, it is important to give each new therapy an adequate trial. If patients are provided with adequate support during the transition, the benefits of the switch will be given an opportunity to emerge while the side effects diminish, allowing the patient to become comfortable with the new agent.

The most common clinical complaints associated with antipsychotic therapies are weight gain, sedation, side effects related to hyp
" />trapyramidal symptoms (EPS). Although there is considerable interpatient variability in the risk of each of these types of side effects, there are clear distinctions for relative risk among current agents. For example, risperidone has been most closely associated with hyperprolactinemia (Figure 1) and olanzapine with weight gain (Figure 2).⁶

Figure 1.

<img4040|center>

Figure 2.

<img4041|center>

Switches to reduce or eliminate side effects that threaten QoL or adherence are reasonably based on characteristi
. This is particularly relevant in patients who experience a side effect characteristic of that medication and wish to switch to another agent with less likelihood of producing that event. A classic example is the weight gain that has been most closely associated with olanzapine but there are other examples. There are no formal guidelines for switch strategies based on side effects, but reasonable choices can be derived from published studies (Table 3).

Table 3.

<img4042|center>

Summary

The expanding list of antipsychotic therapies, particularly second-generation drugs with a broad array of mechanisms and distinct profiles of expected side effects, has permitted for more ambitious targets of well-being to be considered in patients with schizophrenia. The conventional neuroleptics played a critical role in allowing patients to control psychoses and overt positive symptoms but at the price of EPS and a limited likelihood of reintegrating into normal activities of daily life. With the current selection of therapies, there is a far greater likelihood of recapturing key components of the individual who was lost in the acute episodes of schizophrenia or mood swings associated with bipolar disorder. The newer therapies are not without side effects, but an empiric approach to an optimal treatment strategy can often match patients with a drug that is effective, tolerable and poses minimal or no long-term safety concerns.

References

1. McIntyre et al. Antipsychotic-induced weight gain: bipolar disorder and leptin. J Clin Psychopharmacol 2003;23(4):323-7.

2. Birt J. Management of weight gain associated with antipsychotics. Ann Clin Psychiatry 2003;15:49-58.

3. Mackin et al. Metabolic disease and cardiovascular risk in people treated with antipsychotics in the community. Br J Psychiatry 2007;191:23-9.

4. Compton MT, Miller AH. Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull 2002;36:143-64.

5. Casey et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacol 2003;28(1):182-92.

6. Henderson DC, Doraiswamy PM. Prolactin-related and metabolic adverse events of atypical antipsychotic agents. J Clin Psychiatry 2008;69(suppl 1):32-44.

7. Weiden et al. Long-term changes in weight and plasma lipids during maintenance treatment with ziprasidone. Neuropsychopharmacol 2008;33:985-94.

8. Hanssens et al. The effect of antipsychotic medication on sexual function and serum prolactin levels in community-treated schizophrenic patients: results from the Schizophrenia Trial of Aripiprazole (STAR) study (NCT00237913). BMC Psychiatry 2008;8:95.

9. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry 2003;64(suppl 19):6-12.

10. Edwards SJ, Smith CJ. Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: a mixed treatment comparison of randomized controlled trials. Clin Ther 2009;31(pt 1):1345-59.

SWITCHING ANTIPSYCHOTIC THERAPIES IN THE OUTPATIENT SETTING: A SUPPORTIVE CARE PERSPECTIVE

Editorial Review:

Donna Kydd, RNEC, CPMHN(C)

Canadian Mental Health Association, Oshawa, Ontario

The observation that patients diagnosed with psychiatric disorders engaged in their own care do better is particularly relevant for those switching their treatment from one antipsychotic to another. Whether a patient initiates the request or their clinician recommends a change in treatment, patients need to be engaged in understanding the goals of treatment and associated relative risks and benefits. They need to monitor their own response with respect to both symptom control and tolerance of side effects. They need to feel supported by their clinician to cope with the effects of medication changes.

Points to Consider

The request for a change in therapy from a patient is frequently provoked by side effects such as weight gain and sedation. Female patients tend to be particularly concerned by weight gain. Also, weight gain is associated with a variety of comorbid health problems including hypertension and diabetes. The decision to switch antipsychotic treatment must be made prudently with full consideration for potential benefits and risks. Antipsychotic change may not be the first choice for a patient who has been otherwise doing well. For example, motivated patients might consider a rigorous exercise program to avoid the weight gain associated with some antipsychotic agents. Fortunately, the current range of therapeutic choices provides a reasonable opportunity to tailor treatment based on risk for specific side effects.

Once a decision is made to switch antipsychotic therapy, it is critical that clinicians fully and accurately describe to patients potential side effects in advance of a change in treatment. The risk of not doing so may result in loss of clinician credibility. Clarity and honesty are essential. If the clinician loses the trust of their patient, it becomes increasingly difficult to collaborate in establishing the relative benefits and identifying strategies to deal with side effects of a new medication. Often, the major casualty of a loss of trust is a lack of treatment adherence, ultimately leading to treatment failure. In general, there is a good correlation between the degree to which a patient has been prepared for anticipated effects of a new medication and the likelihood of a successful treatment transition.

During the transitioning phase of antipsychotic switching, the level of side effects and degree of symptom control may be affected. This is often transient and selflimiting in nature and will resolve once the patient is stabilized on the new medication. Patient support with management of side effects such as increased anxiety and sedation is essential to enhance transition success and, hopefully, appreciate the advantages of the new medication. Many patients are able to provide a very accurate depiction of the relative severity of these side effects and of treatment efficacy, thus assisting clinicians to determine if further action is required.

Necessity of Increased Patient Support

Due to the risk of a change in the types of side effects as well as a risk of inadequate symptom control, the level of support to patients should be increased during the transition period. From a practical standpoint, weekly contact is often sufficient, but the quality of the contact may be as important as its frequency. Patients need to sense that their concerns are being addressed. Making spontaneous telephone calls to patients to inquire about their coping with the transition is one approach for conveying caring and collaboration. It is often deeply appreciated by patients. Good communication with patients reduces the risk for treatment non-adherence.

Treatment goals need to be highly personalized because illness course and the response to therapy in a patient diagnosed with schizophrenia are extremely heterogeneous. For some, the goal may simply be to control positive symptoms. For others, the target of adequate treatment may be a relatively higher level of reintegration into normal activities. In patients who discontinue therapy because of perceived intolerability or lack of efficacy, it is generally unhelpful to be judgmental. Rather, enlisting patients to identify and address barriers to successful therapy can generate the empowerment that leads to a successful treatment program.

Summary

Choices in antipsychotic agents have created a higher threshold for the definition of treatment success based on efficacy and tolerability. Patients must be actively engaged in their own treatment because therapies are not uniformly effective or without side effects. The components of effective transition management during a switch in antipsychotic treatment are less defined by specific steps in an algorithm than they are by practical principles of good communication and supportive care. Particularly in the outpatient setting, patients play a critical role in defining and accepting the therapy that works best for them.

LIFELONG CARE OF SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS

Editorial Review:

Roger S. McIntyre, MD, FRCPC

Head, Mood Disorders Psychopharmacology Unit, University Health Network, Associate Professor of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario

Switching antipsychotic therapy in patients with schizophrenia or bipolar disorder is generally performed on the basis of poor symptom control or intolerable side effects. However, these are chronic disorders in which the long-term effects of therapy must be considered parallel to the immediate goal of improving the patient’s quality of life. This orientation is increasingly drawing attention to the longterm impact of antipsychotic therapies on important risks to general health such as cardiovascular disease (CVD).¹ Although the reasons for the higher rates of CVD in patients with schizophrenia appear to be multifactorial and include high rates of smoking and obesity—both of which have a prevalence that is as much as three times that observed in individuals without schizophrenia^2,3— there has been an increasing emphasis on selecting antipsychotic agents that do not exacerbate these risks.

Efficacy and Safety of Antipsychotics

The complexity of the issues surrounding the relative efficacy and safety of antipsychotic therapies was captured in CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), one of the largest studies to compare antipsychotic therapies.⁴ In that study, almost 1500 patients at 57 sites were randomly assigned to one of four atypical agents (risperidone, olanzapine, quetiapine, ziprasidone) or the typical antipsychotic perphenazine. At entry, the average time since antipsychotic therapy was first prescribed in this population was approximately 14 years. The study was remarkable in its similarity of medication discontinuation rates over the 18 months of the study. Overall, 74% (range, 62% to 84%) of patients discontinued their assigned antipsychotic therapy. Rates did not differ significantly between olanzapine, perphenazine or ziprasidone, but patients were significantly less likely to discontinue olanzapine than quetiapine (P<0.001) or risperidone (P=0.002). However, discontinuation for weight gain or metabolic side effects (P<0.001) was greater on olanzapine relative to other therapies.

In CATIE, a substantial proportion of patients entered the study already taking olanzapine, risperidone or quetiapine, which were all available when the study was initiated. As a result, these patients were effectively randomized to switch or stay on the baseline therapy. When this group was evaluated separately, discontinuation rates were lower among those who stayed with their baseline therapy.⁵ Although this provides support for the premise that therapy should not be switched without cause, it does not permit an evaluation of the benefits of switching in patients who are not well controlled on or who are not tolerating their current therapy. In CATIE, the predominant reasons for discontinuation, particularly those due to adverse events, differed among agents, corroborating existing evidence that there is no optimal schizophrenia therapy.

Rather, the results underscore the need for multiple options and the potential benefit of switching between therapies in order to find the optimal balance of efficacy and safety.

Monitoring Iatrogenic Metabolic Risks

Most of the iatrogenic risk of CVD from antipsychotic therapy is an indirect result of drug-related weight gain. Although some antipsychotic drugs may directly contribute to insulin resistance,⁶ there has been increasing concern about the variable effects of atypical antipsychotics for promoting metabolic disturbances secondary to obesity.⁷ Not all atypicals are closely associated with weight gain and not all patients placed on an atypical agent with strong associations with weight gain develop this side effect, but monitoring patients for weight gain has been recommended as part of a routine clinical management.
t; This requires acquiring baseline measures for weight (particularly in the form of body mass index [BMI]), fasting plasma glucose, fasting plasma lipids, blood pressure (BP) and waist circumference. While measures of BP, plasma lipids and plasma glucose should be repeated three months after starting a new therapy and then annually, BMI should be undertaken more frequently, such as monthly for the first three months, then quarterly for the first year before moving to annual evaluations (Table 1).

Table 1.

<img4043|center>

The highest risk of weight gain is associated with clozapine and olanzapine, followed by risperidone and quetiapine.4 Ziprasidone and aripiprazole are associated with relatively low risks of weight gain.^9,10 The relative risks of weight gain are likely to be the primary explanation for the association of both clozapine and olanzapine with an increased risk of diabetes.¹¹ Both of these agents are also associated with an increased risk of significant dyslipidemias. In some studies, risperidone and quetiapin
044" />iated with diabetes and dyslipidemia.⁴ Ziprasidone and aripiprazole have not been convincingly associated with any these metabolic disturbances (Table 2). However, these relative risks should be placed in the context of the patient so that agents that pose a relatively low risk of metabolic disturbances are given a greater priority in those who already are obese or who have a significant number of baseline CV risk factors. Switching treatments should be considered in those who develop metabolic disturbances on therapy.

Table 2.

<img4044|center>

Table 3.

<img4045|center>

Hyperprolactinemia is another potential threat to a health outcome that is not evenly distributed among currently available agents. A direct result of dopamine inhibition, the risk of clinically significant hyperprolactinemia is greatest among conventional antipsychotics and those atypical agents with a particularly strong D₂ binding, such as risperidone.¹² Overt symptoms of hyperprolactinemia, such as gynecomastia in men, can be disturbing and may prompt patients who develop elevated prolactin levels to request a change in therapy.

However, prolactin levels should also be monitored because of their association with health risks, including osteoporosis in men and women,¹³ as well as several hormone-related cancers in women, including breast cancer.¹⁴

Smoking and Akathisia

The extraordinarily high rate of smoking in individuals with schizophrenia, which has been reported in nearly 70% of patients in some studies,¹⁵ is another potentially important target of initiatives to improve health in this population. Although it has been theorized abnormalities in nicotinic receptors,¹⁶ the health benefits of smoking cessation or even reducing the number of cigarettes may be substantial. Strategies such as nicotine replacement therapy are attractive if theories about nicotinic receptor stimulation explain the association between smoking and schizophrenia. Although it has been reported that smoking relieves akathisia,¹⁷ it is not clear whether atypical agents with a relative low risk of akathisia can reduce the need for smoking. Further studies of the propensity for smoking among individuals with schizophrenia may provide more information about the benefit:risk ratio of quitting.

Treatment Paradigms

It is easy to urge clinicians to apply management strategies that minimize a full range of health risks as they offer agents that are both effective and well tolerated, but the reality is likely to be more complex. For example, the most effective agent in a given individual may not be the best tolerated or the safest in regard to long-term risks. Similarly, it may be difficult to switch a patient who has achieved excellent symptom control after several failures even if a potential risk from therapy is substantial. Patients and families must participate in a clear discussion of the relative advantages and disadvantages of available strategies. The availability of multiple atypical agents with relative differences in mechanism of action, safety and tolerability increases the likelihood that an agent can be identified with many or most of the attributes important to the patient; however, there will be trade-offs and a low likelihood of identifying a drug without limitations.

Individualization of therapy is fundamental to management of a heterogeneous disorder such as schizophrenia, but this concept should be expanded to consider adjunctive strategies beyond selection of an antipsychotic agent. For example, in patients taking a therapy associated with weight gain, exercise programs may not only control the risk but also provide a CV benefit inherent to physical activity. In patients taking an antipsychotic that is disturbing the sleep cycle, either by causing daytime sedation or nighttime insomnia, dosing schedules might be adjusted so that a sedating agent is taken in the evening while a stimulating drug is taken in the morning.¹⁸ In patients with agitation despite otherwise well-controlled schizophrenia, it may be possible to provide an anxiolytic that controls the complaint. In all cases, it is important to re-evaluate whether solutions remain effective as the patient’s circumstances evolve.

Switching therapies is not the only solution and often may not be the best option whether the goal is disorder control, avoiding side effects, or reducing the long-term risks of therapy. However, it may often be the most effective solution. The unique features of the available agents should be carefully considered in matching treatment to the broad and sometimes competing clinical goals. In the context of dose adjustments and adjunctive therapies, there may be several opportunities to provide a patient with a regimen that both the clinician and the patient recognize as yielding a reasonable balance of benefits and risks.

Summary

The immediate goal of controlling and stabilizing the symptoms of schizophrenia or bipolar disorder is an essential first step, keeping in mind that these are chronic disorders. The introduction of a broad array of atypical antipsychotics over the past decade has permitted more ambitious goals in managing both immediate and long-term health risks. While it is important to frequently reassess how treatments can be fine-tuned to advance recovery and improve QoL, the effect of treatment on other health risks, particularly CVD, should also influence therapeutic choices. Switching therapies in response to long-term risks is one of several solutions, but individualized care is an important response to the broad and sometimes competing goals in the treatment of schizophrenia and bipolar disorder.

References

1. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis 2006;(2)3:A42.

2. Davidson et al. Cardiovascular risk factors for people with mental illness. Aust N Z J Psychiatry 2001;35(2):196-202.

3. Dixon et al. The association of medical comorbidity in schizophrenia with poor physical and mental health. J Nerve Ment Dis 1999;187(8):496-502.

4. Lieberman et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-23.

5. Essock et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry 2006;163:2090-5.

6. Houseknecht et al. Diabetogenic effects of some atypical antipsychotics: rapid, whole-body insulin resistance following a single dose. Diabetologia 2005;48(suppl 1):A212.

7. Newcomer et al. Fasting plasma lipids, glucose and insulin, and C-reactive protein are related to adiposity in schizophrenia. Schizophr Res 2003;60(suppl 1):363.

8. Weiden et al. Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a roadmap. J Clin Psychiatry 2007;68(suppl 7):1-48.

9. Simpson et al. Randomized, controlled, doubleblind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry 2004;161(10):1837-47.

10. Jody et al. Meta-analysis of weight effects with aripiprazole. Eur Neuropsychopharmacol 2002;12(suppl 3):290.

11. American Diabetes Association et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27(2):596-601.

12. Henderson DC, Doraiswamy PM. Prolactin-related and metabolic adverse effects of atypical antipsychotic agents. J Clin Psychiatry 2008;69(suppl 1):32-44.

13. Klibanski et al. Decreased bone density in hyperprolactinemic women. N Engl J Med 1980;303(26):1511-4.

14. Hankinson et al. Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1999;91(7):629-34.

15. Goff et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 2005;80(1):45-53.

16. Sacco et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotine receptor mechanisms. Arch Gen Psychiatry 2005;62(6):649-59.

17. Barnes et al. Smoking and schizophrenia: is symptom profile related to smoking and which antipsychotic medication is of benefit in reducing cigarette use? Aust NZ J Psychiatry 2006;40(6-7):575-80.

18. Kane JM, Sharif ZA. Atypical antipsychotics: sedation versus efficacy. J Clin Psychiatry 2008;69(suppl 1): 18-31.