Donna A. Wirshing, MD

While prescription of an antipsychotic 			medication for 			schizophrenia is the first step 			of treatment and for the resolution of 			an acute episode of psychosis, it is 			increasingly recognized that comprehensive 			care requires the integration 			of adjunctive therapies and attention to 			long-term treatment goals, including 			relapse prevention and psychosocial 			rehabilitation. In the absence of a cure 			for schizophrenia, clinicians can optimize 			outcomes by combining pharmacotherapy 			with a treatment approach 			that incorporates symptom monitoring, 			assessment of treatment adherence and 			medication side effects, management 			of medical and psychiatric comorbidities, 			and nonpharmacologic therapies 			directed at functional rehabilitation and 			improved quality of life.

Relapse prevention and treatment adherence

The main goal in the treatment of schizophrenia is to reduce symptoms and minimize the risk of relapse or the reappearance of symptom exacerbations. Although there is no single definition of relapse, rehospitalization, symptomatic worsening, self-injury, and suicidal or homicidal ideation are all factors used in determining relapse in research and clinical settings.

Schizophrenia is a complex and 			chronic disorder that requires long-term 			treatment. Although other treatment 			methods such as psychotherapy, stress 			management, and education can help 			in delaying the occurrence of relapse, 			antipsychotic therapy is the cornerstone 			of relapse prevention. Consequently, 			adherence to a drug regimen is crucial 			for reducing the risk of relapse.

There are 3 basic ways of assessing medication adherence. First, clinicians can elicit reports from patients, family members, and caregivers regarding adherence, although such reports can be inaccurate. A more reliable technique is to have patients bring in their medication bottles at each visit to perform pill counts. Finally, plasma levels of certain antipsychotics may be obtained to determine whether a medication is being taken, although this method might fail to detect partial adherence. Switching to an injectable, long-acting antipsychotic may be suitable for certain patients and produce beneficial results in efficacy, tolerability, and relapse prevention.

 Injectable antipsychotics are not a panacea for maintaining adherence, but their administration in the clinic allows for verification that each dose has been received.

Patients and family members should be informed about the benefits and side effects of medications so that they can actively participate in the treatment effort.

 In long-term studies of schizophrenia conducted in the 1980s, family education was the most effective psychosocial treatment available. Adherence therapy and psychosocial skills training are also highly regarded.

Alcohol and drug abuse, social anxiety, and depression are all conditions prevalent among patients with schizophrenia. Each can negatively affect a patient's quality of life and treatment outcome and should be attended to as a regular component of aftercare. Between one third and one half of schizophrenic patients use alcohol and/or other substances; this puts them at increased risk for relapse, treatment nonadherence, hospitalization, violence, and suicide.

 found that the combination of cognitive-behavioral drug relapse prevention strategies and social and independent living skills training improved drug and alcohol abstinence, medication adherence, and quality of life.

Dual-diagnosis programs are more likely to produce beneficial results for patients with schizophrenia than any 12-step program alone because they are designed to take into account the various symptomatic, cognitive, and social limitations of patients with schizophrenia.

 Accordingly, dual-diagnosis programs typically follow a "harm-reduction" model in which a decrease in drug use and its associated consequences, rather than total abstinence, is the goal of treatment. An ideal dualdiagnosis program is shaped on 2 basic principles:

 treatment of schizophrenia 				and substance abuse.

 treatment program in 				which a set of clinicians (eg, physicians, 				nurses, case managers) work as a team 				on both disorders.

Other important elements include 			intensive case management, motivational interventions, counseling, staged 			interventions, social support interventions, 			and regular urine drug screens.

In a study conducted by Pallanti and colleagues,

 36.3% of the schizophrenic patients were found to be suffering from social anxiety disorder. These patients had higher rates of past suicide attempts and alcohol and drug dependence. They also rated poorly in employment, socialization, and personal well-being as measured by the Social Adjustment Scale. Symptoms of social anxiety, such as social withdrawal, are similar to but distinct from negative symptoms of schizophrenia.

 The added burden of anxiety may cause further decline in a patient's quality of life.

 because social anxiety is multifaceted, multiple assessments can be used to measure its symptoms more directly.

About 10% of schizophrenic patients successfully complete suicide.

 Multiple risk factors have been identified, ranging from previous suicide attempts, substance abuse, hopelessness, depression, and male sex

 to lack of social support, lack of problem-solving skills, and stress.

 While patients who have recently been released from the hospital are more likely to attempt suicide, Desai and colleagues

 were not able to find a correlation between suicide risk and quality of mental health care. They report that suicide rates are too unstable to clearly be attributed to the quality of a treatment facility or its delivery of care.

The most common indicator of suicide risk is depression. Illness insight can lead to depression and hopelessness in some patients.

 Anhedonia and anergia are among the negative symptoms common to schizophrenia and depression. Difficulties in making a distinction between the 2 disorders may result in a patient's depression being left untreated. Assessments such as the Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale may aid physicians in diagnosing depression and instituting treatment earlier.

Clinicians should monitor patients at baseline and throughout treatment for changes in insight regarding their condition

 and be alert to the possibility of suicide if they begin feeling hopeless motivaabout their recovery.

 In 2002, clozapine (Clozaril) was approved by the FDA for reducing the risk of suicide in schizophrenic and schizoaffective patients. Meltzer

 has recently reviewed studies supporting the use of clozapine to reduce suicidal behaviors and examining reasons for its lack of use (ie, adverse effects such as agranulocytosis, metabolic abnormalities, seizures, hypotension, and hypersalivation).

Managing medication-related comorbidities

A large number of reports have linked atypical antipsychotics to weight gain and associated health outcomes.

 Excess body weight also puts patients with schizophrenia at increased risk for stroke, gallbladder disease, osteoarthritis, and some forms of cancer.

 According to the American Diabetes Association (ADA) consensus statement,

 clozapine and olanzapine (Zyprexa) appear to cause the greatest amount of weight gain among the atypical antipsychotics. These medications are also associated with an increased risk of dyslipidemia and diabetes. Type 2 diabetes may occur because of insulin resistance caused by weight gain or altered fat distribution, or as a result of direct effects of the drugs on insulin receptors. Carefully monitoring patients' blood glucose levels may ultimately prevent diabetes and significant illnesses associated with diabetes, particularly cardiovascular disease, renal disease, peripheral neuropathy, and limb loss.

The ADA suggests obtaining several 			screening measures when a patient 			starts taking an atypical antipsychotic. 			These include baseline assessment of 			personal and family history of obesity, 			diabetes, dyslipidemia, hypertension, 			and cardiovascular disease, as well as 			baseline and subsequent monitoring of 			body mass index, waist circumference, 			blood pressure, and fasting plasma 			glucose and lipid measurements. 			Patients at risk for diabetes (fasting 			glucose level of 100 to 125 mg/dL) and 			patients with diabetes (fasting plasma 			glucose level of 126 mg/dL or more) 			should in particular be monitored for 			symptoms of diabetes and diabetic 			ketoacidosis, including polyuria, excessive 			thirst, weight loss, nausea or vomiting, 			dehydration, rapid respiration, and 			clouding of sensorium.

Fortunately, behavioral approaches to weight control, such as nutritional intervention and increased activity, can prevent or counter antipsychoticinduced weight gain.

 Patients should be encouraged to weigh themselves and exercise regularly. Even a simple exercise, such as brisk walking for a half hour per day, can be beneficial in maintaining or reducing weight. We encourage our patients to learn how to control their portions and reduce their fat intake, as opposed to cutting carbohydrates or counting calories, because fat requires a greater amount of energy to burn off. Keeping food and exercise diaries is helpful for both patients and clinicians in managing caloric intake, determining problem foods, and crafting healthier eating habits.

We are currently testing a series of classes adopted from the Diabetes Prevention Program

 participants in our program have enjoyed the Healthy Lifestyles classes and have lost or maintained weight. The key is to establish lifestyle changes because even weight-loss medications are ineffective without changes in eating and exercise habits. We are also working with caregivers to help our participants achieve the changes necessary to reach their weight loss goals. Weight management can improve quality of life and self-image

 and can halt a downward spiral leading to other health problems and depression.

Psychiatric rehabilitation and interventions focusing on the functional impairments of an illness are vital for optimizing the patient's position in the community.

 The symptoms of schizophrenia, particularly the negative symptoms (social withdrawal, lack of motivation, and anhedonia), will impair a patient's function in the community. These factors can negatively affect a person's everyday life and self-esteem. Barkic and colleagues

 reported significant improvement in cognitive functioning after switching patients from a first-generation antipsychotic to risperidone (Risperdal). Their results and other findings supporting the use of a newer antipsychotic over a first-generation antipsychotic for functional outcomes may be a function of the newer drugs' effects on biologic mechanisms affecting cognitive functioning, their decreased risk of extrapyramidal side effects, or the improvements they produce in mood and motivation.

 Pharmacotherapy aimed at symptom control at the lowest possible dosage will enhance patient functionality.

Pharmacotherapy must be augmented by psychosocial interventions. A multi-staged cognitive therapy for psychotic disorders that teaches patients to assess, cope with, understand, selfevaluate, and manage risks associated with their illness may significantly improve positive symptoms.

 Many researchers have reported improvement in adherence, cognitive and social function, and employment when skills training, psychosocial interventions, and supportive services were included as components of treatment.

 For example, supported employment may compensate for the effects of cognitive impairment on employment.

 Other specific psychotherapeutic interventions directed at improving overall functioning may include cognitivebehavioral therapy, occupational therapy, family therapy, and motivational interviewing.

While domain-specific interventions do produce successful results,

 found that overall, programs involving concrete problem solving and principles of motivational interviewing were most effective. Rossotto and coworkers

 found that an outpatient adaptation of a community reentry module for patients with schizophrenia and patients with schizoaffective disorder more than doubled the likelihood of keeping clinical appointments and drastically lowered rehospitalization rates in the 12-month period following completion of the study. The weekly sessions incorporated motivational interviewing, video demonstrations, role playing, problem-solving exercises, and in-class and community assignments to help bridge the gap between inpatient hospitalization and outpatient treatment. Educating patients about their illness and teaching coping skills should be the minimal nonpharmacologic treatment patients receive.

Teaching patients coping skills in 			order to better respond to their symptoms, 			medication side effects, and 			stigmatization may help improve functionality 			and quality of life in schizophrenia. 			Stigmatization particularly 			affects quality of life by serving as a 			barrier to employment. Social factors 			are a greater influence on employment 			than any intrinsic characteristic of 			schizophrenia.

Rates of employment among the mentally ill have been dropping since the deinstitutionalization movement.

 This may be a result of a lack of emphasis on employment during rehabilitation or the patient's own fear of losing government disability income. Occupational therapy can improve the quality of time spent by patients with schizophrenia on a daily basis

 and give patients the necessary tools to find and maintain employment.

Although antipsychotic therapy is the 			chief component of the management of 			schizophrenia, a number of other 			elements can be integrated into a comprehensive treatment plan. Clinicians 			should be aware of the possibility 			of social, cognitive, emotional, and 			medical impairments associated with the 			illness so that they can be better prepared 			to identify and tackle symptoms and 			medication side effects. Patients need 			to be monitored closely, even while 			psychiatric symptoms are in remission 			during antipsychotic treatment.

Check-in appointments once per 			week just for supportive therapy are 			beneficial when patients make the transition 			from the hospital to the community. 			We recommend tapering visits to 			every 2 weeks after 6 months, then 			monthly visits thereafter. It is important 			to remember that no single treatment 			method can fully cater to all the 			different aspects of a patient's wellbeing. 			Beneficial long-term outcomes 			in the community lives of persons with 			mental illness may be more effectively 			achieved by integrated methods of treatment 			applied by a collaborative group 			of clinicians.

		Ms Mahgerefteh is a research assistant and 			healthy lifestyles coach at the Schizophrenia 			Research Clinic at the VA Greater Los Angeles 			Healthcare System.
		Dr Pierre is associate clinical professor of 			psychiatry at the University of California, Los 			Angeles, David Geffen School of Medicine and 			Staff Psychiatrist at the VA Greater Los 			Angeles Healthcare System.
		Dr Wirshing is associate professor of psychiatry 			at the University of California, Los 			Angeles, David Geffen School of Medicine and 			is co-chief of the schizophrenia inpatient 			treatment unit and the schizophrenia research 			clinic of the VA Greater Los Angeles 			Healthcare System. The authors have no conflicts 			of interest to report regarding the subject 			matter of this article.
		

 Leucht S, Barnes TR, Kissling W, et al. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. 

 Moller HJ, Llorca PM, Sacchetti E, et al. Efficacy and safety of direct transition to risperidone longacting injectable in patients treated with various antipsychotic therapies. 

 Kopelowicz A, Liberman RP. Integrating treatment with rehabilitation for persons with major mental illnesses. 

 Le Fauve CE, Litten RZ, Randall CL, et al. Pharmacological treatment of alcohol abuse/dependence with psychiatric comorbidity. 

 Shaner A, Eckman T, Roberts LJ, Fuller T. Feasibility of a skills training approach to reduce substance dependence among individuals with schizophrenia. 

 Drake RE, Mueser KT. Psychosocial approaches to dual diagnosis. Schizophr Bull. 2000;26:105-118.
 

 Drake RE, Essock SM, Shaner A, et al. Implementing dual diagnosis services for clients with severe mental illness. 

 Pallanti S, Quercioli L, Hollander E. Social anxiety in outpatients with schizophrenia: a relevant cause of disability. 

 Braga RJ, Mendlowicz MV, Marrocos RP, Figueira IL. Anxiety disorders in outpatients with schizophrenia: prevalence and impact on the subjective quality of life. 

 Wetherell JL, Palmer BW, Thorp SR, et al. Anxiety symptoms and quality of life in middle-aged and older outpatients with schizophrenia and schizoaffective disorder.

Articles

While an antipsychotic medication is the first step of treatment for schizophrenia, it is increasingly recognized that comprehensive care requires the integration of adjunctive therapies and attention to long-term treatment goals.

Treatment Challenges in Schizophrenia: A Multifaceted Approach to Relapse Prevention

Achieving treatment adherence in schizophrenia is a great challenge. The reasons for lack of treatment adherence are complex, vary considerably from patient to patient, and have been categorized as follows: patient-related factors (e.g., persecutory delusions, lack of insight, health care beliefs), medication-related factors (e.g., lack of efficacy, distressing side effects), environmental factors (e.g., caregiver support, cost) and clinician-related factors (e.g., therapeutic alliance) (Fenton et al., 1997).

Conventional antipsychotic medications such as haloperidol (Haldol) and fluphenazine (Permitil, Prolixin) used to treat schizophrenia have a number of untoward extrapyramidal side effects (EPS), including severe restlessness, akathisia, parkinsonism and tardive dyskinesia (Ames et al., 1996). Patients who take these medications can also feel depressed or anxious if they experience antipsychotic-induced dysphoria (Van Putten and May, 1978). Sexual side effects and cognitive side effects--sedation and inability to concentrate--also negatively impact a patient's adherence. The only three approved long-acting antipsychotics that may improve adherence--because they offer an assured delivery system--are the conventional depot forms: fluphenazine decanoate, fluphenazine ethanoate and haloperidol decanoate. Some evidence from the literature on these agents does suggest decreased risk of relapse, however, their noxious side effects may prevent a person from continuing with the bimonthly injections--thus negatively impacting treatment adherence.

 The level of denial of illness among people suffering from schizophrenia is quite high. Research on the reasons why patients with schizophrenia do not take their medication has indicated that patients with grandiose delusions are most likely to reject medication so as to avoid confrontation with a reality that is not so glamorous. For example, it is much better to be lost in the delusion of being Jesus than to confront suboptimal living circumstances, such as a homeless shelter. This phenomenon was noted by the late Theodore Van Putten, M.D.,  and his colleagues who realized that patients who had a negative initial impression of medication would be likely to discontinue medication in the future (Van Putten, 1974). Other researchers built upon this work and developed a scale that measures patients' attitudes toward medications (Awad et al., 1995).

The newer antipsychotics, including clozapine (Clozaril), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa) and ziprasidone (Geodon)--and now aripiprazole (Abilify)--are better tolerated by patients due to their more favorable EPS profile (Wirshing et al., 1997). Some agents can be associated with significant side effects such as weight gain, diabetes, dyslipidemia and sexual dysfunction (Burke et al., 1994; Wirshing et al., 1999; Wirshing et al., 2002). 

It is estimated that approximately 50% of patients with schizophrenia do not take their prescribed medications as directed (Lacro et al., 2002). Of these patients, 65% to 75% will relapse within one year of discontinuation. Lack of medication adherence translates into a huge economic burden of relapse and rehospitalizations (Norquist and Regier, 1996). Despite their improved tolerability in terms of EPS and dysphoria, recent work suggests that adherence to the newer, gentler, second-generation antipsychotic medications does not appear to be much better than adherence with conventional agents. Dolder and colleagues (2002) demonstrated rates of compliant refills of conventional antipsychotic medications to be 50.1%, compared to 54.9% for the second-generation medications. A recent study at the U.S. Department of Veterans Affairs, Serious Mental Illness Treatment, Research and Evaluation Center utilized the Medication Possession Ratio (MPR), a ratio of the number of days' supply of antipsychotic medication each veteran had received by the number of days' supply they needed to receive to take their antipsychotic continuously, and found that 49,003 patients with schizophrenia with poor adherence (MPR<0.8) were 2.4 times more likely to be admitted to the hospital than patients with high MPRs (Valenstein et al., 2002). These studies indicate that other interventions may be necessary to enhance medication taking behaviors in people with severe mental illness.

Although clinicians may avoid some nonadherence to medication by adequately addressing patient concerns about side effects of medication, other strategies need to be implemented to better engage patients in their own health care. Providing patients with education about their mental and physical health empowers them to collaborate with their clinicians to make rational treatment decisions. Existing options to increase adherence include psychosocial skills training and targeted adherence training. The Community Re-Entry Program is a brief set of classes developed by Robert Liberman, M.D., and colleagues that consists of multi-modal videotapes, workbooks and live classes (Lieberman et al., 1998). Active community outreach can and should be utilized in patients who are reluctant to come in for medication (Miller et al., 1999).

Simple rules clinicians may want to try in their practice to assist their patients with medication adherence are:

Avoid polypharmacy if possible.The more pills a person must remember to take, the greater the difficulty in remembering them.

In patients who are treatment reluctant, de-emphasize the long-term nature of the treatment and break it down into smaller time periods (Weiden, 2003) (see Case Study).

Keep on top of side-effect issues. It is relatively simple to keep a checklist of side effects in a patient waiting area to remind you and the patient why prescribed medication may be destined for the garbage. The Approaches to Schizophrenia Communication (ASC) is a fairly straightforward side-effect rating scale that is quick and easy to use (Weiden and Miller, 2001).

Help educate family members about strategies to deal with nonadherence. Resources for families include 

 by Xavier Amador, Ph.D., and Anna-Lica Johanson, Ph.D. (2000; Vida Press), and 

 by E. Fuller Torrey, M.D. (2001; Quill). Amador and Johanson's book draws from a new application of cognitive-behavioral therapy/compliance therapy (Kemp et al., 1998). 

Support from other families dealing with this illness can be very helpful. Referrals to local chapters of support groups such as the National Alliance of the Mentally Ill are useful.

In the near future we may be able to dispense the first long-acting formulation of a second-generation medication--risperidone microspheres (Risperdal Consta). This drug has already been approved in several countries. Because relapse rates are less for risperidone compared to conventional agents, as demonstrated in a well-designed study by Csernansky and colleagues (2002), we envision that a guaranteed delivery system will further boost these encouraging results. Long-acting formulations of several other second-generation medications may also be available in the near future and are under study. Many patients may benefit from the availability of long-acting formulations, since the need to take daily oral medication will be obviated by--in the case of risperidone--bimonthly injections. Other possible formulations of long-acting, surgically implanted antipsychotic medications, such as the formulation of haloperidol being developed with the support of the National Alliance for Research on Schizophrenia and Depression, are also promising (Siegel et al., 2002). A surgically implantable formulation would be much like the contraceptive levonorgestrel (Norplant), which is implanted in women for long-term prevention of pregnancy.

Ames D, Wirshing WC, Marder SR (1996), Advances in antipsychotic pharmacotherapy: clozapine, risperidone, and beyond. Essential Psychopharmacol 1:5-26.
 

Awad AG, Hogan TP, Voruganti LN, Heslegrave RJ (1995), Patients' subjective experiences on antipsychotic medications: implications for outcome and quality of life. Int Clin Psychopharmacol 10(suppl 3):123-132.
 

Burke MA, McEvoy JP, Ritchie JC (1994), A pilot study of a structured interview addressing sexual function in men with schizophrenia. Biol Psychiatry 35(1):32-35.
 

Csernansky JG, Mahmoud R, Brenner R, The Risperidone-USA-79 Study Group (2002), A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. [Published erratum N Engl J Med 346(18):1424.] N Engl J Med 346(1):16-22 [see comments].
 

Dolder CR, Lacro JP, Dunn LB, Jeste DV (2002), Antipsychotic medication adherence: is there a difference between typical and atypical agents? [Published erratum Am J Psychiatry 159(3):514.] Am J Psychiatry 159(1):103-108.
 

Fenton WS, Blyler CR, Heinssen RK (1997), Determinants of medication compliance inschizophrenia: empirical and clinical findings. Schizophr Bull 23(4):637-651.
 

Kemp R, Kirov G, Everitt B et al. (1998), Randomised controlled trial of compliance therapy. 18-month follow-up. Br J Psychiatry 172:413-419 [see comment].
 

Lacro JP, Dunn LB, Dolder CR et al. (2002), Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 63(10):892-909.
 

Liberman RP, Wallace CJ, Blackwell G et al. (1998), Skills training versus psychosocial occupational therapy for persons with persistent schizophrenia. Am J Psychiatry 155(8):1087-1091 [see comments].
 

Miller AL, Chiles JA, Chiles JK et al. (1999), The Texas Medication Algorithm Project (TMAP) schizophrenia algorithms. J Clin Psychiatry 60(10):649-657.
 

Norquist GS, Regier DA (1996), The epidemiology of psychiatric disorders and the de facto mental health care system. Annu Rev Med 47:473-479.
 

Siegel SJ, Winey KI, Gur RE et al. (2002), Surgically implantable long-term antipsychotic delivery systems for the treatment of schizophrenia. Neuropsychopharmacology 26(6):817-823.
 

Valenstein M, Copeland LA, Blow FC et al. (2002), Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care 40(8):630-639 [see comment].
 

Van Putten T (1974), Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 31(1):67-72.
 

Van Putten T, May R (1978), "Akinetic depression" in schizophrenia. Arch Gen Psychiatry 35(9):1101-1107.
 

Weiden PJ (2003), Promoting compliance in schizophrenia-one month at a time. Current Psychiatry 1:74.
 

Weiden PJ, Miller AL (2001), Which side effects really matter? Screening for common and distressing side effects of antipsychotic medications. J Psych Prac 7:41-47.
 

Wirshing DA, Wirshing WC, Kysar L et al. (1999), Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 60(6):358-363.
 

Wirshing DA, Wirshing WC, Marder SR et al. (1997), Atypical antipsychotics: a practical review. Medscape Psychiatry & Mental Health eJournal 2(5). Available at: www.medscape.com/viewarticle/430841_print. Accessed March 19, 2003.
 

Wirshing DA, Pierre JM, Marder SR et al. (2002), Sexual side effects of novel antipsychotic medications. Schizophr Res 56(1-2):25-30.

There are many factors that contribute to patients with schizophrenia not taking their medication, including side effects and lack of education. What can clinicians do to help their patients adhere to treatment? Should clinicians be spending more time educating their patients? How will long-acting medications affect adherence issues?

Donna A. Wirshing, MD

Articles

Treatment Challenges in Schizophrenia: A Multifaceted Approach to Relapse Prevention

Schizophrenia Treatment Challenges