Treatment Challenges in Schizophrenia: A Multifaceted Approach to Relapse Prevention

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.¹

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.² 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.³ 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.

Managing comorbidities

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.⁴ Shaner and coinvestigators⁵ 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.⁶ 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:

• Simultaneous treatment of schizophrenia and substance abuse.

• An integrated 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.⁷

In a study conducted by Pallanti and colleagues,⁸ 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.⁸ The added burden of anxiety may cause further decline in a patient's quality of life.^9,10 According to Kingsep and associates,¹¹ because social anxiety is multifaceted, multiple assessments can be used to measure its symptoms more directly.

About 10% of schizophrenic patients successfully complete suicide.^12,13 Multiple risk factors have been identified, ranging from previous suicide attempts, substance abuse, hopelessness, depression, and male sex² to lack of social support, lack of problem-solving skills, and stress.¹³ While patients who have recently been released from the hospital are more likely to attempt suicide, Desai and colleagues¹⁴ 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.¹⁵ 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 condition¹⁵ and be alert to the possibility of suicide if they begin feeling hopeless motivaabout their recovery.¹² In 2002, clozapine (Clozaril) was approved by the FDA for reducing the risk of suicide in schizophrenic and schizoaffective patients. Meltzer¹⁶ 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.¹⁷ Excess body weight also puts patients with schizophrenia at increased risk for stroke, gallbladder disease, osteoarthritis, and some forms of cancer.¹⁸ According to the American Diabetes Association (ADA) consensus statement,¹⁹ 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.^20-22 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 Program²³ in our research. Thus far,²⁰ 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-image²⁰ and can halt a downward spiral leading to other health problems and depression.

Maximizing functionality

Psychiatric rehabilitation and interventions focusing on the functional impairments of an illness are vital for optimizing the patient's position in the community.²⁴ 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 colleagues²⁵ 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.²⁶ 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.²⁷ 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.^5,28-31 For example, supported employment may compensate for the effects of cognitive impairment on employment.³² 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,³³ Zygmunt and associates³¹ found that overall, programs involving concrete problem solving and principles of motivational interviewing were most effective. Rossotto and coworkers³⁴ 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.³⁵ 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 basis³⁶ and give patients the necessary tools to find and maintain employment.

Conclusion

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.

References:

References

1.

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.

Am J Psychiatry

. 2003;160:1209-1222.

2.

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.

Int Clin Psychopharmacol

. 2005;20:121-130.

3.

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

Psychiatr Serv

. 2003;54:1491-1498.

4.

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

Alcohol Clin Exp Res

. 2004;28:302-312.

5.

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

Psychiatric Serv

. 2003;54:1287-1289.

6.

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

7.

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

Psychiatric Serv

. 2001;52:469-476.

8.

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

Am J Psychiatry

. 2004;161:53-58.

9.

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

J Psychiatr Res

. 2005;39:409-414.

10.

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.

J Clin Psychiatry

. 2003;64:1476-1482.

11.

Kingsep P, Nathan P, Castle D. Cognitive behavioural group treatment for social anxiety in schizophrenia.

Schizophr Res

. 2003;63:121-129.

12.

Meltzer HY. Treatment of suicidality in schizophrenia.

Ann N Y Acad Sci

. 2001;932:44-60.

13.

Siris SG. Suicide and schizophrenia.

J Psychopharmacol

. 2001;15:127-135.

14.

Desai RA, Dausey DJ, Rosenheck RA. Mental health service delivery and suicide risk: the role of individual patient and facility factors.

Am J Psychiatry

. 2005;162:311-318.

15.

Bourgeois M, Swendsen J, Young F, et al. Awareness of disorder and suicide risk in the treatment of schizophrenia: results of the international suicide prevention trial.

Am J Psychiatry

. 2004; 161:1494-1496.

16.

Meltzer HY. Suicide in schizophrenia, clozapine, and adoption of evidence-based medicine.

J Clin Psychiatry

. 2005;66:530-533.

17.

Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications.

J Clin Psychiatry

. 2004;65:13-26.

18.

Wirshing DA, Danovitch I, Erhart SM, et al. Update on atypicals: practical tips to manage common side effects.

Curr Psychiatry

. 2003;2:49-57.

19.

American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes.

J Clin Psychiatry

. 2004;65:267-272.

20.

Evans S, Newton R, Higgins S. Nutritional intervention to prevent weight gain in patients commenced on olanzapine: a randomized controlled trial.

Aust N Z J Psychiatry

. 2005;39:479-486.

21.

Kalarchian MA, Marcus MD, Levine MD, et al. Behavioral treatment of obesity in patients taking antipsychotic medications.

J Clin Psychiatry

. 2005;66:1058-1063.

22.

Wirshing DA, Smith RA, Erickson ZD, et al. A wellness class for inpatients with psychotic disorders.

J Psychiatr Pract

. 2006;12:24-29.

23.

Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

N Engl J Med

. 2002;346:393-403.

24.

Torrey WC, Green RL, Drake RE. Psychiatrists and psychiatric rehabilitation.

J Psychiatr Pract

. 2005;11:155-160.

25.

Barkic J, Filakovic P, Radanovic-Grguric L, et al. The influence of risperidone on cognitive functions in schizophrenia.

Coll Anthropol

. 2003;27(suppl 1):111-118.

26.

Velligan DI, DiCocco M, Bow-Thomas CC, et al. A brief cognitive assessment for use with schizophrenia patients in community clinics.

Schizophr Res

. 2004;71:273-283.

27.

Glynn SM. The challenge of psychiatric rehabilitation in schizophrenia.

Curr Psychiatry Rep

. 2001;3:401-406.

28.

Lehman AF, Buchanan RW, Dickerson FB, et al. Evidence-based treatment for schizophrenia.

Psychiatr Clin North Am

. 2003;26:939-954.

29.

Oka M, Otsuka K, Yokoyama N, et al. An evaluation of a hybrid occupational therapy and supported employment program in Japan for persons with schizophrenia.

Am J Occup Ther

. 2004;58:466-475.

30.

Percudani M, Barbui C, Tansella M. Effect of second-generation antipsychotics on employment and productivity in individuals with schizophrenia: an economic perspective.

Pharmacoeconomics

. 2004;22:701-718.

31.

Zygmunt A, Olfson M, Boyer CA, Mechanic D. Interventions to improve medication adherence in schizophrenia.

Am J Psychiatry

. 2002;159:1653-1664.

32.

McGurk SR, Mueser KT. Cognitive functioning, symptoms, and work in supported employment: a review and heuristic model.

Schizophr Res

. 2004;70:147-173.

33.

Bustillo J, Lauriello J, Horan W, Keith S. The psychosocial treatment of schizophrenia: an update.

Am J Psychiatry

. 2001;158:163-175.

34.

Rossotto E, Wirshing DA, Liberman RP. Rehab rounds: enhancing treatment adherence among persons with schizophrenia by teaching community reintegration skills.

Psychiatric Serv

. 2004;55:26-27.

35.

Marwaha S, Johnson S. Schizophrenia and employment-a review.

Soc Psychiatry Psychiatr Epidemiol

. 2004;39:337-349.

36.

Minato M, Zemke R. Time use of people with schizophrenia living in the community.

Occup Ther Int

. 2004;11:177-191.