Management of Schizophrenia with Comorbid Conditions
Yoshio Hirayasu, MD, PhD
American Psychiatric Association 153rd Annual Meeting
Day 4 - May 17, 2000

Introduction
Comorbid conditions, including impairment of cognitive function, depression, obsessive-compulsive behavior, substance abuse, and aggressive behavior, reflect on prognosis of both acute as well chronic schizophrenia. In a symposium during the 153rd annual meeting of American Psychiatric Association in Chicago, Illinois, experts extensively discussed management of the comorbid conditions of schizophrenia.

Cognitive-Functional Rehabilitation in Older Patients
Projected distributions of US patients with schizophrenia by age will be 1.6% of the total population aged 45 years and older, and 1.5% aged younger than 45 by 2050. The distributions in 1990 were 0.6% and 0.1%, respectively. Dilip V. Jeste, MD,[1] of Veterans Affairs Medical Center in San Diego, Calif, has presented assessment and treatment strategies on old schizophrenic patients with cognitive impairment. Measurement of direct assessment of functioning status (DAFS),[2] designed to evaluate ability for daily life in the community, revealed that schizophrenics showed lower function in communication, transportation, finance, and shopping compared with subjects without schizophenia. Cognitive impairment without dementia was common in patients with schizophrenia and independent of manifestations of negative symptoms. Cognitive deficits in schizophrenia may result from physical comorbidity, medication (eg, anticholinergics), substance abuse, sensory deficits, depression, and institutionalization.

Psychosocial intervention in addition to pharmacotherapy has been effective in chronic schizophrenics with cognitive impairment. Theses interventions include cognitive behavioral therapy (CBT), cognitive rehabilitation, and social skill training (SST). Sensky and colleagues[3] have recently reported that negative symptoms as well as positive symptoms were improved for both a schizophrenic group with CBT (n=46) and without CBT (n=44). In addition, the efficacy of the CBT on the negative symptoms sustained for 9 months of follow-up while the schizophrenics without CBT deteriorated during the follow-up period. For older schizophrenics, combination of CBT and SST (Cognitive Behavioral Social Skill Training [CCBSST]) was found to be useful to improve their cognitive skills. Dr. Dilips's group has developed CBSST programs for individual elderly schizophrenics.

Management of Obsessive-Compulsive Schizophrenia
Obsessive-compulsive symptoms are often recognized in a prodromal stage in patients with schizophrenia, and it is often difficult to cure with standard treatment. Michael Y. Hwang, MD,[4] of FDR Veterans Affairs Medical Center in Montrose, New York, discussed the comorbidity of obsessive compulsive disorder in patients with schizophrenia. It has been a long controversy whether obsessive-compulsive schizophrenia is a distinct subtype or not. Comorbidity with obsessive-compulsive symptoms is often misdiagnosed or even neglected by psychiatrists. DSM-IV criteria for schizophrenia describe some schizophrenic individuals as manifesting symptoms of both obsessive-compulsive disorder and schizophrenia. The biological basis of obsessive-compulsive disorder has been extensively studied, including neurological disorders, brain injury, as well as genetic, neuropsychological, and neuroimaging studies. Epidemiologic reviews of schizophrenia revealed that the probability for comobidity with obsessive compulsive disorder is 3.5% to 15%. Another study[5] suggests that obsessive-compulsive comorbidity leads to a poorer clinical course, lower levels of functioning, and longer periods of hospitalization compared with schizophrenics who are not obsessive-compulsive.

Although no standard treatment has been established for treatment of obsessive-compulsive schizophrenia, a series of case reports[6] indicated that clozapine improved the obsessive-compulsive symptom. A combination of risperidone (mean dose, 2.75 mg/day) and a selective serotonin reuptake inhibitor improved refractory obsessive-compulsive schizophrenia (n=21). Well-designed double-blind studies are required to assess the effectiveness of atypical neuroleptics on obsessive-compulsive symptoms.

Management of Schizophrenia with Depression
Median prevalence of depression is about 25% in schizophrenia. Depressive comorbidity is associated with substantial suffering, decrease in functional status, poor outcome, and suicide idea/behavior. Samuel G. Siris, MD,[7] of Hillside Hospital in Glen Oaks, New York, has reviewed differential diagnoses for schizophrenics with depression including organic/medical condition, affective/hedonic dysregulation, adverse effect of medication, and substance abuse. Negative symptoms may present as a phenotype of depression in schizophrenia. Neuroleptics can induce akinesia and akathisia, which mimicks depression in schizophrenia. Neuroleptics might directly induce dysphoria associated with depressive symptoms. Disappointment reaction also accounts for postpsychotic depression and demoralization syndrome. Lithium has reported to be the most effective pharmacologic intervention among various treatment strategies. Psychosocial intervention is also effective to reduce depressive symptoms.

Dr. Siris and colleagues have recently carried out a double-blind trial of imipramine compared with placebo for depressive schizophrenics who had been medicated with fluphenazine and benzodiazepine. This study suggested that imipramine significantly improves Clinical Global Impression Scale scores as well as depressive symptoms. However, psychotic symptoms did not change over time during the trial. These findings suggest that an adjunctive antidepressant may help to improve depression with schizophrenia. A long-term double-blind trial has also revealed that imipramine reduced the relapse rate for schizophrenia.

Schizophrenia and Comorbid Substance Abuse
Douglas M. Ziedonis, MD,[8] of Robert Wood Johnson Medical School in Piscatway, New Jersey, has summarized the comorbidity of the abuse of various substances in patients with schizophrenia. According to a study in CMHC outpatients, 35% of schizophrenics are currently diagnosed with alcoholic abuse. Other abused substances were cocaine (20%), heroin (3%), and marijuana (15%). Nicotine use was the most common in this study, with a range of 70% to 90% in patients with schizophrenia. Heavy smokers (more than 20 cigarettes per day) had 4 times the risk for multiple substance abuse. These patients absorb nicotine more effectively and efficiently, leading to increased nicotine levels in the body. High nicotine levels also increase P450 enzyme activity, resulting in the necessity of higher dose neuroleptics for effective treatment.

Screening and assessment for substance abuse are important for an early intervention. CAGE (ask individuals their experiences; Cut down, be Annoyed, Guilty, seek Eye-opener; for their substance use) strategy for early screening has been useful in evaluating risk for substance abuse. If patients agreed with more than 2 items, the risk for substance abuse should be seriously considered. Substance abuse is associated with relapse of psychosis, multiple hospitalization, legal problems/violence, social isolation/homelessness, noncompliant with medication, HIV risk, and family problems.

Specific psychosocial approaches, including step-by-step behavioral therapy, are effective for the treatment of stimulant abusers. However, many limitations are considered in schizophrenia when planning treatment strategy, including therapeutic alliance, low motivation, cognitive limitations, low self-efficacy, and maladaptive interpersonal skills. A study showed that low motivation was found in abusers of alcohol (53%), cocaine (66%), marijuana (71%), heroin (87%), and nicotine (91%) in 224 patients with schizophrenia. Medication strategies have been reviewed for nicotine abuse with schizophrenia. Several studies reported that there was a significant decrease in reported daily cigarette use during clozapine treatment compared with the level of use when patients had been treated with typical neuroleptics.[9,10]

Information on this treatment program is available through the National Clearinghouse for Alcohol and Drug Information (NCADI): 1-800-729-6686 and at http://www.health.org.

Schizophrenia and Persistent Aggressive Behavior
Violence is the major cause for admission to acute psychiatry units and hospitals. Leslie L. Citrome, MD,[11] of Nathan Kline Institute in Orangeburg, New York, extensively reported on management of aggressive behavior in schizophrenia. Epidemiology revealed that co-occurring substance abuse and intoxication increase the risk of violence in patients with schizophrenia. The Epidemiology Catchment Area (ECA) study of 20,000 samples revealed that schizophrenics had 5- to 6-fold higher probability for violence. High risk of violence in schizophrenia has been a robust finding in nearly every culture in the world. Ten percent of patients attack others within 24 hours after their admission in hospitals. Short-term and long-term studies show the same incidence, with 5% to 7% probability for incidence of a violent attack. Assessment of the cause of the violent episode was particularly important, including the need to rule out somatic conditions (acute or chronic), adverse effect of medications, comorbidity with substance abuse, and risk assessment by criminal record. The pattern of violence was divided into transient and persistent. Transient violence is associated with environmental factors and positive symptoms of psychosis, while persistent violence is related to neurologic impairment and psychopathy, but not aggressiveness or positive symptoms.

Several medication strategies are considered for treatment of persistently aggressive psychotic patients, including conventional neuroleptics, atypical neuroleptics, and mood stabilizers. A recent study[12] revealed the effectiveness of clozapine on violence in patients with schizophrenia. Another study found that only 3 of 70 patients had a high hostility score on the Brief Psychiatric Rating Scale after treatment with clozapine.[13] Valproate has been well used to treat violent behavior, although evidence has been weak because most of findings were reported in case reports. Lithium and b-blocker also have been effective to reduce violence on some schizophrenics.

Summary
Adequate assessment and treatment are important to improve prognosis of schizophrenic patients. Systematic assessment and efficient medication are essential for management of comrobidity of schizophrenia. In addition, psychosocial treatment has been proved to be effective on several comorbid conditions. However, multiple comorbidities are also common and lead patients to be more refractory in schizophrenia. Further, studies are required to develop more effective treatment on comorbidities in schizophrenia.

References
Jeste DV, Granhom E, McQuaid J, et al. Cognitive-functional rehabilitation in older patients. Program and abstracts from the 153rd Annual American Psychiatric Association Meeting, May 13-18, 2000; Chicago, Illinois. Abstract 56C.

Loewenstein DA, Amigo E, Duara R, et al. A new scale for the assessment of functional status in Alzheimer's disease and related disorders. J Gerontol. 1989;44(4):114-121.

Sensky T, Turkington D, Kingdon D, et al. A randomized controlled trial of cognitive-behavioral therapy for persistent symptoms in schizophrenia resistant to medication. Arch Gen Psychiatry. 2000;57(2):165-172.

Hwang MY, Losonczy MF, Lee M, Chrichton J. Management of obsessive-compulsive schizophrenia. Program and abstracts from the 153rd Annual American Psychiatric Association Meeting, May 13-18, 2000; Chicago, Illinois. Abstract 56B.

Hwang MY, Morgan JE, Losconzcy MF. Clinical and neuropsychological profiles of obsessive-compulsive schizophrenia: a pilot study. J Neuropsychiatry Clin Neurosci. 2000;12(1):91-94.

Saxena S, Wang D, Bystritsky A, Baxter LR Jr. Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder. J Clin Psychiatry. 1996;Jul;57(7):303-306.

Siris SG. Management of schizophrenia with depression. Program and abstracts from the 153rd Annual American Psychiatric Association Meeting, May 13-18, 2000; Chicago, Illinois. Abstract 56A.

Ziedonis DM, Smelson DA, Krejci J, et al. Schizophrenia and comorbid substance abuse. In: Program and abstracts from the 153rd Annual American Psychiatric Association Meeting, May 13-18, 2000; Chicago, Illinois. Abstract 56D.

McEvoy J, Freudenreich O, McGee M, Vander Zwaag C, Levin E, Rose J. Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry. 1995;37(8):550-552.

George TP, Sernyak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry. 1995;56(8):344-346.

Citrome LL, Volavka J. Schizophrenia and persistant aggressive behavior. Program and abstracts from the 153rd Annual American Psychiatric Association Meeting, May 13-18, 2000; Chicago, Illinois. Abstract 56E.

Wilson WH, Claussen AM. 18-month outcome of clozapine treatment for 100 patients in a state psychiatric hospital. Psychiatr Serv. 1995;46(4):386-389.

Volavka J, Zito JM, Vitrai J, Czobar J. Clozapine effects on hostility and aggression in schizophrenia. Clin Psychopharmacol. 1993;13(4):287-289.