Balance and Gait Deficits in Schizophrenia Compounded by the Comorbidity of Alcoholism

BRIEF REPORTS

15 states after zolpidem and placebo: a H2 O-PET study. J Sleep hashi K: Activity of midbrain reticular formation and neocortex Res 2000; 9:161–173 during the progression of human non-rapid eye movement 4. Kajimura N, Kato M, Okuma T, Sekimoto M, Watanabe T, Taka- sleep. J Neurosci 1999; 19:10065–10073 hashi K: A quantitative sleep EEG study on the effects of benzo- 9. Talairach J, Tournoux P: Co-Planar Stereotaxic Atlas of the Hu- diazepine and zopiclone in schizophrenic patients. Schizophr man Brain: Three-Dimensional Proportional System. Stuttgart, Res 1995; 15:303–312 Germany, Georg Thieme, 1988 5. Rechtschaffen A, Kales A (eds): A Manual of Standardized Ter- 10. Sakai F, Mansari M, Jin JS, Zhang JG, Vanni-Mercier G: Posterior minology, Techniques and Scoring System for Sleep Stages of hypothalamus in the regulation of wakefulness and paradoxi- Human Subjects: NIH Publication 204. Bethesda, Md, Public cal sleep, in The Diencephalon and Sleep. Edited by Mancia M, Health Service, National Institutes of Health, 1968 Marini G. New York, Raven Press, 1990, pp 171–198 6. Herscovitch P, Markham J, Raichle ME: Brain blood flow mea- 11. Koyama Y, Hayaishi O: Firing of neurons in the preoptic/ante- 15 sured with intravenous H2 O, I: theory and error analysis. J rior hypothalamic areas in rat: its possible involvement in slow Nucl Med 1983; 24:782–789 wave sleep and paradoxical sleep. Neurosci Res 1994; 19:31– 7. Raichle ME, Martin WRW, Herscovitch P, Mintum MA, Makkam 38 15 J: Brain blood flow measured with intravenous H2 O, II: imple- 12. Veselis RA, Reinsel RA, Beattie BJ, Mawlawi OR, Feshchenko VA, mentation and validation. J Nucl Med 1983; 24:790–798 DiResta GR, Larson SM, Blasberg RG: Midazolam changes cere- 15 8. Kajimura N, Uchiyama M, Takayama Y, Uchida S, Uema T, Kato bral blood flow in discrete brain regions: an H2 O positron M, Sekimoto M, Watanabe T, Nakajima T, Horikoshi S, Ogawa K, emission tomography study. Anesthesiology 1997; 87:1106– Nishikawa M, Hiroki M, Kudo Y, Matsuda H, Okawa M, Taka- 1117

Brief Report

Edith V. Sullivan, Ph.D. nonschizophrenic patients with alcohol dependence, and 27 age-matched comparison men. Margaret J. Rosenbloom, M.A. Results: All three patient groups were impaired relative to the Adolf Pfefferbaum, M.D. comparison subjects. The comorbid group was significantly more impaired than the alcoholic group on most tests and was more impaired than the schizophrenia patients, especially Objective: Alcoholism carries a liability of balance and gait in- when tested with eyes open. stability that persists with sobriety. Such deficits are less well documented in schizophrenia and may be compounded by co- Conclusions: Rigorous quantitative testing revealed gait and morbidity with alcoholism, which is prevalent in schizophrenia. balance deficits in schizophrenia, even without alcohol dependence, and exacerbated deficits in schizophrenia comorbid with Method: The authors administered quantitative ataxia tests to alcoholism. The enhancement of postural stability expected 10 patients comorbid for schizophrenia and alcohol depen- with visual information was dampened in comorbid patients, dence/abuse, 10 nonalcoholic patients with schizophrenia, 24 implicating compromised sensorimotor integrative abilities.

(Am J Psychiatry 2004; 161:751–755)

Disequilibrium and gait peculiarities were featured in erbates existing deficits of brain volume in prefrontal and classic descriptions (1, 2) of patients with schizophrenia, anterior temporal gray matter (16) and produces deficits in even before the advent of neuroleptics, and are detectable the anterior superior cerebellar vermis (17) and pons (18), with clinical neurological assessment (3–5). Ataxia of even in schizophrenia patients with remote histories of al- stance and gait is also salient behavioral sequelae to coholism and low levels of lifetime alcohol consumption chronic alcohol abuse (4, 6, 7) and may arise from com- relative to alcoholic patients without schizophrenia. Given promise of the anterior superior cerebellar vermis (post- this heightened vulnerability for patients comorbid for mortem [6, 8, 9] and in vivo [10]). both schizophrenia and alcoholism, especially in the an- Comorbidity of ataxia with alcohol use disorders is highly terior superior cerebellar vermis, we assessed gait and prevalent in schizophrenia (e.g., references 11, 12, 13) and balance by using quantitative ataxia tests to determine has an adverse impact on schizophrenia’s clinical course whether comorbid patients would show greater postural in- (for reviews, see references 14, 15). Such comorbidity exac- stability than patients with either condition alone.

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TABLE 1. Demographic and Clinical Characteristics of Healthy Comparison Subjects, Patients With Alcoholism Only, Patients With Schizophrenia Only, and Patients With Both Disorders Brief Psychiatric Education Handedness Lifetime Alcohol Rating Scale Age (years) IQa (years) Testb Intake (kg)c Score Group Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Healthy comparison subjects (N=27) 47.9 11.6 113.2 7.2 17.1 2.6 23.7 13.1 52.8 86.1 — Patients with alcoholism (N=24) 49.1 11.1 107.0 8.3 13.6 3.2 24.6 14.9 1288.1 797.3 — Patients with schizophrenia (N=10) 42.9 10.3 109.1 9.7 14.3 1.9 19.3 12.3 35.4 33.1 37.8 10.9 Patients with comorbid schizophrenia and alcoholism (N=10) 45.3 4.5 104.9 8.1 13.9 1.5 24.6 14.9 126.4 140.6 39.1 8.9 a Based on the National Adult Reading Test. b Right-handedness=14–30; left-handedness=50–70 (Crovitz and Zener [27]). c Quantitative alcohol use data were available for nine patients with schizophrenia and nine patients with comorbid schizophrenia and alcoholism.

Method tients with schizophrenia (t=1.89, df=16, p<0.10). The three patient groups had equivalent years of education and National Adult All subjects were men and gave written informed consent to Reading Test IQs. The comorbid group did not differ significantly participate in the research. The patients were recruited from a from the schizophrenia group in BPRS scores. Veterans Administration medical center and included 10 with a Gait and static balance were assessed with the Walk-a-Line DSM-III-R axis I diagnosis of schizophrenia only, 10 comorbid for Ataxia Battery (28), consisting of three parts, each performed first DSM-III-R-defined schizophrenia and alcohol dependence or with eyes open and then with eyes closed. First, the subject stood abuse, and 24 with DSM-III-R-defined alcohol dependence only. with feet placed heel to toe and arms folded across the chest for No patient met criteria for any other axis I disorder, with the ex- 60-second trials (“stand heel to toe”). Next, the subject stood on ception of two of the comorbid patients who had a history of past one foot for 30-second trials (“stand on one foot”). Finally, the cannabis abuse. subject walked heel to toe for 10 steps (“walk heel to toe”). Each The patients with schizophrenia were tested for gait and bal- condition was performed twice unless the subject achieved a per- ance while inpatients; the patients with alcoholism were tested fect score on the initial trial. when returning for follow-up studies (19, 20). Alcoholic patients Because gait and balance performance can decline with age, reported a wide range of days of sobriety (1 to 1,994, median=204) we applied linear regression to data from the larger group of at the time of testing. The comorbid patients also reported a wide healthy comparison subjects spanning the adult age range (20 to range of days of sobriety (17 to 3,285, median=88). The length of 70 years) to derive age-corrected standardized z scores for each sobriety did not differ between these groups (Mann-Whitney U= participant (10). Values for each group reflect the extent to which 117, df=32, p=0.91). it deviated from age norms. Group differences in performance for All schizophrenia patients had been treated pharmacologi- each composite were assessed with four-group, one- or two-way cally; when tested, five schizophrenia and seven comorbid pa- ANOVAs and follow-up Scheffé tests. Associations between vari- tients were taking atypical antipsychotic medications, three ables were assessed with Pearson’s correlations and confirmed schizophrenic and two comorbid patients were taking typical an- with Spearman’s tests because of small group sizes. tipsychotic medications, one schizophrenic patient was tempo- rarily unmedicated, and the medication status was unknown for Results one schizophrenic and one comorbid patient. Current symptom severity was evaluated in patients with schizophrenia by using Composite scores for the eyes-open and eyes-closed the Brief Psychiatric Rating Scale (BPRS) (21), administered by conditions (Figure 1) showed significant effects of group two raters with established reliability. Lifetime alcohol consump- (F=15.97, df=3, 65, p=0.0001) and condition (F=13.24, df= tion was assessed by using a semistructured interview (22–25) in all patients with alcoholism and healthy comparison subjects, 1, 65, p=0.0005); the interaction (F=6.41, df=3, 65, p= nine of the 10 comorbid patients, and nine of the 10 patients with 0.0007) indicated greater deficits in all three patient schizophrenia only. groups with eyes open than with eyes closed. With one ex- The healthy comparison group was recruited from the local ception (alcoholics with eyes closed), follow-up tests community and comprised 27 men selected from a larger group showed that all patient groups had deficits in both condi- of 61 men (e.g., reference 10) to age-match the patient groups. All had been screened to exclude any axis I disorder, substance abuse tions relative to the performance of the healthy compari- in the year before the study, and alcohol consumption of more son group, and the comorbid group had deficits relative to than four drinks a day for over a month. the alcoholic group. One-way analyses of variance (ANOVAs) of demographic vari- Composite scores for the three test parts—stand heel to ables (Table 1) across all groups yielded significant differences in toe, stand on one foot, and walk heel to toe (Figure 2)— education (F=8.39, df=3, 67, p<0.0001), general intelligence (esti- irrespective of visual condition, also showed effects of mated with the National Adult Reading Test [26]) (F=3.76, df=3, 67, p<0.05), and total lifetime consumption of alcohol (F=33.98, df=3, group (F=14.89, df=3, 132, p=0.0001) and test part (F=3.70, 65, p<0.0001) but not age (F=1.00, df=3, 67, p=0.42) or handedness df=2, 132, p=0.028) but no interaction effect (F=1.70, df=2, (F=1.80, df=3, 65, p=0.15), measured quantitatively (27). Follow-up 132, p=0.13). Scheffé tests indicated significantly lower Scheffé tests (alpha=0.05) revealed that the group with alcoholism scores than the comparison group on all three measures consumed more alcohol than all other groups. Differences be- by the comorbid group, the two static balance measures tween the schizophrenia and healthy comparison groups were not significant; the comorbid patients tended to drink more than the by the schizophrenia group, and one measure (stand on healthy comparison subjects (t=1.88, df=34, p<0.10) and the pa- one foot) by the alcoholic group. The comorbid group had

752 http://ajp.psychiatryonline.org Am J Psychiatry 161:4, April 2004 BRIEF REPORTS

FIGURE 1. Composite Ataxia Performance for Healthy Com- FIGURE 2. Performance on Three Ataxia Tests, Collapsed parison Subjects, Patients With Alcoholism Only, Patients Over Eyes-Open and Eyes-Closed Conditions, for Healthy With Schizophrenia Only, and Patients With Both Disordersa Comparison Subjects, Patients With Alcoholism Only, Patients With Schizophrenia Only, and Patients With Both Disordersa 1 Healthy comparison Patients with schizophrenia subjects (N=27) only (N=10) Patients with alcoholism Patients with schizophrenia only (N=24) and alcoholism (N=10) 0 1

–1 0

Healthy comparison –2 subjects (N=27) –1 Patients with alcoholism b

Age-Corrected z Score Age-Corrected only (N=24) b c Patients with schizophrenia –3 –2 b only (N=10)

Patients with schizophrenia Age-Corrected z Score and alcoholism (N=10) c,d c,e –4 –3

Eyes Open Eyes Closed a ANOVAs showed significant group (F=15.97, df=3, 65, p=0.0001) and condition (F=13.24, df=1, 65, p=0.0005) effects as well as a significant interaction (F=6.41, df=3, 65, p=0.0007). The eyes-open Stand heel to toe Stand on one foot Walk heel to toe condition provided a more sensitive measure of disease-related deficits than the eyes-closed condition because the comparison Task group performed near the rating ceiling with eyes open but not a with eyes closed. ANOVAs showed significant group (F=14.89, df=3, 132, p=0.0001) and test type (F=3.70, df=2, 132, p<0.03) effects. b Significantly different from comparison subjects (p<0.005, post hoc significantly greater deficits than the alcoholic group for Scheffé test). c Significantly different from comparison subjects (p<0.001, post hoc standing heel to toe and standing on one foot. Overall, the Scheffé test). extent of the comorbid group’s deficit was the sum of the d Significantly different from alcoholism-only group (p<0.05, post schizophrenia group’s and alcoholism group’s deficits. hoc Scheffé test). e Significantly different from alcoholism-only group (p<0.01, post Ataxia scores were not associated with lifetime alcohol hoc Scheffé test). consumption or length of sobriety in alcoholics or comorbid patients. Further, BPRS scores did not predict ataxia over their lifetime relative to the nonpsychotic alcoholics. scores in either schizophrenia group, with or without alco- The group included only men; whether a similar pattern holism comorbidity. An ANOVA for factors of medication occurs in women remains to be studied. type (typical versus atypical) and diagnosis (schizophre- The lack of statistically significant performance differ- nia versus comorbid) revealed no effect of medication or a ences between comorbid patients and schizophrenia pa- medication-by-diagnosis interaction. tients is consistent with a recent report also employing balance tests requiring standing in the Romberg position and Discussion walking heel to toe (29). In that study, although the two This study identified deficits in balance and gait relative schizophrenia groups did not show statistically significant to age norms in patients with alcoholism, even following differences in performance, the mean score of the comor- substantial periods of sobriety, as well as in patients with bid group (where higher scores were in the impaired direc- schizophrenia but without a history of alcoholism. The tion) was more than double that of the group with schizo- patients with schizophrenia who had also met lifetime cri- phrenia but without alcoholism. teria for alcoholism showed a compounded deficit (effect Gait performance in comorbid and schizophrenia pa- size across all tests ranged from SD=1.1 to SD=3.6), hence, tients could have been affected by antipsychotic medica- greater than that observed in either condition alone (effect tion. Some studies have reported that patients taking neu- sizes ranging from SD=0.6 to SD=1.2 for alcoholism and roleptics perform significantly less well than untreated SD=0.9 to SD=2.1 for schizophrenia). Comorbid patients patients on fine motor coordination (e.g., reference 30). were significantly more impaired than alcoholics, even Others have reported that atypical neuroleptics are associ- though they had consumed only one-eighth of the alcohol ated with better motor coordination than typical neuro-

Am J Psychiatry 161:4, April 2004 http://ajp.psychiatryonline.org 753 BRIEF REPORTS leptics in patients with schizophrenia (31). In this group, 7. Sullivan EV, Rosenbloom MJ, Pfefferbaum A: Pattern of motor schizophrenia and comorbid patient groups did not differ and cognitive deficits in detoxified alcoholic men. Alcohol Clin Exp Res 2000; 24:611–621 in medication type, and there were no significant medica- 8. Victor M, Adam RD, Mancell EL: A restricted form of cerebellar tion type effects or group-by-medication interactions. degeneration occurring in alcoholic patients. Arch Neurol Thus, the relatively poorer performance of the comorbid 1959; 1:577–688 patients than the schizophrenia patients is probably not 9. Torvik A, Torp S: The prevalence of alcoholic cerebellar atro- solely a medication effect. phy: a morphometric and histological study of an autopsy ma- The additive untoward effect of alcoholism on an al- terial. J Neurol Sci 1986; 75:43–51 10. Sullivan EV, Deshmukh A, Desmond JE, Lim KO, Pfefferbaum A: ready compromised schizophrenic motor system (4, 32) Cerebellar volume decline in normal aging, alcoholism, and parallels our earlier reports of exacerbated regional brain Korsakoff’s syndrome: relation to ataxia. Neuropsychology volume in the prefrontal cortex (16), cerebellar vermis, 2000; 14:341–352 hemisphere gray matter (17), and pons (18) in patients co- 11. Cuffel BJ: Prevalence estimates of substance abuse in schizo- morbid for both conditions. A possible mechanism under- phrenia and their correlates. J Nerv Ment Dis 1992; 180:589– lying this excessive postural instability is disruption of the 592 12. Fowler IL, Carr VJ, Carter NT, Lewin TJ: Patterns of current and cerebellar systems required for maintaining posture and lifetime substance use in schizophrenia. Schizophr Bull 1998; balance, also present in schizophrenia-alcoholism comor- 24:443–455 bidity (17). The results of the present study provide sup- 13. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, port for the working hypothesis that alcohol abuse, which Goodwin FK: Comorbidity of mental disorders with alcohol occurs in about half the population of schizophrenia pa- and other drug abuse: results from the Epidemiologic Catch- ment Area (ECA) study. JAMA 1990; 264:2511–2518 tients (33), results in increased vulnerability of the brains 14. Buckley PF: Substance abuse in schizophrenia: a review. J Clin of patients with schizophrenia to the exogenous toxin—al- Psychiatry 1998; 59(suppl 3):26–30 cohol. A manifestation of this increased vulnerability, 15. Dixon L: Dual diagnosis of substance abuse in schizophrenia: readily demonstrated by standardized gait assessment, prevalence and impact on outcomes. Schizophr Res 1999; places comorbid patients at risk of falling. Contributing to 35(suppl):S93–S100 this liability is a possible compromise of sensorimotor in- 16. Mathalon DH, Pfefferbaum A, Lim KO, Rosenbloom MJ, Sulli- tegration, implicated by the especially reduced ability of van EV: Compounded brain volume deficits in schizophrenia- alcoholism comorbidity. Arch Gen Psychiatry 2003; 60:245– the comorbid group to stabilize balance with visual cues. 252 17. Sullivan EV, Deshmukh A, Desmond JE, Mathalon DH, Rosen- Presented in part at the 41st annual meeting of the College of Neu- bloom MJ, Lim KO, Pfefferbaum A: Contribution of alcohol ropsychopharmacology, Dec. 8–12, 2002, San Juan, Puerto Rico. Re- abuse to cerebellar volume deficits in men with schizophrenia. ceived March 8, 2003; revision received Aug. 19, 2003; accepted Aug. Arch Gen Psychiatry 2000; 57:894–902 25, 2003. From the Department of Psychiatry and Behavioral Sci- 18. Sullivan EV, Rosenbloom MJ, Serventi KL, Deshmukh A, Pfeffer- ences, Stanford University School of Medicine; and the Neuroscience Program, SRI International, Menlo Park, Calif. Address reprint re- baum A: Effects of alcohol dependence comorbidity and anti- quests to Dr. Sullivan, Department of Psychiatry and Behavioral Sci- psychotic medication on volumes of the thalamus and pons in ences, 401 Quarry Rd., Stanford University School of Medicine, Stan- schizophrenia. Am J Psychiatry 2003; 160:1110–1116 ford, CA 94305–5723; [email protected] (e-mail). 19. Pfefferbaum A, Sullivan EV, Mathalon DH, Shear PK, Rosen- Supported by grants from the National Institute on Alcohol Abuse bloom MJ, Lim KO: Longitudinal changes in magnetic reso- and Alcoholism (AA-10723 and AA-05965) and NIMH (MH-58007 and nance imaging brain volumes in abstinent and relapsed alco- MH-30854). holics. Alcohol Clin Exp Res 1995; 19:1177–1191 20. Pfefferbaum A, Sullivan EV, Rosenbloom MJ, Mathalon DH, Lim KO: A controlled study of cortical gray matter and ventricular References changes in alcoholic men over a five year interval. Arch Gen 1. Kraepelin E: Dementia Praecox and Paraphrenia (1919). Trans- Psychiatry 1998; 55:905–912 lated by Barclay RM; edited by Robertson GM. Huntington, NY, 21. Overall JE, Gorham DR: The Brief Psychiatric Rating Scale. Psy- Robert E Krieger, 1971 chol Rep 1962; 10:799–812 2. Bleuler E: Dementia Praecox or the Group of Schizophrenias 22. Skinner HA: Development and Validation of a Lifetime Alcohol (1908). Translated by Zinkin J. New York, International Univer- Consumption Assessment Procedure. Toronto, Addiction Re- sities Press, 1950 search Foundation, 1982 3. Manschreck TC, Ames D: Neurologic features and psycho- 23. Skinner HA, Sheu WJ: Reliability of alcohol use indices: the life- pathology in schizophrenic disorders. Biol Psychiatry 1984; 19: time drinking history and the MAST. J Stud Alcohol 1982; 43: 703–719 1157–1170 4. Deshmukh A, Rosenbloom MJ, Pfefferbaum A, Sullivan EV: Clin- 24. Pfefferbaum A, Lim KO, Zipursky RB, Mathalon DH, Lane B, Ha ical signs of cerebellar dysfunction in schizophrenia and alco- CN, Rosenbloom MJ, Sullivan EV: Brain gray and white matter holism. Schizophr Res 2002; 57:281–291 volume loss accelerates with aging in chronic alcoholics: a 5. Sanders RD, Keshavan MS, Forman SD, Pieri JN, McLaughlin N, quantitative MRI study. Alcohol Clin Exp Res 1992; 16:1078– Allen DN, van Kammen DP, Goldstein G: Factor structure of 1089 neurologic examination abnormalities in unmedicated schizo- 25. Pfefferbaum A, Rosenbloom MJ, Crusan K, Jernigan TL: Brain phrenia. Psychiatry Res 2000; 95:237–243 CT changes in alcoholics: the effects of age and alcohol con- 6. Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syn- sumption. Alcohol Clin Exp Res 1988; 12:81–87 drome and Related Neurologic Disorders Due to Alcoholism 26. Nelson HE: The National Adult Reading Test (NART). Windsor, and Malnutrition, 2nd ed. Philadelphia, FA Davis, 1989 UK, Nelson, 1982

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27. Crovitz HF, Zener KA: Group test for assessing hand and eye 31. Gallhofer B, Bauer U, Lis S, Krieger S, Gruppe H: Cognitive dys- dominance. Am J Psychol 1962; 75:271–276 function in schizophrenia: comparison of treatment with atyp- 28. Fregly AR, Graybiel A, Smith MS: Walk on floor eyes closed ical antipsychotic agents and conventional neuroleptic drugs. (WOFEC): a new addition to an ataxia test battery. Aerosp Med Eur Neuropsychopharmacol 1996; 6(suppl):S13–S20 1972; 43:395–399 32. Sullivan EV, Fama R, Shear PK, Cahn-Weiner D, Stein M, Zipur- sky RB, Pfefferbaum A: Motor sequencing deficits in schizo- 29. Allen D, Goldstein G, Forman S, Keshavan M, van Kammen D, phrenia: a comparison with Parkinson’s disease. Neuropsy- Sanders R: Neurologic examination abnormalities in schizo- chology 2001; 15:342–350 phrenia with and without a history of alcoholism. Neuropsy- 33. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, chiatry Neuropsychol Behav Neurol 2000; 13:184–187 Goodwin FK: The de facto US mental and addictive disorders 30. Cleghorn JM, Kaplan RD, Szechtman B, Szechtman H, Brown service system: Epidemiologic Catchment Area prospective 1- GM: Neuroleptic drug effects on cognitive function in schizo- year prevalence rates of disorders and services. Arch Gen Psy- phrenia. Schizophr Res 1990; 3:211–219 chiatry 1993; 50:85–94

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