Fluvoxamine treatment of alcoholic amnestic disorder

EUROPEANNEUROPSYCHOPHARMACOLOGY ELSEVIER

European Neuropsychopharmacology 5 (1995) 27-33

Fluvoxamine treatment of alcoholic amnestic disorder P e t e r R. Martin 1, B r y o n A d i n o f f 2, Elizabeth Lane, June M. Stapleton, G e o r g e A . H . B o n e , H e r b e r t Weingartner, M a r k k u Linnoila*, Michael J. E c k a r d t Laboratory o f Clinical Studies, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, N1H Building 10, Room 3C103, 9000 Rockville Pike, Bethesda, MD 20892, USA

Received 27 July 1994; accepted 18 August 1994

Abstract

The serotonin uptake inhibitor fluvoxamine was assessed in treatment of alcohol-induced Korsakoff's syndrome (KS) using fixed (4 weeks, 200 mg/day) or individualized (6 weeks, plasma concentration />400 ng/ml) dosing in randomized placebocontrolled double-blind crossover studies. Cognitive functions and concentrations of the major cerebrospinal fluid (CSF) metabolites of serotonin (5-HIAA), norepinephrine (MHPG), and dopamine (HVA) were determined in abstinent, nondepressed KS patients (aged 45-75), at baseline and placebo (3-4 weeks), and after 3-4 (n = 10) or 6 (n = 4) weeks of fluvoxamine administration. Fluvoxamine decreased CSF 5-HIAA compared to placebo (P < 0.003) without consistent changes in HVA or MHPG. Reductions in 5-HIAA correlated with improvements on the Wechsler Memory Scale Memory Quotient (P < 0.05), independent of effects on attention/vigilance or Beck Depression Inventory scores. Reductions in 5-HIAA correlated with plasma fluvoxamine (P < 0.03) only for fluvoxamine concentrations below 450 ng/ml. These findings suggest improvement of memory consolidation and/or retrieval in patients with Korsakoff's syndrome by fluvoxamine via serotonergic mechanisms.

Keywords: Korsakoff's syndrom; Fluvoxamine; Serotonin; Memory; Treatment

I. Introduction

The prevalence of brain dysfunction in detoxified alcoholics has been estimated to be 50-70% with approximately 10% having an alcoholism-associated chronic organic mental disorder resulting in significant psychosocial problems (Eckardt and Martin, 1987). Accordingly, alcoholism constitutes a major cause of dementia, second only to Alzheimer's disease and perhaps multi-infarct dementia (Cummings and Benson, 1992). Severe cerebral impairment in alcoholics that persists after cessation of alcohol consumption is currently conceptualized in terms of two clinically defined chronic organic mental disorders: alcohol amnestic disorder, commonly called Korsakoff's syndrome (KS), and dementia associated with alcohol*Corresponding author. Tel.: (301) 496-8996; Fax: (301)4020445. ]Present address: Division of Alcohol and Substance Abuse, Departments of Psychiatry and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA. 2 Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA. Elsevier Science B.V. S S D I 0924-977X(94)00129-4

ism (DAA) (Martin et al., 1986; Wilkinson and Carlen, 1981; APA, 1987; Lishman, 1981). Improvements in CNS function may be anticipated with continued abstinence (Wilkinson and Carlen, 1981). Accordingly, effects of pharmacologic treatments to augment cognitive functions in the alcoholic patient who is no longer drinking, or drinking to a greatly diminished degree, may be confounded by the spontaneous recovery associated with abstinence (Martin et al., 1989). Furthermore, it is possible that the same treatments may both augment cognitive functiGns and reduce alcohol consumption. Although these issues are clearly interdependent, they nevertheless are distinct and merit individual attention. Much recent work addresses the pharmacologic reduction of drinking through modulation of central neural circuits which mediate the reinforcing effects of alcohol (Volpicelli et al., 1992; Fuller et al., 1986; Dorus et al., 1989; Naranjo et al., 1992; George et al., 1992). However, considering the magnitude of the problem, the treatment of alcoholism-associated chronic organic mental disorders has not been extensively studied (Martin and Nimmerrichter, 1993).

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P.R. Martin et al. / European Neuropsychopharmacology 5 (1995) 27-33

Clinical heterogeneity complicates treatment of alcohol-induced chronic organic brain disease because multiple interacting factors that can adversely affect brain functioning are present in many patients (Martin et al., 1986). Accordingly, drug trials in the chronic alcoholic with cerebral impairment have shown inconsistent results among various classes of neuropsychopharmacologic agents and considerable interindividual differences among patients in response to any given treatment (Martin and Nimmerrichter, 1993). In a preliminary study, we have reported that the serotonin uptake inhibitor, fluvoxamine, improved memory for recently acquired information in six patients with KS, but not in those with DAA (Martin et al., 1989). For KS patients, a significant correlation was found between fluvoxamine-associated improvement in performance on memory tests and decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) suggesting that facilitation of serotonergic neurotransmission may ameliorate the episodic memory failure in these patients. Specifically, those patients who had plasma fluvoxamine concentrations above 350 ng/ml showed the largest changes in CSF 5-HIAA concentrations and the greatest improvements in memory functioning, whereas those with plasma concentrations below 150 ng/ml had negligible changes in CSF 5-HIAA concentrations and memory function. Therefore, these preliminary findings suggested that with individualized titration of dose, fluvoxamine may be a clinically useful agent in the treatment of brain-impaired chronic alcoholics with predominant amnestic features. We now report our findings for an expanded sample of KS patients, four of whom were studied for a longer treatment duration with individualized dosing of fluvoxamine titrated to blood levels determined to be adequate based on our preliminary findings.

2. Experimental procedures 2.1. Subjects Nine men and one woman, aged 45-75 years, were diagnosed as having a clinically stable organic mental disorder attributable to heavy long-term alcohol consumption (Martin et al., 1986; Wilkinson and Carlen, 1981; APA, 1987; Lishman, 1981). Results from six of these patients have previously been reported (Martin et al., 1989). History, medical and neuropsychiatric evaluations, laboratory tests (including CT or MRI scan and clinical EEG), observations of cognitive improvement during abstinence prior to the study, and in some instances a longitudinal follow-up over a 2-7-year period all failed to support other recognizable organic mental disorders (Cummings and Ben-

son, 1992; Martin and Welch, 1993). Baseline neuropsychological studies were performed on all subjects as part of the clinical evaluation after at least 3 weeks of supervised abstinence when neuropsychological functions are reasonably considered to have stabilized (Eckardt and Martin, 1987). The test battery (Eckardt and Martin, 1987; Weingartner et al., 1983) was designed to obtain a general assessment of cognitive skills and an in-depth examination of memory functions. Results from neuropsychiatric and neuropsychological assessments satisfied DSM-IIIR criteria (APA, 1987) for alcohol amnestic disorder. All patients received adequate dietary supplementation during their hospitalization to ensure that none had nutritional deficiencies when studied. No patient had a major cardiovascular, renal, endocrine, or active hepatic disease, or a psychiatric disorder other than alcohol dependence (APA, 1987; Seizer, 1971; Spitzer et al., 1978; Endicott, 1978). No patient was administered any psychoactive medications or had access to alcohol throughout their evaluation and study periods.

2.2. Trial design In our preliminary report (Martin et al., 1989), six men were randomly assigned to receive placebo or fluvoxamine maleate for 4 weeks in a double-blind crossover design starting at 100 mg/day (given in two divided doses at 10:00 a.m. and 10:00 p.m.) that was increased to 200 mg/day after 7 days. One patient's dose was decreased to 150 mg/day throughout the study secondary to fatigue, sleepiness, and weight loss, and one patient's dose was decreased to 100 mg/day secondary to sleepiness, rash, bruxism, dizziness, and 'loss of spark'. In order to evaluate response to fluvoxamine over an extended dosage range and longer treatment interval, in four additional KS patients (three men and one woman), the experimental design consisted of a 9week, double-blind crossover period divided into a 3-week placebo and a 6-week fluvoxamine period with the order determined randomly. During the 6-week drug period, the first 3 weeks were used to achieve the maximum tolerated drug dose, at which the patient would be maintained during the last 3 weeks of drug administration. Plasma fluvoxamine concentrations were determined each Monday and Thursday prior to the morning dose and the results were used by a physician (independent of the study) to titrate the drug dosage. Based on our earlier work (Martin et al., 1989), our goal was to approximate a plasma fluvoxamine concentration of 400 ng/ml in each patient; this constituted doses of 100-600 mg/day. (Importantly, the patient who received fluvoxamine 100 mg/day had

P.R. Martin et al. / European Neuropsychopharmacology 5 (1995) 27-33

plasma concentrations above 500 ng/ml and reported side effects consistent with receiving fluvoxamine.)

2.3. Lumbar punctures Lumbar punctures were performed during the baseline period and at the end of each course of fluvoxamine or placebo. All patients received a lowmonoamine diet for at least 72 h before collection of specimens. All lumbar punctures were performed between 8:30 and 9:30 a.m. with patients in the lateral decubitus position after at least an 8-h fast and bed rest. The first 12 ml of CSF was mixed thoroughly, aliquoted in 1-ml portions, frozen immediately, and stored at -70°C in polypropylene tubes without preservative. A further series of CSF aliquots (1-2 ml) were collected in polypropylene tubes without preservative or with 0.1 N acetic acid or ascorbate, frozen in dry ice at bedside, and stored at -70°C.

2.4. Laboratory procedures The major CSF metabolites of norepinephrine (3methoxy-4-hydroxyphenylglycol (MHPG)), dopamine (homovanillic acid (HVA)), and serotonin (5-hydroxyindoleacetic acid (5-HIAA)) were analyzed with highpressure liquid chromatography (Scheinin et al., 1983). The measurement of plasma fluvoxamine concentrations was based on the method of de Jong (1980). The internal standard (clovoxamine) and fluvoxamine in plasma were derivatized with fluroescamine. The samples were filtered and extracted on a C-18 solid phase. Fluvoxamine and clovoxamine derivatives were separated with high-pressure liquid chromatography on a C-8 column using a mobile phase of methyl alcohol-phosphate buffer (0.01 mol/1, pH 7.0) 65:35 pumped at 1 ml/min. Derivatives were detected by fluorescence on a fluorometer (FS970, Kratos, Ramsey, NJ), with excitation at 380 nm, and a 418-nm emission filter. Concentrations were calculated by comparison of peak height ratios with those obtained from a calibration line. Most patient samples were analyzed in duplicate on different days and the median value of interassay difference was 14%.

2.5. Assessment of neuropsychological functions Vigilance~attention was assessed by asking patients to identify six repeated words out of a list of 18 highly familiar and categorically related words (Weingartner et al., 1983) and by the Digit Span subtest of the Wechsler Adult Intelligence Scale (WAIS) (Martarazzo, 1972). Overall cognitive functioning was examined by performance on Trails A (Reitan, 1958), Digit Symbol subtest (WAIS), and Orientation and Mental

29

Control tests of the Wechsler Memory Scale (WMS) (Prigatano, 1978; Russell, 1975). Tasks related to frontal lobe functioning included the Wisconsin Card Sorting Test (Grant and Berg, 1948), Trails B (Reitan, 1958), Prose (Bower et al., 1979), and the Brown-Peterson Consonant Trigrams task (Peterson and Peterson, 1959). Overall memory functioning was measured with the WMS. Automatic memory processes were assessed with frequency-monitoring tasks (Weingartner et al., 1983; Hasher and Zacks, 1979). Semantic or knowledge memory was evaluated by performance on Semantic Categories (Lezak, 1983), Sentence Completion (Kleinman, 1980), Information (WMS), and Prose (Bower et al., 1979). Episodic memory for visual stimuli was examined with the Visual Reproductions task of the WMS and Pictures/ Words Test (Weingartner et al., 1984), and episodic memory for verbal stimuli was examined with recall of related words (Weingartner et al., 1983; Prigatano, 1978; Hasher and Zacks, 1979; Wickens, 1970), unrelated words (Buschke, 1973), and related sentences from the WMS. Alternative versions of the tests were administered whenever possible to minimize improvement from having repeatedly taken the same set of tests in a relatively short time. Although a positive effect of fluvoxamine on performance could be demonstrated by improvement over baseline and by improvement over placebo, the latter is considered to be more rigorous.

3. Results

Age, education, intelligence, and selected measures of memory functioning are listed in Table 1. As would be expected, overall memory performance was de-

Table 1 D e m o g r a p h i c s and cognitive abilities Measurement

Mean ± SD

A g e (years) Education (years) Handed

63 ± 10 40-75 14 ± 2 11-18 all right-handed but one person

Wechsler Adult Intelligence Scale VIQ PIQ FSIQ

108 ± 15 104 ± 15 107 ± 15

82-134 78-133 79-136

96 ± 19 5± 2 1± 1 7± 3

63-120 3-9 0-4 2-11

3± 4 8± 3

0-11 4-14

Wechsler M e m o r y Scale M e m o r y Quotient Passages Passage, 20 rain Visual Reproductions Visual Reproductions, 20min Associate Learning

Range

P.R. Martin et al. / European Neuropsychopharmacology 5 (1995) 27-33

30 -100 -

ceived 6 weeks of fluvoxamine treatment, an additional reduction of CSF 5-HIAA was observed in patients whose plasma fluvoxamine levels stayed below 450 ng/ml. In contrast to the effects of fluvoxamine on 5HIAA, there were no consistent changes in CSF concentrations of HVA or MHPG. Fluvoxamine was well tolerated by the patients, and few side effects were noted; specifically, the nausea that had been frequently reported in previous studies on fluvoxamine was not observed (Curran and Lader, 1986; Wilson et al., 1983; Claassen et al., 1977). Comparisons (matched t-tests) between baseline scores and those attained after 3-4 weeks of fluvoxamine revealed improvement (P ~<0.05) for WMSMQ (Prigatano, 1978), remembering passages of related material, and free recall of related words (Vigilance, Weingartner et al., 1983; Associate Learning, Prigatano, 1978; and Pictures/Words, Weingartner et al., 1984). Comparisons of scores between placebo and 3-4 weeks of fiuvoxamine revealed no improvement. It is noted, however, that those individuals who demonstrated the largest improvement on WMSMQ also showed the largest improvement on tests of vigilance and/or attention (Weingartner et al., 1983; Matarazzo, 1972), even though these changes were not significantly correlated when the entire sample was considered. After correcting for differences in vigilance by analysis of covariance, there was a trend for WMSMQ to be higher (P < 0.1) after 3-4 weeks of fluvoxamine treatment than placebo. Selected tests and scores after 3-4 weeks of fluvoxamine treatment are depicted in Table 2. A significant correlation (P <~0.05; both Pearson's r and Spearman's rank) was observed between the magnitude of reduction in 5-HIAA from placebo to 3-4 weeks of fluvoxamine treatment and amount of improvement on WMSMQ (Prigatano, 1978) (see Fig.

-90~ .8o-

i

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•

-20

.

50

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i

100

200

300

400

SO0

800 1000

Plasma Fluvoxamlne Concentration, ng/mL

Fig. 1. Relationship between plasma fluvoxamine concentration and reduction in 5-hydroxyindoleacetic acid ( 5 - H I A A ) after 3 - 4 weeks of administration of fluvoxamine to nine patients with alcoholic Korsakoff's s y n d r o m e (closed triangles). O p e n triangles indicate values after an additional 3 weeks of fluvoxamine treatment in four of these patients.

creased compared to IQ and also was significantly lower than values obtained for normal volunteers in our previous studies (Martin et al., 1992). One patient inadvertently received fluvoxamine during all phases, so all comparisons for this patient were between baseline and after 4 weeks of fluvoxamine. As a serotonin uptake inhibitor, fluvoxamine is expected to reduce the CSF concentrations of 5H I A A , and there was a statistically significant (P < 0.003) decrease in CSF concentrations of 5-HIAA (pmol/ml) in nine patients after 3-4 weeks of fluvoxamine treatment (73.3 +-24.4) compared to placebo (112.6 --- 38.1). There was a significant correlation (r = - 0.77, P < 0.03) between change in the CSF 5-HIAA concentration and plasma fluvoxamine level at 3-4 weeks for all patients (n = 8) in whom plasma fluvoxamine levels were below approximately 450 ng/ml (Fig. 1). Furthermore, among the patients who re-

Table 2 Cognitive p e r f o r m a n c e in patients diagnosed with Korsakoff's psychosis after 3 - 4 or 4 - 6 weeks of t r e a t m e n t with fluvoxamine Test

Vigilance/Attention Vigilance G e n e r a l Cognition Trails A Digit Symbol Memory Wechsler M e m o r y Scale MQ Associate Learning Passages Related Words Pictures/Words U n r e l a t e d Words Results are m e a n s ± SD.

Baseline

Fluvoxamine

Placebo

3 - 4 weeks

4 - 6 weeks

4± 1

4 -+ 1

5± 1

5 +- 1

46 ± 13 6± 3

43 - 11 7 -+ 3

44 +-- 13 7± 2

39 --- 10 8± 3

96 ± 19 8± 3 5 +- 2 4 -4- 3 9 --- 6 5± 1

104 ± 22 10 ± 4 7 +- 2 5 -+ 3 14 ± 4 5± 1

106 9 7 6 14 6

± 24 +--4 ± 2 ± 2 --_4 ± 1

102 +- 24 9± 3 7± 2 5 -+ 2 17 +- 7 5 -+ 1

P.R. Martin et al. / European Neuropsychopharmacology 5 (1995) 27-33 30

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20-

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-15-20

A

-;o

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-~o -,io -~o -do -Vo -~o -~;o -Ioo R e d u c t i o n In 5-HIAA, p m o l / m l ( F l u v o x a m l n e - Placebo)

Fig. 2. Relationship between reduction in CSF 5-hydroxyindoleacetic acid (5-HIAA) and change in Wechsler MemoryScale MemoryQuotient after 3-4 weeks of administrationof fluvoxamine to nine patients with alcoholic Korsakoff'ssyndrome (closed triangles) (P < 0.05). Open trianglesindicatevaluesafter an additional 3 weeks of fluvoxaminetreatment in four of these patients.

2). Among the four patients who received fluvoxamine for 6 weeks, further improvements in memory compared to those observed at 3 weeks were noted only for the three patients in whom CSF 5-HIAA concentrations decreased during this interval. None of the baseline neuropsychological Or biochemical characteristics of the patients were significantly correlated with reductions in CSF 5-HIAA or improvements in WMSMQ during fluvoxamine treatment. Furthermore, WMSMQ scores were not related to scores on the Beck Depression Inventory (Beck and Beck, 1972), nor was there a significant carry-over effect such that placebo scores were elevated after treatment with fluvoxamine.

4. Discussion

In this report, we extend our preliminary observations that the serotonin uptake inhibitor, fluvoxamine, can ameliorate the episodic memory failure in patients with alcohol amnestic disorder (Martin et al., 1989) using an expanded sample studied over a longer period and a wider dosage range. Our major finding is that 3-4 weeks of fluvoxamine treatment is associated with a modest improvement in performance on the Wechsler Memory Scale compared to placebo, independent of any effects on attention/vigilance. This improvement in memory was correlated with reductions in CSF 5-HIAA suggesting that serotonergic mechanisms are implicated in the amnesia of alcoholic KS. It is important to note that with adequate plasma levels, clinical improvement was observed after 3-4

31

weeks of fluvoxamine treatment. In those patients who were administered fluvoxamine for up to 6 weeks, further improvements in memory were only noted if plasma levels rose, but remained below 450 ng/ml. At levels above this, the magnitude of the reduction in CSF 5-HIAA, and increase in WMSMQ, diminished. In one patient, in whom atypically high plasma concentrations of fluvoxamine were obtained with a dose of only 100 mg/day, some improvement in WMSMQ was noted as plasma fluvoxamine decreased (but remained above 450 ng/ml). Although the mechanistic basis of this type of apparent dose-response relationship (described for nortriptyline treatment of endogenous depression (Guthrie et al., 1987; van Harten, 1993)) remains to be clarified, a possible explanation may be the complement of serotonin receptor subtypes that are activated with increasing inhibition of serotonin uptake (Stahl, 1993). Although the time course of memory improvement in patients with KS is reminiscent of the classical antidepressant response (Quitkin et al., 1984), it must be emphasized that none of these patients manifested clinical evidence of depression and cognitive performance was not related to scores on the Beck Depression Inventory. Furthermore, baseline neuropsychological or biochemical characteristics of patients were not predictive of the magnitude of reductions in CSF 5-HIAA or improvement in WMSMQ during fluvoxamine treatment. Finally, that improvements in episodic memory were noted when differences in vigilance were covaried suggests that fluvoxamine provides benefit by its effects on consolidation/storage and/or retrieval (Martin and Welch, 1993). It is recognized that a limitation of this study is the small sample size. However, this is unavoidable due to the difficulty of obtaining, in one center, patients in whom the diagnosis of alcohol amnestic disorder can be made with confidence using strict clinical and psychometric criteria (Martin and Nimmerrichter, 1993). Nevertheless, we believe it is important to report our cumulative experience with fluvoxamine treatment of alcohol amnestic disorder, acquired over more than 5 years, because it may have clinical implications beyond this restricted diagnostic group, considering recent reports (Naranjo et al., 1985, 1992) of reductions in alcohol consumption by augmentation of serotonergic neurotransmission in less severely impaired alcoholics. Based on our findings, it is suggested that longitudinal studies of pharmacological reduction of alcohol consumption by serotonergic agents in moderately impaired alcoholics should also include measures of cognitive functioning as there may be a continuum of impairment in certain cerebral functions and shared neuropathological abnormalities in alcoholics with and without formally diagnosable chronic organic mental disorders (Martin et al., 1989).

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P.R. Martin et al. / European Neuropsychopharmacology 5 (1995) 27-33

Furthermore, investigations of other serotonin uptake inhibitors and serotonin receptor agonists in the treatment of alcohol amnestic disorder may elucidate the role of serotonergic dysfunction in its pathogenesis.

Acknowledgements We acknowledge the assistance of Drs. David Nutt, David George, and Susan Shoal and Thomas Hart, Elizabeth Davis, Robert Rawlings, and Michelle Towle and the critical review of Dr. Fridolin Sulser.

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