Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder

Pimy.

Neuro-Psychop-

& Bbl. Psychlat 1997, Vol. 21, pp. 601-609 Copyright 0 1997 Elsevier sdence Inc. PrInted in the USA. All rights rrsel-ved 0278~6846197 $32.00 + .oO

ELSEVIER

PII SO27B-5546(97)00035-3

SIDE EFFECTS OF LOW DOSE NEUROLEPTICS AND THEIR IMPACT ON CLINICAL OUTCOME IN GENERALIZED ANXIETY DISORDER CORNELIUS WURTHMANN l, ECKHARD KLIESER2 and ERLO LEHMANN3

1Department of Psychiatry, University of Magdeburg, 2Protestant Hospital Gelsenkirchen, University Hospital and 3Department of Psychiatry, University of Duesseldorf, FRG

(Final form, January 1997)

Abstract

Wurthmann, Cornelius, Eckhard Klieser and Erlo Lehmann: Side Effects of Low Dose Neuroleptics and their Impact on Clinical Outcome in Generalized Anxiety Disorder. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1997, a, pp. 601-609. 0 1997 Ekvier Science Inc. 1. The present study was designed to determine the impact of neuroleptic side effects on cliical outcome in generalized anxiety disorder. 2. 205 outpatients entered the study. In an open label design fluspirilene 1Smg per week was administered for a period of 6 weeks. 3. Consistent with previous studies fluspirilene demonstrated again anxiolytic propeaies and was in general tolerated well. 4. However, in responders significantly less side effects were observed than in nonresponders. The interaction between tolerability and clinical outcome is the main finding of the present study. 5. In conclusion, the data suggest, that neuroleptic treatment of generalized anxiety disorder should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorders side effects are observed, phannacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome. Keywords: fluspirilene, generalized anxiety disorder, neuroleptics, pharmacotherapy, side effects Abbreviations: generalized anxiety disorder (GAD)

In pharmacotherapy of GAD benzodiazepines (Schweizer and Rickels, 1991) and antidepressants (Kahn et al., 1987; Wurthmann, 1996) are promising. Several studies have demonstrated, that low dose neuroleptics are also effective in GAD, too (Heinrich e.t al.,l990; Heinrich and Lehmann, 1992; Klieser and Wurthmann, 1995). It was also shown, that rationally grounded guidelines about which of these 601

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treatments is to choose in an individual suffering from chronic GAD can be derived from single-subject experiments (Wurthmann et a1.,1996). Results from another study suggest the usefulness of test therapy in neuroleptic treatment of these patients (Wurthmann et al., 1995). Based on clinical response or nonresponse within the first one or two weeks of neuroleptic treatment, test therapy provides prediction of therapeutic success following a continous treatment over several weeks. In the U.S., unlike in the F.R.G., the use of antipsychotic agents to treat anxiety disorders is not regarded as ethical, because of potential adverse reactions such as parkinsonism, tardive dyskinesia and weight gain (Tegeler et al.,l990). Because patients with GAD are very concerned with their physical health, the present study was designed to determine the impact of neuroleptic side effects on clinical outcome in GAD

Methods Subjects Ah subjects were under ambulatory treatment of psychiatrists or general physicians, were at least 18 years of age and met the diagnostic criteria for GAD according to ICD 10 (WHO, 1992). To be included in the study, each patient was also required to be seriously impaired by anxiety symptoms, assessed by a four-point ( absent; minimal; moderate; serious) global clinical assessment scale. Patients were excluded, if they suffered from other psychiatric disorders, physical or neurological abnormalties. Pregnant and nursing women were excluded as well. Studv Design In an open label design all patients received fluspirilene 1.5mgper week. Since fluspirilene demonstrated statistically efficacy in open and placebo-controlled trials and since the aim of the study was not to investigate the principal question of GAD treatment by neuroleptics, a placebo-control was not included in the present study. Fluspirilene was administered as a depot injection. The period of observation was 6 weeks. Consumption of psychotropic comedicatioh or alcohol was prohibited. The study was performed in accordance with prevailing laws and guidelines of pharmacological trials. Informed consent was obtained from all patients after the procedure was fXy explained, Assessment Assessments were carried out at the screening visit, after I,3 and 6 weeks. The screening assessment included collection of demographic, medical and illness information, laboratory assessments,

Side effects of low dose neuroleptics electrocardiogramm, electroencephalogram

603

and physical evaluation. Vital signs were taken

throughout the study. Furthermore, at the screening visit all patients underwent a clinical interview to establish ICD 10 diagnosis of GAD, while excluding patients suffering from other psychiatric disorders. Psychopathology was assessed by a four-point rating scale (l=absent; 2=minimal; 3=moderate; 4=serious). The following symptoms, frequently adhering to anxiety patients, were evaluated: anxiety, depressiok cardiac complaints, vertigo, sweating, dysphagia and other somatic complaints (f.e. indigestion). On a four-point scale therapeutic efficacy (marked improvement, improved, slight improvement, unchanged or deteriorated) and tolerability (very good, good, moderate, poor) were globally assessed (Lehmann, 1984). All side effects were recorded by inquiry and by physical examination. Clinical interviews, diagnostic assessment and ratings were performed by treating psychiatrists, collaborating with our study group since many years and therefore being experienced in the use of the instruments mentioned above. Data Analvses For each visit the frequencies and standard deviations of all clinical parameters were obtained. The interdependence between clinical outcome and tolerability was computed by Chi2-test. In addition, we performed an analysis of responders. For this reason all patients were randomly assigned to two samples. Analysis of baseline comparability among treatment groups was done by means of Pearson Chi2-test. The analyses of variance and Mann-Whitney-U-test included evaluation of sex, age, height, weight, heart rate, blood pressure and psychopathology. Furthermore, the number of side effects recorded during the whole trial and the degree of anxiety symptoms in week 6 were compared by Pearson Chi2-test. In both groups then a discriminant analysis was performed in order to identify predictors of therapeutic response. These predictors were crossvalidated. Those patients were defined as responders, where in week 6 anxiety was only mild or absent.

Results 205 outpatients (59 male, 75 female) entered the study. All subjects met ICD 10 criteria for GAD In Table 1 sample characteristics are summarized.

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Table 1

Demographic and Clinical Characteristics * at Baseline

No. of subjects Sex male female Age (Y) Height (cm) Weight (kg) Blood pressure syst. (mm Hg) Blood pressure diast. (mm Hg) Heart rate (b.p.m.)

205 59 146 41.3 (12.4) 168.4 ( 7.5) 66.4 (11.1) 132.2 (18.0) 82.8 ( 9.5) 79.5 ( 9.5)

*Sample characteristics are presented as mean (SD).

Assessments of psychopathology are shown in Table 2. Therapeutic effects and frequencies of side effects are presented in Table 3 and Table 4. In week 6 77% of the patients were improved or markedly improved. 16.1% of the patients reported on side effects within the last 6 weeks. The most common side effects within the whole treatment period were fatigue (5.!2%), weight gain (4.4%) and mild parkinsonlike symptoms(2%). The interaction between anxiety symptoms and globally assessed tolerability is shown in Table 5. In responders throughout the study significantly less side effects were observed @<.OOl) than in nonresponders. Hence tolerability is a predictor of clinical outcome.

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Table 2

Psychopathology at Baseline and under Treatment*

anxiety depression cardiac complaints other somatic complaints vertigo sweating dysphasia

baseline

week 1

week 3

week 6

4.0 (0.0) 2.74 (1.06) 2.74 (0.07) 2.42 (1.10) 1.87 (1.03 2.05 (I .OO) 1.74 (0.96)

3.04 (0.71) 2.12 (0.72) 2.16 (0.92) 1.96 (0.92) 1.56 (0.76) 1.63 (0.76) 1.45 (0.70)

2.34 (0.74) 1.75 (0.62) 1.78 (0.81) 1.66 (0.88) 1.37 (0.64) 1.37 (0.59) 1.24 (0.49)

1.92 (0.71) 1.58 (0.61) 1.55 (0.72) 1.49 (0.71) 1.26 (0.53) 1.28 (0.50) 1.17 (0.45)

*Data are presented as mean (SD)

Table 3

Global Clinical Effects after 6 Weeks

marked improvement improved slight improvement unchanged or deteriorated missing value

n

%

56 103 24 17 5

27.3 50.2 11.7 8.3 2.4

Based on the discriminant analysis in sample 1 (Table 6) responders can be described by the following characteristics: at baseline and after one week of treatment they rarely complain of somatic symptoms. Already in week 1 the later responders show good clinical improvement and they show only

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minimal or no neuroleptic side effects. By these variables in sample 1 appropriate prediction of clinical outcome in week 6 was observed in 85% of the patients, in sample 2 (crossvalidation) in 84.69%.

Table 4

Frequencies of Side Effects*

n

week 1 %

Subjects complaining of side effects

23

11.2

21

10.2

14

6.8

weight gain fatigue vertigo cardiovascular complaints sweating mouth dryness parkinsonlike symptoms akathesia gastrointestinal symptoms visual disturbance other symptoms

4 12 2 _ 1 1 2 _ _ 1 1

2.0 5.9 1.0 _ 0.5 0.5 1.0 _ 0.5 0.5

6 3 _ 1 2 2 3 1 1 1 2

2.9 1.5 _ 0.5 1.0 1.0 1.5 0.5 0.5 0.5 1.0

8 1 -2 -1 -2

3.9 0.5 _

week 3 n %

week 6 n %

1.0 0.5 1.0

*Data are presented as absolute and relative (“A) fhequencies

In the discriminant analysis based on sample 2 (Table 7) the authors found again, that the patients with a favourable clinical outcome in week 6 (responders) showed already in week 1, a marked improvement. Furthermore, a low heart rate and an elevated diastolic blood pressure at baseline predicted therapeutic response at the end of the treatment period. By these variables in sample 2 appropriate prediction was observed in 84.69% of the patients, in sample 1 (cossvalidation) in 85%.

Consistent with previous open labeled and double blind studies fluspirilene 1.5mg per week demonstrated again anxiolytic properties in GAD (Heimich and Lehmann, 1992; Wurthmann et al., 1993; Wurthmann et al., 1995) and was in general tolerated well (Heinrich and Lehmann, 1992). However, when side effects appeared, they indicated an unfavourable clinical outcome. This is the main finding of the present study. Questions remain, how to interpret this result?

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Side effects of low dose neuroleptics

Table 5

Interaction between Anxiety Symptoms in Week 6 and Tolerability

tolerabilty

very good

anxiety symptoms absent minimal moderate serious

Chi2 = 3862;

good

moderate

poor

37 50 9 3

10 58 9 2

2 7 2 1

0 1 4 0

49 116 24 6

99

79

12

.5

195

D.F. = 9; p<.ool

Table 6

Discriminant Analysis Based on Sample 1

y = - 0.1961 + 0.5619 + 0.6811 + 1.0102

(constant) x somatic complaints (baseline) x anxiety (week 1) x neuroleptic side effects (week 1)

Table 7

Discriminant Analysis based on Sample 2

y= + +

0.3663188 0.4746294 0.6322754 1.247247

D - 01 (constant) D - 01 x blood pressure diast. (baseline) D - 01 x heart rate (baseline) x anxiety (week 1)

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The concerns of patients with GAD are diffise, involving thoughts of loss of control and heightened vigilance for threats of a social and physical nature. The centrality of this diise

pattern of worry for

patients with GAD has been sufficiently documented (Borcovec et al., 1991). Therefore a variety of psychotherapeutic approaches have been developed to modify these cognitions (Chambless and Gillis, 1993). Our hypothesis is, that in patients who experience neuroleptic side effects, these sensations produce evidence of their basic worries, pertaining to physical health, which elicit further apprehension by a vicious circle of cognitive feedback.

Conclusion

The data suggest, that neuroleptic treatment of GAD, should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorder side effects are observed, pharmacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome. A question to be addressed by future research is, whether side effects in benzodiazepine and antidepressant treatment of GAD have an impact on clinical outcome, too.

References

BORCOVEC, T.D.; SHADICK, R. and HOPKINS, M. (1991) The nature of normal and pathological worry. In: Chronic anxiety and generalized anxiety disorders, R. Rapee and D.H. Barlow (Eds.), pp 29-5 1, Guilford, New York. CHAMBLESS, D.L. and GILLIS, M. (1993) Cognitive therapy of anxiety disorders. J. Consult. Clin. Psychol. &l: 248-260 HUNRICH, K.; LEHMANN, E.; TEGELER, J. and WLJRTHMANN, C. ( 1996) Fundamentals and results of controlled studies in neuroleptanxiolysis. In: Psychiatry: A world perspective, C.N. Elsevier Science Publishers, Steftis, A. D. Rabavilas and C. R. Soldatos (Eds.), pp 248-253, Amsterdam. HEINRICH, K. and LEHMANN, E. (1992) Low dose neuroleptanxiolysis in anxiety states. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 16: 135-143. KAHN, RJ..; McNAIR, D.M. and FRANKENTHALER, L.M. (1987) Tricyclic treatment of generalized anxiety disorder. J. Affect. Disord. 13: 145-15 1. KLIESER, E. and WURTHMANN, C. ( 1995) Niedrigdosierte Neuroleptika, andere Tranquilizer: Indikationen. In: Neuropsychopharmaka - Tranquilizer und Hypnotika, P. Riederer, G. Law and W. Pdldinger (Eds.), pp 178-185, Springer, Wien.

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LEHMANN, E. (1984) Practible and valid approach to evaluate the efficacy of nootropic drugs by means of rating scales. Pharmacopsychiatria Q: 71-75. In Chronic SCHWEIZER E. and RICKELS, K. (1991) Pharmacotherapy of generalized anxiety. anxiety, generalized anxiety disorder and mixed anxiety-depression, R. Rapee and D.H. Barlow (Eds.), pp 104-108, Guilford, New York. TEGELER, J.; LEHMANN, E.; WEIHER, A. and HEINRICH, K. (1990) Safety of long-term neuroleptanxiolysis with fluspirilene 1.5mg per week. Pharmacopsychiat. 22: 259-264. WORLD HEALTH ORGANIZATION (1992) The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. WHO, Geneva. WURTHMANN, C.; KLIESER E. and LEHMANN, E. (1993) Dose-effect relationship of fluspirilene in generalized anxiety disorder? In: Current therapeutical approaches in panic and other anxiety disorder, Collegium Intemationale Neuro-Psychopharmacologicurn @is.), p 113, Karger, Basel. WURTHMANN, C.; KLIESER, E.; LEHMANN, E. and Pester U. (1995)Test therapy in the treatment of generalized anxiety disorders with low dose fluspirilene. Prog. Neuro-Psychopharmacol & Biol. Psychiat.&1049-1060. WURTHMANN, C. (1996) Trizyklika bei Angsterkrankungen. In: Angst- und Panik-Erkrankungen, S. Kasper and H.J. Moller (Eds.), pp 299-313, Gustav Fischer Verlag, Jena. WURTHMANN, C.; KLIESER E.; LEHMANN, E. and KRAUTH, J. (1996) Single-subject experiments to determine individually differential effects of anxiolytics in generalized anxiety disorder. Neuropsychobiology 22: 196-201.

Inquiries and reprint requests should be addressed to:

Priv.-Doz.Dr.med.Comelius Wurthmann Department of Psychiatry, University of Magdeburg Leipziger Strasse 44 39 120 Magdeburg, FRG