Effects of adjunctive verapamil administration in chronic schizophrenic patients

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EFFECTS OF ADJUNCTIVE VERAF~ IN CHRONIC SCHIZOPHRENIC

ADMINISTRATION PATIENTS

GYORGY BARTKO$, SZABOLCS HORVATH, GYORGY ZADOR and EDE FRECSKA* National Institute for Nervous and Mental Diseases, Budapest, Hungary

(Final form, October 1990)

Abstract Bartko, Gyorgy, Szabolcs Horvath, Gyorgy Zador and Ede Frecska: Effects of adjunctive verapamil administration in chronic schizophrenic patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1991, =:343-349. 1. 2.

3.

The efficacy of adjunctive verapamil on psychopathological symptoms and tardive dyskinesia was investigated in 22 chronic schizophrenic patients, who had partially responded to neuroleptics. After 28 days verapamil administration (240 mg/day) a significant improvement was found in anxiety-depression, and in some positive and Three of the 22 patients showed clinically negative symptoms. pronounced global improvement. The treatment was ineffective in tardive dyskinesia.

Kevwords: psychopathology,

schizophrenia, tardive dyskinesia, verapamil.

Scale Involuntary Movements (AIMS), Abbreviations: Abnormal Diphenylbutylpiperidine (DPBP), Brief Psychiatric Rating Scale (BPRS), Research Diagnostic Criteria (RDC), Scale for the Assessment of Negative Symptoms (sANs), Scale for the Assessment of Positive Symptoms (SAPS),

Introduction Verapamil a calcium channel

antagonist widely used in the treatment of

cardiovascular diseases has been demonstrated to have beneficial effects in mania and other neuropsychiatric disorders. Recently, Gould et al. (1983) have suggested that the ability of pimozide and other drugs of the diphenylbutylpiperidine group (DPBP) to relieve negative symptoms of schizophrenia

is related to their potency in calcium

channel antagonism while the classical neuroleptics are lacking this effect. Verapamil is structurally

similar to DPBP neuroleptics and blocks calcium

channels similarly. Present address:

Department of Psychiatry, Mount Sinai Medical Center, New York, USA

343

344

G. Bartko et ai.

Bloom et

al.

(1987) reported

the

therapeutic

efficiency

verapamil in the treatment of a refractory schizophrenic.

of

adjunctive

Giannini et al.

(1985) found verapamil alone to be as effective in acute schizophrenia as haloperidol.

In Prices' study

(1987) both haloperidol and verapamil were

superior to placebo in decreasing psychotic symptoms of acute schizophrenics. Tourjman et al.

(1987) demonstrated

added to neuroleptic Pickar

et

al.

some therapeutic effects of verapamil

therapy of chronic

(1987)

treated

schizophrenic patients.

chronic

schizophrenic

However,

patients

recently

withdrawn from neuroleptics with verapamil and found increases in paranoia during the treatment period.

Two other studies (Grebb et al. 1986, Uhr et

al. 1988) demonstrated the inefficacy of verapamil in chronic schizophrenia. However, all studies employed small sample sizes and verapamil doses may have been to low to exert a therapeutic effect. Verapamil may also have some role in explaining tardive

dyskinesia

supersensitivity.

through

prevention

of

and perhaps preventing

neuroleptic

induced

dopamine

In a case report [Barows and Childs, 1986) and Reiter et

al's study 11989) it was found to improve tardive dyskinesia of schizophrenic patients treated with verapamil. The goal of the present study was to ecafuate the therapeutic effect of adjunctive dyskinesia

verapamil of

on

chronic

the positive schizophrenic

and

negative

patients

symptoms

partially

and

tardive

responding

to

neuroleptics. Methods Patient population The 22 (18 male, 4 female) patients participating in the study were selected among the chronic schizophrenics, hospitalized for at least 6 months at the

long-term

Diseases.

ward of

the National

Institute

for Xervous

and Mental

They all gave informed consent for participation in the study.

The diagnoses

were made on the basis of the Research Diagnostic Criteria (RDC) of Spitzer et al. (1978). Six of the patients were paranoid , 3 were The mean + SD catatonic, 9 were disorganized and 4 were undifferentiated. f number Cl mean +SD 57.6 years, the 36.5 was the patients age of

hospitalizations was 9.0 L 6.5, and the mean + SD duration of their illness All were free of somatic, neurologic, or secondary was 13.4 + 8.2 years. The patients responded partially to neurc.lleptic psychiatric disorders. treatment and continued to Fhow mild to marked positive symptoms during their All patients required to have moderate to severe negative hospitalization. symptoms.

Effects ofverapamilinchronlc schfiophrenla

Study

The

345

Desiqn patients

were

receiving

neuroleptics

(haloperidol,

thioridazine,

flupentixol), which were held at a constant dose for at least 3 weeks before and throughout the trial.

The mean + SD dose of neuroleptics was 611 5 2.95

mg/day in chlorpromazine equivalents (Davis, 1969).

After an initial symptom

rating, verapamil was administered at 80 mg three times a day

(240 mg/day

total) orally for 28 days. Assessment Instruments The Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 19621, the Scale for the Assessment of Positive Symptoms

(SAPS) (Andreasen, 1981) and

the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1981) were used to rate psychopathological

symptoms.

dyskinesia was assessed on the Abnormal

The

severity of

tardive

Involuntary Movement Scale

(AIMS)

Both ratings were made by the same clinical psychiatrist at (Guy, 1976). baseline and on day 28. The BPRS scores were analyzed as total score and by each of the five factors, and the SANS and SAPS scores were analyzed as summary score (sum of the global ratings) and by each of the subscale scores (global rating). Data analysis Statistical analysis were performed by Wilcoxon test (one-tailed), Results Twenty eight days after the verapamil administration the pretreatment BPRS total score, the scores of the anxiety/depression factors decreased significantly, avolition/apathy.

and thought disturbance

The delusion subscale score of SAPS, the

anhedonia/asociality

subscale

scores

of

SANS

and

summary score improved significantly after treatment with verapamil

SANS (Table

1). In three of the 22 patients, who had exhibited prominent both positive and negative symptomatology during the last 6 months before trial a clinically relevant global improvement was observed after the verapamil administration.

346

G. Bartko

et al.

Table 1 Psychopathological Ratings in 22 Chronic Schizophrenic Patients at Baseline and on Day 28 of Verapamil Administration

At baseline

On day 28

Significance* (P)

Brief Psychiatric Ratinq Scale Anxiety/depression

6.4+_3.0

5.2~2.3


Anergia

6.822.9

6.3~2.8

NS

Thought disturbance

9.655-O

7.5~4.2

co.01

Activation

5.022.4

5.1+2.4

NS

Hostility/suspiciousness

5.452.5

5.152.9

NS

33.228.8

29.229.0

Hallucinations

1.451.8

1.2~1.6

NS

Delusions

1.9+1.5

1.451.5

co.05

1.821.3

1.751.4

NS

Bizarre behavior

0.6+1.4

O-7+1.6

NS

Total score

5.7L2.9

5.0-3.0

NS

Affective flattening

2.550.8

2.151.0

NS

Alogia

1.9t1.5

l-7+1.7

NS

Avolition/apathy

2.4~0.8

1.5,l.l


Anhedonia/asociality

2.6~1.2

l-6+1.1


Attentional impairment

2.4~1.8

2.0~1.7

NS

11.823.7

8.953.5

co.01

Total score

co.01

Scale for the Assessment of Positive Symptoms

Positive formal thought disorder

Scale for the Assessment of Neqative Symptoms

Total score

' Wilcoxon test Total

AIMS

scores

show$d

a nonsignificant

verapamil treatment (Table 2).

decrease

on

day

28 of

the

Effects ofverapamll inchronic schizophrenia

347

Table 2 Abnormal Involuntary Movement Scale Ratings in 22 Chronic Schizophrenic Patients at Baseline and on Day 28 of Verapamil Administration

At baseline

Significancei

On day 28

(P)

AIMS total score

2.822.9

NS

2.152.5

* Wilcoxon test (one tailed) No major side effects emerged during the study. Discussion Our open study demonstrated

a beneficial adjuvant effect of verapamil on

anxiety/depression, and on some positive and negative symptoms of 22 chronic schizophrenic patients responding partially to neuroleptic treatment.Three of the 22 patients showed a clinically pronounced improvement both in positive and negative

symptoms

after

28

days

verapamil

administration.

It

was

subjective impression, that more patients would have improved if the study had been longer or if the doses of verapamil had been higher.

Our results

confirm the similar studies of Tourjman et al. (1987) and Bloom et al. (1987) and are in contrast

with general

lack of response noted by other authors

(Pickar et al. 1987, Grebb et al. 1986, Uhr et al. 1988). The mechanism by which verapamil exerts its adjunctive effects is unclear. Gould et al.

(1983) suggested

synergistically

that verapamil

to diminish dopaminergic

and

the neuroleptics

transmission,

through

acted

a calcium

channel blocking mechanism. The authors could not observe an improvement in the symptoms of tardive dyskinesia

after

treatment

However our population

with

did not

movements as their patients did.

as Reiter et al. (1989) did. show a severe grade abnormal involuntary verapamil

348

G.

Bartkoet&,

Conclusions The

results

neuroleptic to

the

suggest

treatment

necessity

therapeutic

that

of chronic

of

utility

verapamil

may

pursuing

controlled

of calcium

prove

schizophrenia.

channel

a

useful

The authors

investigations

blockers

adjunct

draw to

assess

in schizophrenic

to

attention the

patients.

References ANDREASEN,

N.C.

Iowa City, ANDREASEN,

N.C.

Iowa City, BARROWS,

D.M..

Biol.

GIANNINI,

Proc.

Natl.

N.P.V.

report.

effect

of

Prog.

Verapamil

in

Neuro-Psychopharmacol.

drugs.

Antischizophrenia

In: Abstracts

effects

IVth World

of

Congress

of

R.C.

Acad.

1-J.

type

(1983)

Antischizophrenic

act as calcium-channel

Sci. USA a:5122-5215

and TAYLOR, trial

E.H.

(1986)

of verapamil

A negative

in chronic

doubleblind

schizophrenia.

a:691-694 ECDEU

(1976)

ADM 76-338

Assessment

Washington

Manual DC, U.S.

for PsychopharmacologY Department

of Health,

Welfare and GORHAM,

Rep.

Psychiatry

Hillside

The Brief

(1962)

Psychiatric

Rating

Scale.

0. and DORAN, administration

A.

(1987)

Clinical

to schizophrenic

and biochemical

patients.

Arch.

s:113-119

(1987) J. Clin.

s., ADLER,

dyskinesia

D.J.

=:799-808

of verapamil

W.A.

=:26-27

(1987)

of antipsychotic

and REYNOLDS,

clinical

D., WOLKOWITZ,

effects

dyskinesia

=:1485

(1985)

R.

612.10).

K.M.M.

SHELTON,

J-E.

Psychol.

REITER,

A case

equivalence

No.

MURPHY,

(Ed)

Education

Gen.

An anti-tardive

and NAIR,

and LOISELLE,

Psychiatry

OVERALL,

Symptoms.

Psychiatry

Publication

PRICE,

Dose

controlled

W.

of Positive

u:185-188

(Abstract

J.A.,

Biol.

PICKAR,

(1986)

of the diphenylbutilpiperidine

placebo

Symptoms.

Res. 1:35-39

antagonists.

GUY.

A.

S.V.

A.J.

R-J.,

drugs

for the Assessment

TOURJMAN,

(1969)

Biological

GREBB.

Scale

schizophrenia.

verapamil

of Negative

of Iowa

Am. J. Psychiatry

Psychiatry J-M.

for the Assessment

[letter)

J. Psychiat.

GOULD,

(1981)

M. and CHILDS.

refractory

DAVIS,

Scale

of Iowa

University

verapamil. BLOOM,

(1981)

University

Antipsychotic Psychiatry and ANORIST,

and psychosis

effects

of verapamil

in schizophrenia.

2:225-230 B.(1989)

in schizophrenic

Effects

of verapamil

patients.

J. Clin.

on tardive Psychiatrl

Effects ofverapamil inchronicschizophrenia

SPITZER,

R-L.,

Criteria. TOURJMAN,

S.V.,

the treatment UHR,

S.B.,

ENDICOTT,

Rationale BLOOM,

Dr. Gyorgy Pilgrim Clinical

and VASAIVAN schizophrenia.

K. and BERGER,

on negative

and reprint

P.A.

symptoms

requests

Bartko

Psychiatric Neuroscience

Box A, Bldg.

Center Center

11

Brentwood,

U.S.A.

D.M.

(1978) Arch.

NAIR,

Research

Gen. N.P.

(1987)

Psychopharmacol. (1988)

of chronic

NY 11717

should

Diagnostic

Psychiatry

Effects

be addressed

to:

=:773-782

Verapamil Bull.

in

23:227-229

of verapamil

schizophrenia.

=:351-352

Inquires

West

E.

reliability.

of chronic

JACKSON,

administration Res.

J. and ROBINS, and

349

Psychiatr.