ORIGINAL ARTICLE

A double-blind comparative study of clinical efficacy of verapamilversus lithium in acute mania

GURVINDER PAL SINGH

Department of Psychiatry 1202, Government Medical College and Hospital, Sector 32 B, Chandigarh, India

AbstractObjectives. The importance of intracellular calcium ions to processes that may be involved in mania and the calciumantagonist action of mood stabilizers suggest a role of verapamil in the treatment of mania. This study was undertaken tocompare the clinical efficacy and tolerability of verapamil versus lithium in manic patients. Methods. Patients with acutemania were randomized to receive lithium (N�25) or verapamil (N�25) in a 4-week double-blind comparative study. Bothgroups were homogeneous with regard to demographic and disease variables. The primary efficacy measures were the meanchange from the baseline to the last assessment in BRMS (Bech�Raefelson Mania Rating Scale) and YMRS (Young-ManiaRating scale) total score. The rating scales were administered to the patients on day 1, 3, 5, 7, 11, 13, 17, 21, 28 of the study.Attendant’s assessment of relief and adverse events were recorded during the study. Results. Both treatment groups showedsignificant decrease in mean BRMS and YMRS score assessed at different points of time. The study showed an equalefficacy of verapamil compared with lithium in the treatment of mania. The findings were supported by good tolerability ofverapamil treatment. Conclusion. This study found equal benefit of verapamil over lithium in treating acute mania.

Key Words: Verapamil, lithium, calcium channel blockers, mania

Introduction

The patient with acute mania is a source of great

distress for family members and attending staff. The

symptoms of mania significantly interfere with the

patient’s ability to function normally [1]. There are

many challenges in treating these patients. The

mechanism of action of antimanic agents is a topic

of debate amongst researchers in the field of

biological psychiatry. The research for a novel

molecule for an effective treatment of mania is still

a mystery in the 21st century.

Calcium metabolism is altered in various forms of

mood disorder [2�7]. All currently used mood

stabilizers somehow seem to show direct or indirect

calcium antagonistic properties [8�13]. With respect

to calcium, carbamazepine exerts strong antagonistic

properties by blocking L-type calcium channels [8].

Valproate inhibits T-type voltage-dependent chan-

nels [9]. Lamotrigine also exerts part of its action by

calcium antagonistic effects on L-, N- and P-type

channels [10,11]. Chronic treatment with valproate

contributes to calcium homeostasis in the endoplas-

mic reticulum. The effect of lithium on serum and

cerebrospinal fluid calcium levels has prompted

several researchers to suggest a potential role of

calcium channel blockers as antimanic drugs [13].

In some clinical trials, calcium channel blockers

have shown promising results in the treatment of

mania. Double-blind data results on verapamil have

been mixed [14�23]. Verapamil was found to be

equal in clinical efficacy in comparison to lithium

and superior to placebo in small case series and

double-blind trials [18]. In one double-blind study

of 20 patients with bipolar mania, verapamil was

reported to be a more effective mood-stabilizing

agent than lithium [19]. Holister and Trevino [21]

listed 61 partially successful reports on trial of

calcium antagonists in bipolar disorder. Walton et

al. [22] found lithium to be superior to verapamil in

mania.

Although data are available from developed coun-

tries, calcium channel blockers as antimanic agents

have not been studied extensively in India. With the

research being in its infancy, no definite conclusion

has been drawn about the status of verapamil as

antimanic agent. Hence, the present study was

undertaken to evaluate the clinical efficacy of ver-

apamil in comparison with lithium in manic patients.

Correspondence: Dr Gurvinder Pal Singh, MD, H. No. 1202, GF, Sector 32 B, Chandigarh, India, 160030. E-mail: gpsluthra@rediffmail.com

International Journal of Psychiatry in Clinical Practice, 2008; 12(4): 303�308

(Received 26 October 2007; accepted 16 May 2008)

ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Informa UK Ltd.

DOI: 10.1080/13651500802209670

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Material and methods

This hospital-based, randomized, double-blind, par-

allel group study was designed to compare the effects

of verapamil with lithium during a 4-week treatment

period in patients hospitalized for a manic episode.

This study was conducted in the Department of

Psychiatry, Government Medical College Patiala,

Punjab, northwest region of India. The study pro-

tocol was reviewed and approved by the appropriate

institutional ethical committee in accordance with

the standards and guidelines laid down in the

Declaration of Helsinki. Written informed consent

was obtained from all patients and their guardians

prior to any study-related activities. They were

informed that they could terminate their participa-

tion at any time for any reason.

Inclusion and exclusion criteria

Eligible subjects were adult inpatients (age range 18�50 years) hospitalized with a diagnosis of manic

episode or bipolar disorder current manic episode

according to the ICD-10 Classification of Mental

and Behavioral Disorders [23]. At screening and

randomization patients were required to have a score

of more than 10 on the Beck Raefelson mania rating

scale (BMRS) [24]. Among female subjects, non-

pregnant females or females not planning conception

were included.

Patients were excluded if they had received any

pharmacological treatment or ECT within 1 month

prior to the study. Other exclusion criteria were

clinically significant electrocardiogram, history of

seizure disorder, substance abuse, mental retarda-

tion, comorbid medical or psychiatric disorder.

Patient population and study medication

All manic patients attending the psychiatry out-

patient of the Department of Government Medical

College, Patiala, India, were screened. A total of 50

patients fulfilling the selection criteria were admitted

into psychiatric ward and underwent a comprehen-

sive physical and psychiatric examination and appro-

priate laboratory investigations. Sociodemographic

data and clinical profile of the patients were recorded

in the semistructured proformas. Baseline efficacy

parameters (BMRS and YMRS) [24,25] scores were

assessed in manic patients.

On day 1, patients were randomly assigned to

treatment with verapamil or lithium. All medication

was administered in a double-blind fashion. Double-

blinding was maintained throughout the study.

Verapamil was flexibly dosed and initiated at a target

dose of 160 mg on day 1, 240 mg on day 2 and

adjusted upto 320 mg/day thereafter. Lithium dosing

was initiated on day 1 at a dose of 900 mg/day and

then on adjusted dose to maintain serum lithium

concentration between 0.8 and 1.2 meq/l and was

monitored throughout the study by an investigator

independent of the dosing investigator. Study blind-

ing was maintained by collecting blood samples from

all patients at least 12 h after administration of the

previous dose of study medication. Serum lithium

estimation was done by flame photometric method

[26]. Serum lithium concentrations were determined

on days 7, 14 and 21. In addition, the investigator

who administered psychiatric rating scales remained

blinded to treatment for the duration of the study.

Rescue medications permitted in the study proto-

col during the study were injectable haloperidol 5 mg

to control agitation and nitrazepam 10 mg for

insomnia. Use of concomitant anti-cholinergic med-

ication was allowed (trihexyphenidyl) in relation to

an adverse event of extrapyramidal symptoms.

Efficacy assessment

The primary efficacy measures were the following

scales:

Table I. Baseline demographic data and disease characteristics.

Characteristics Group I (lithium)

Group II

(verapamil) P value

N�25 N�25

Age (years)

Range 18�50 years 19�50 years �0.05

N (%) N (%)

Gender

Male 18 (72) 20 (80) �0.05

Female 7 (28) 5 (20)

Marital status

Married 19 (76) 17 (68) �0.05

Unmarried 6 (24) 8 (32)

Rural/Urban

Urban 10 (40) 11 (44) �0.05

Rural 15 (60) 14 (56)

Family history

Positive 9 (36) 7 (28) �0.05

Negative 16 (64) 18 (72)

Duration of current episode

B1�3 months 16 (64) 17 (68) �0.05

1�3 months 5 (20) 6 (24)

�3 months 4 (16) 2 (8)

Table II. Mania rating scale scores in the two groups.

Day of

assessment

Treatment

group

No. of

patients

BRMS score

(Mean9SD)

YMR score

(Mean9SD)

Baseline Lithium 25 22.693.84 26.695.61

Verapamil 25 23.493.29 28.895.24

Day 7 Lithium 25 15.692.98 18.8494.28

Verapamil 25 15.4892.66 20.1695.42

Day- 13 Lithium 25 11.5692.53 14.3693.36

Verapamil 25 11.4893.13 14.694.27

Day 21 Lithium 25 4.2892.09 8.7292.37

Verapamil 25 7.5292.14 9.4493.08

Day 28 Lithium 25 3.2491.92 5.7692.57

Verapamil 25 4.492.53 6.093.05

304 G.P. Singh

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Bech�Rafaelsen Mania Rating Scale (BMRS):

This is an 11-item scale to evaluate severity of manic

symptoms. Each item is rated on a five-point

spectrum in which 1�mild, and 4�severe or

extreme. The inter-rater reliability of this scale is

0.97 to 0.98.

Young Mania Rating Scale (YMRS): This scale

has 11 items and is based upon the patients’

subjective report of his or her clinical condition

over the previous 48 h. There are four items that are

graded on a 0�8 scale, while the remaining seven

items are graded on a 0�4 scale. The inter-rater

reliability of YMRS is 0.93.

Primary efficacy assessments were conducted on

day 1, 3, 5, 7, 11, 13, 17, 21 and 28. The primary

efficacy endpoint was the change from baseline in

assessment scale scores at days 7 and 13. Secondary

endpoints were change from baseline in efficacy

assessment scale scores at day 28.

The other secondary endpoints at days 14 and 28

were information gathered from the attendants of

the patients regarding improvement in acute manic

symptoms.

Safety and tolerability

Safety assessment was based on vital signs, clinical

laboratory tests and electrocardiogram (ECG). Vital

signs measurements were performed at regular

intervals of the clinical trial. Patients were examined

on all study days for any adverse events. Adverse

events observed by the investigator were recorded in

the adverse event profile performas.

Statistical analysis

Nominal and ordinal data were analyzed by

non-parametric tests, and time interval data were

analyzed by parametric tests. Fisher’s exact prob-

ability test was used to compare patient character-

istics and disease particulars in the two groups.

Chi-square and Mann�Whitney U-tests were used to

compare the data in these groups. The Friedman’s

two-way analysis of variance (ANOVA) was used for

ordinal data in related sample. The median test was

used to compare mean dose of rescue haloperidol in

the two groups.

Results

A total of 50 patients were randomly allocated to

receive verapamil (n�25) or lithium (n�25). The

demographics of the treatment groups were generally

similar at base line (Table I). In this study, male

patients (n�38, 76%) outnumbered female (n�12,

24%) patients. Majority of the patients were married

(n�36, 72%), were from rural background (n�29,

58%) and were illiterate. Disease characteristics were

similar in terms of family history of mood disorder

and BMRS and YMRS scores of all patients groups

at baseline. Family history of bipolar disorder was

present in 32% (n�16) of the total sample. All

randomized patients who received lithium or ver-

apamil comprised the intent to treat population.

There was no dropout in either group.

Mean baseline BRMS and YMRS scores were

comparable among both the groups (Table II). The

baseline mean BRMS score of the patient in lithium

treatment group was 22.44, which declined to 15.6

at the end of first week, to 11.56 at the end of day 13,

to 3.24 at the end of the fourth week. In the

verapamil treatment group, baseline BRMS score

was 23.44, at the end of first week this declined to

15.48 and 11.48 on day 13. At the end of study

BRMS score declined to 4.4 (Table III). BRMS and

YMRS score in both groups significantly decreased

with treatment over a period of 28 days (PB0.001).

A comparison of primary and secondary endpoints

between the two active treatments relative to each

other at days 7, 13, 28 showed similar improvements

in BRMS scores with verapamil and lithium therapy

at the assessment days. There was no statistically

significant difference in the efficacy measures be-

tween the two study groups (Table IV).

Table III. Comparison of Baseline BRMS and YMRS score.

Mania rating scale and group BRMS Mean (SD) Range Group Total Rank total Z value P value

1 (lithium) 22.44 (3.84) 17�31 561 571.0 1.28 �0.05 NS

2 (verapamil) 23.44 (3.29) 18�35 586 704.0

YMRS

1 (lithium) 26.68 (5.61) 16�40 667 722.5 1.64 �0.05 NS

2 (verapamil) 28.84 17�40 693 552.5

Table IV. Comparison of BRMS score on days 13 and 28.

Day and treatment group Mean (SD) Range Group total Rank total Z value P value

Day 13 Lithium 11.56 (2.53) 6�17 289 632.0 0.13 �0.05 N.S.

Day 13 Verapamil 11.48 (4.28) 3�17 287 643.0

Day 28 Lithium 3.24 (1.92) 1�10 81 726.0 1.697 �0.05 NS

Day 28 Verapamil 4.4 (2.57) 0�10 110 549.0

Verapamil vs lithium in mania 305

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Table V shows that the onset of improvement in

the two groups was from the 5th day onwards.

Similarly, there was no significant difference in

secondary endpoint (attendant’s assessment of im-

provement) on days 14 and 28 in the treatment

groups (Tables VI and VII).

Table VI shows the side effect profile of patients

receiving lithium carbonate and verapamil. In

lithium-treated patients; 20% patients had tremors,

12% had salivation and nausea and vomiting was

seen in 8% of the patients. In verapamil-treated

patients, 16% had constipation, 8% had tremors and

salivation was in 8% of the patients. This study also

evaluated the need for rescue haloperidol and antic-

holinergic medication in the verapamil- and lithium-

treated groups and the difference was not statistically

significant (P�0.05).

Discussion

In the present study, verapamil and lithium treat-

ment produced significant improvement in all effi-

cacy measures. Hence both verapamil and lithium

have been found to be effective for patients with

mania. There was no statistical significant difference

in the mean changes in BRMS and YMRS scores

throughout the study period. This finding narrates

that both drugs are equally effective. These results

are consistent with previous similar stu-

dies[4,7,18,19] Dosage schedule and treatment

procedure adopted in this study was similar to other

previous studies by Giannini et al. [18] and Du-

bovsky et al. [4,15].

Initial open and blind studies of verapamil were

positive in the treatment of acute mania.

Despite these positive reports, some studies failed

to demonstrate significant improvement on primary

efficacy measures [22,27]. The research design of

study conducted by Walton et al. [22] was single

blind. In contrast to these findings, the present study

was double-blinded and showed the antimanic

efficacy of verapamil. Giannini et al. [19], in a

double-blind study, reported that verapamil was

more effective than lithium as mood stabilizer. The

difference in efficacy of the present study from the

study conducted by Giannini et al. [19] could be

attributed to duration of the drug trial. Giannini

et al. [19] conducted a long-term study of 6 months

duration.

Another interesting finding of this study was that

both treatments verapamil and lithium have almost

similar onset of action. Both drugs showed signifi-

cant decrease in total BMRS scores from day 5

onwards. The present study is also in agreement with

other studies using a different calcium channel

blocker (nimodipine). It has been reported that

both lithium and nimodipine decreased the affective

disturbances in patients with rapid cycling bipolar

disorder [28].

In this study there was a trend showing more side

effects in group treated with lithium in comparison

to the verapamil group, but there was no statistically

significant difference in the side effects between the

two groups. No serious side effect was reported and

patients tolerated the trial medication well in both

the groups.

Calcium channel inhibitors share a number of

specific characteristics with lithium. In the cardiac

conduction system, both lithium and verapamil

decrease the spontaneous depolarization of the sinus

node and slow conduction through the AV node.

Lithium and verapamil have similar identical effects

on water metabolism, thyroid function and glucose

tolerance and blockage of a-adrenergic receptors.

Table V. Comparison of time to onset of decrease in BRMS score.

Group D a y 0 1 3 5 7 10 13 17 21 28

Lithium (Ri�Ru) 20 48 73* 97* 111.1* 144.5* 171* 197* 221.5*

Verapamil (Ri�Ru) 23 50.5 73.5* 101* 126* 146.5* 174.5* 188.5* 223.5*

(Ri�Ru )�difference in sum of ranks from baseline.

Cut off point ]57.58.

*Significantly different from baseline.

Table VI. Attendant’s assessment of improvement on 14th and 28th days.

Day 14 Day 28

Assessment of improvement

Group I N�25

N (%)

Group II N�25

N (%)

Group I N�25

N (%)

Group II N�25

N (%)

No improvement 0 0 0 0

25% improvement 15 (60) 11 (44) 1 (4) 0

50% improvement 9 (36) 11 (44) 7 (28) 8 (32)

75% improvement 1 (4) 3 (12) 12 (48) 13 (52)

Rank total 579.5 695.5 642.0 633.0

Z�1.1156 ; Z�0.0776.

P�0.05 (NS); P�0.05 (NS).

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Lithium and other mood-stabilizing agents seem to

work by regulating calcium ion hyperactivity.

The strength of the present study included a large

sample of 50 patients with established diagnosis of

mania with strict diagnostic criteria. Moreover, the

study was double-blind, randomized and controlled.

The study design permitted freedom to the clinician

to treat the patient in the best possible way. This is

the first Indian study comparing the clinical efficacy

of verapamil with lithium in acute mania. There was

homogeneity in sociodemographic and disease par-

ticulars in both groups. Standardized assessment

scales were used which had high inter-rater reliability

and assessments were done at regular intervals.

Adequate doses of medication, short duration of

trial and good response and highly acceptable

adverse effect profile may have ensured no dropout

rate. We started medication at a low dose and

increased stepwise. This may be an important reason

for the high number of patients who decided to

remain on the drug.

The limitations of the present study include

inability to monitor plasma levels of verapamil and

short duration without a crossover. In the present

study, crossover design was not employed because,

in this part of India, an adequate number of patients

was available for enrollment. Moreover, it would

have been unethical to retain patients in the ward for

a longer duration as the trial duration has to be long

in a crossover design. All the patients were inpatient

and therefore our findings may not be generalized to

an outpatient population. The study inclusion cri-

teria of the Bech�Raefelson Mania Rating Scale

score was on the lower side and barely enough to

assess the severity of the illness. This clinical trial is

not powered as a non-inferiority study, and is not

able to definitively state that the treatments are

equivalent. Thus, the findings of this study need to

be approached with considerable caution in view of

important limitations.

We recognize that our data are preliminary and

that this trial was prospectively powered to detect

differences between the therapeutic effects of lithium

and verapamil. The findings of this study should be

interpreted in the context of the research design.

Despite several limitations, our study suggests the

potential usefulness of verapamil in acute treatment

of mania. We presented the data as explicitly as

possible so that readers can formulate their own

interpretations.

In conclusion, verapamil and lithium treatment

produced significant improvement in all efficacy

measures. There was no significant difference in

treatment outcome and side effects between the

verapamil and lithium treatment groups over a

period of 28 days. Future work in the area needs to

explore the treatments with verapamil and further

studies are suggested to compare long term efficacy

by conducting long term studies.

Acknowledgements

The author acknowledges the following for guidance

and help in this research work: Dr Kuldip C.

Sharma; Professor and Head Department of Psy-

chiatry, Government Medical College and Hospital,

Patiala, Punjab, India; Dr Kiranjeet Kaur, Professor

and Head, Department of Biochemistry, Govern-

ment Medical College Patiala, India; Dr P.P. Khosla,

Assistant Professor, Department of Pharmacology,

Govertment Medical College, Patiala, India.

Key points

. First comparative study from India to assess

efficacy and tolerability of verapamil versus

lithium in treatment of mania

. Verapamil was well tolerated by all study sub-

jects

. There was no significant difference in treatment

outcome and side effects between the two

treatment groups (verapamil or lithium) over a

period of 4 weeks

References

[1] Tohen M, Tsuang MT, Goodwin DC. Prediction of out-

come in mania by mood-congruent or mood-incongruent

psychotic features. Am J Psychiatry 1992;/149:/1580�4.

[2] Dubovsky SL, Murphy J, Christianho J, Lee C. The calcium

second messenger system in bipolar disorders: data support-

ing new research directions. J Neuropsychiatry Clin Neurosci

1992;4:3�14.

[3] Czyrak A, Mogilnicka E, Siwanowicz J, May J. Some

behavioural effects of repeated administration of calcium

channel antagonists. Pharmacol Biochem Behav

1990;35:557�60.

[4] Dubovsky SL, Franks RD, Allen S, Murphy J. Calcium

antagonist in mania: a double-blind study of verapamil.

Psychiatry Res 1986;18:309�20.

[5] Dubovsky SL. Calcium antagonists as novel agents for

manic-depressive disorder. In: Schatberg AF, Nemeroff

CB, editors. Textbook of psychopharmacology. 2nd ed.

Washington, DC: American Psychiatric Press; 1998. p

455�69.

[6] Bowden CL, Huang LG, Javors MA, Johnson JM, Seleshi E,

McIntyre K, et al. Calcium function in affective disorders

and healthy controls. Biol Psychiatry 1988;/23:/367�76.

Table VII. Treatment-emergent side-effects.

Side effect

Lithium

N�25

Verapamil

N�25

Akathisia 3 (12) 1 (4)

Tremors 5 (20) 2 (8)

Rigidity 1 (4) 1 (4)

Salivation 3 (12) 2 (8)

Sedation 1 (4) 2 (8)

Nausea and vomiting 2 (8) 0 (0)

Diarrhea 1 (4) 0 (0)

Constipation 1 (4) 4 (16)

Glossitis 1 (4) 1 (4)

Sweating 2 (8) 0 (0)

Values in parentheses are percentages.

Verapamil vs lithium in mania 307

Int J

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ch C

lin P

ract

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

11/0

6/14

For

pers

onal

use

onl

y.

[7] Dubovsky SL, Franks RD. Intracellular calcium ions in

affective disorders: A review and a hypothesis. Biol Psychia-

try 1983;/18:/781�97.

[8] Walden J, Grunze H, Bingmann D, Liu Z, Dusing R.

Calcium antagonistic effects of carbamazepine as a mechan-

ism of action in neuropsychiatric disorders: studies in

calcium dependent model epilepsies. Eur Neuropsychophar-

macol 1992;2:455�62.

[9] Altrup U, Gerlach G, Reith H, Said MN, Speckmann EJ.

Effects of valproate in a model nervous system (buccal

ganglia of Helix pomatia): I. Antiepileptic actions. Epilepsia

1992;33:743�52.

[10] Wegerer JV, Hesslinger B, Berger M, Walden J. A calcium

antagonistic effect of the new antiepileptic drug lamotrigine.

Eur Neuropsychopharamacol 1997;/7:/77�81.

[11] Xie X, Hagan RM. Cellular and molecular actions of

lamotrigine: possible mechanisms of efficacy in bipolar

disorder. Neuropsychobiology 1998;/38:/119�30.

[12] Wang JF, Bown CD, Chen B, Young LT. Identification of

mood stabilizer-regulated genes by different-display PCR.

Int J Neuropsychopharmacol 2001;/4:/65�74.

[13] Smigan L. Long�term lithium treatment, some clinical,

psychological and biological aspects. Acta Psychiatr Scand

1985;/71:/160�70.

[14] Dubovsky SL, Buzan RD. Novel alternatives and supple-

ments to lithium and anticonvulsants for bipolar affective

disorders. J Clin Psychiatry 1997;/58:/224�42.

[15] Dubovsky SL, Franks RD, Lifschitz M. Effectiveness of

verapamil in the treatment of a manic patient. Am J

Psychiatry 1982;/139:/502�4.

[16] Brotman AW, Farhadi AM, Gelenberg AJ. Verapamil treat-

ment of acute mania. J Clin Psychiatry 1986;/47:/136�8.

[17] Barton BM, Gitlin MJ. Verapamil in treatment-resistant

mania:an open trial. J Clin Psychopharamacol 1987;/7:/980�2.

[18] Giannini AJ, Houser WL Jr, Loiselle RH, Giannini MC,

Price WA. Antimanic effects of verapamil. Am J Psychiatry

1984;/141:/1602�3.

[19] Giannini AJ, Taraszewski R, Loiselle RH. Verapamil and

lithium as maintenance therapy of manic patients. J Clin

Pharmacol 1987;/27:/980�2.

[20] Garza-Trevino ES, Overall JE, Hollister LE. Verapamil

versus lithium in acute mania. Am J Psychiatry 1992;/149:/

121�2.

[21] Hollister LE, Trevino ES. Calcium channel blockers in

psychiatric disorders: a review of the literature. Can J

Psychiatry 1999;/44:/658�64.

[22] Walton SA, Berk M, Brook S. Superiority of lithium over

verapamil in mania: a randomized controlled, single-blind

trial. J Clin Psychiatry 1996;/57:/543�6.

[23] World Health Organization. The ICD-10 Classification of

Mental and Behavioral Disorders; Clinical Descriptions and

Diagnostic Guidelines. Geneva; 1992.

[24] Bech P, Bolwig TG, Kramp P, Rafaelsen OJ. The Bech�Rafaelsen Mania scale and the Hamilton Depression Scale:

Evaluation of homogeneity and interobserver reliability. Acta

Psychiatr Scand 1979;/59:/420�30.

[25] Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale

for mania: Reliability, validity and sensitivity. Br J Psychiatry

1978;/133:/429�35.

[26] Varley H, ed. Practical clinical biochemistry, 4th ed. New

Delhi: Arnold-Heineman; 1975.

[27] Janicak PG, Sharma RP, Pandey G, Davis JM. Verapamil for

the treatment of acute mania: a double-blind, placebo

controlled trial. Am J Psychiatry 1998;/155:/972�3.

[28] Goodnick P. Nimodipine treatment of rapid cycling bipolar

disorder [letter]. J Clin Psychiatry 1995;/56:/330.

308 G.P. Singh

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ch C

lin P

ract

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nloa

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info

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ealth

care

.com

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Uni

vers

ity o

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