Brit. 3. Psychiat. (1976), 528, 384—90

Plasma Concentrations of Protriptyline and Clinical Effects in Depressed Women By S. F. WHYTE, Summary.

A. J. MACDONALD,

We studied

the relationship

G. J. NAYLOR between

side effects,

and the drug plasma levels in 28 female depressed triptyline.

After 3@weeks treatment,

patients

and J. P. MOODY

patients

with plasma

clinical

outcome

treated

with pro

levels within

a median

range (630 to 900 nmol/l) showed better responses to the drug than patients with plasma

levels outside

this range.

There were no statistically

significant correlations

between plasma levels and

side effect scores or ‘¿corrected' side effect scores (scores after subtracting pre treatment values) for the group at any time after starting the treatment. But we

found positive correlations between plasma levels and ‘¿corrected'side effect scores for the neurotic subgroup after 14 and 21 days of treatment. Other correlations between plasma levels and side effect scores were non-significant.

INTRODUCTION

For several years there has been considerable interest in means of monitoring the effects of antidepressant

drugs in order to obtain

optimum

therapeutic results. Nortriptyline has probably been more fully investigated than the other tricyclic

antidepressants.

SjOqvist

and

co

workers (1971) have demonstrated a fairly wide range of drug metabolizing abilities for nortriptyline

in

humans

and

also

a

ments

plasma

levels

in depressives

of clinical

improvement

in the patients

under investigation were also made. The rela tionship between these measures and plasma

fairly

wide range in the steady state plasma levels encountered during therapy. Clinical studies from this group indicate that the plasma levels of nortriptyline may have some clinical signi ficance. Asberg and co-workers (1970) found that during the treatment of depression the corrected subjective side effects scores correlate with the plasma concentrations of nortriptyline during the first three weeks of therapy. Other investigations into the relationship between nortriptyline

Burrows and co-workers (1972), however, could find no differences in the nortriptyline plasma levels between responders and non-responders. This present study was an attempt to repli cate the findings of the Scandinavian workers concerning the relationship between plasma levels and subjective side effects, using a very closely related drug, protriptyline. Some assess

levels after 3@ weeks of treatment

has also been

examined. MATERIALS

AND METHODS

Over a period of i o months 33 female in patients aged between i6 and 69 years, who were suffering from a depressive illness and in the judgement of a consultant psychiatrist required antidepressant treatment, took part in the

and

investigation.

At

the

start

no patient

therapeutic outcome (Asberg et al, 1971; Kragh-Sorensen et al, 1973) indicate that an

suffered from a concurrent

optimum

subjects were withdrawn at an early stage and at the end of the study two others were excluded for infringing experimental protocols. Before treatment began there was an initial

clinical

response

to the drug

all were in a satisfactory

may be

associated with a fairly narrow range cf steady state plasma levels. The results of Braithwaite and co-workers (1972) using amitriptyline lend qualified support to these findings.

7-day 384

period

physical illness, and

nutritional

of observation.

During

state. Three

this

time

BY

all

psychotropic

S. F. WHYTE,

A. J. MACDONALD,

medication

was

withdrawn

and where sedation was necessary patients were allocated

day and/or

night

sedation

with mtra

zepam (5—60mg/day) or sodium amylobarbi tone (Ioo—300 mg/day) on a random basis. This

sedation

was continued

for the duration

of the study. Some other drugs were prescribed during the investigation ; these were mostly @ occasional laxatives. In two cases antibiotics were used to treat urinary tract infections, and in another case a single emergency dose of chiorpromazine was given. Protriptyline was administered orally at a starting dose of 10 mg twice daily (io.oo am and 6.oo pm) for three days, after which the dose was increased to so mg four times daily

(io.oo am, 2.00 pm, 6.oo pm and io.oo pm) for at least the next three weeks. During time

clinical

assessments

and

this

laboratory

in

vestigations were performed. Symptoms identical with the known side effects of the drug were rated on a three-point scale by two members of the medical staff (S.F.W. and A.J.M.), using a 28-item check list (Table I) during formal interrogation, before starting protriptyline, vals for a total period

and at twice weekly inter of 24 days. Before starting

protriptyline, patients were assigned to one of three diagnostic categories (depressive psychosis, lCD

296.2,

uncertain,

depressive

neurosis

using criteria

lCD

described

ci al, ‘¿97')and a global assessment improvement on a four-point scale

300.4,

and

by Naylor of clinical was made

G. J. NAYLOR

AND

38@

J. P. MOODY

the side effect scores of the two ratings at each interview were simply totalled. Similarly the five global assessments were summed for each subject to give a composite score. Samples of 20 ml of venous blood were obtained

at

9.30

am

before

drug

therapy

started and at twice-weekly intervals on the same day as the rating interview. These specimens were anticoagulated with o 2 ml 10

per

cent

siliconed centrifuged,

(w/v)

glass and

disodium

sequestrate

centrifuge

tubes

duplicate

4 ml

in

and

then

aliquots

of

plasma were stored in 20 ml stoppered amber glass test tubes at —¿ 15 °Cpending analysis. Routine plasma samples were analysed as described

previously

(Moody,

Whyte

and

Naylor, 1973) along with a quality control specimen. Each plasma was analysed on two separate occasions and the results were averaged. Under operational conditions the precision of the method was ±5°nniolf 1. RESULTS

Plasma levels The mean protriptyline plasma levels for the 28 subjects of this investigation are shown in Table II. The plasma concentrations increased TABLE

II

Protrip@ylineplasma levels encowiteredduring therapy (io mgfour times dali,)

(nmol/l)SE3iio673912!10528281466537577183821 plasma level DaysMean

individually by three members of the medical staff and two members of the nursing staff after 24 days on the drug. For statistical purposes TABLE I

Side effects check list

CNS CVS

Tremor, Dystonia, Ataxia, Numbness

GI

Tachycardia, Postural hypotension Nausea, Epigastric pain, Bad taste, Dry mouth, Constipation

GU

Urinary

retention

Allergic

Skin reactions, Pruritus, Petechiae,

Psychomotor

Urticaria Restlessness, Excitement, Apprehen sion, Tiredness, Weakness, Confusion,

Miscellaneous

Blurred vision, Glaucoma, Sublingual

Drowsiness,

Insomnia

adenitis, Perspiration

8o843

24795

47

in all subjects during the period of study to reach values ranging from 400 to I ,430 nmol/l after 24 days of treatment. This comprises a 3ffold variability in the 24-day plasma level, which is comparable with the 5-fold range reported by Kragh-Sorensen and co-workers (‘973) for

nortriptyline

plasma

levels

in

30

female depressives after four weeks treatment. The 24-day plasma levels of protriptyline did

386 PLASMACONCENTRATIONSOF PROTRIPTYLINE AND CLINICAL EFFECTS IN DEPRESSEDWOMEN not correlate

with

age or diagnosis.

TABLE HI

Moreover,

Clinical response to treatment with protriptyline

weight had only a marginal effect on the plasma concentration. Night sedation may have in fluenced the results, because the mean plasma levels of protriptyline for the sodium amylo barbitone group were lower than the mean values for the nitrazepam and no-sedative

groups. A surprising 19 out

of

28

subjects

observation achieved

steady

presented

attributed protriptyline paration).

to

elsewhere

that

54—20 8—13

2—7

(Modechange)Depressive

state

this contrasts

sharply with the general findings of the Swedish workers (Sjoqvist et al, 197 i). Evidence is to

be

Diagnosis

(Good)

0—I

(No

rate)

(Poor)

was that only the

in the 3@ weeks of investigation;

Global score

this

may

be

the length of the half life of in man (Moody et al, in pre

psychosis

(‘5)

2

3

9

1

(8) (5)

2 2

3 2

3

0

(28)

6

8

12

Depressive neurosis Uncertain oTotal 220 group

Clinical response

@

The overall outcome of the treatment of patients with protriptyline is shown in Table III. Approximately half the patients showed a good or moderate response while receiving the drug. According to diagnosis, the de pressive psychosis group seemed to fare least well on protriptyline, two-thirds of the subjects showing a poor response or showing no change after

clinical @ @

@

3@

weeks.

However,

response between

and the combined groups did not reach

the

difference

the psychotic

neurotic statistical

plasma

S

I@.

,

‘¿C

in

and uncertain significance.

between the 24-day

plasma levels and the global improvement scores. When the subjects are divided equally into good responders (scores 8—20) and poor responders (scores 0—7) the latter have higher

mean

x

group

The relationship between plasma levels and clinical response The relationship between the 24-day plasma level and the global improvement score is shown in Fig. I . The rank order correlation coefficient (r = —¿o424, p < 0 -05) suggests

a weak inverse relationship

x

8

it24 DAYPLASMA LEVEL

FIG. i.—The

relationship

between

I

the

24 day plasma

level and the global improvement score. TABLE IV

Protriptyline plasma levelsfor good responderst and poorresponderstt

DayGoodrespondersPoorrespondersMeanSDNMeanSDN3500271412030147

levels than the good responders

(Table IV). More noteworthy are the differences in the standard deviations of plasma levels between these groups. The variance of the poor responders is statistically significantly greater than the variane of the good responders from

one week's treatment onwards. The data seem to be analogous to the curvilinear relationship

t Globalimprovement scores 8—20. .tt Globalimprovementscores0—7. * **

p