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REVIEW ARTICLE |
Department of Psychological Medicine, Institute of Psychiatry, London, and Istituto di Ricerche Farmacologiche "Mario Negri" Milan, and Dipartimento di Medicina e Sanità Pubblica, Sezione di Psichiatria, Università di Verona, Italy
Department of Psychological Medicine, Guy's, King's and St Thomas' Schools of Medicine, and Institute of Psychiatry, London
Correspondence: Dr Corrado Barbui, Istituto di Ricerche Farmacologiche "Mario Negri", Via Eritrea 62, 20157 Milano, Italy. Tel: 0039 02 39014 431; fax: 0039 02 33 2000 49; e-mail: barbui{at}marionegri.it
See editorial, pp. 99-100,
this issue. 
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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Aims To review the tolerability and efficacy of amitriptyline in the management of depression.
Method A systematic review of randomised controlled trials (RCTs) comparing amitriptyline with other tricyclics/heterocyclics or with an SSRI.
Results We reviewed 186 RCTs. The overall estimate of the efficacy of amitriptyline revealed a standardised mean difference of 0.147 (95% CI 0.05-0.243), significantly favouring amitriptyline. The overall OR for dropping out was 0.99 (95% CI 0.91-1.08) and that for side-effects was 0.62 (95% CI 0.54-0.70), favouring the control drugs. With drop-outs included as treatment failures, the estimate of the effectiveness of amitriptyline v. tricyclics/heterocyclics and SSRIs showed a 2.5% difference in the proportion of responders in favour of amitriptyline (number needed to treat 40, CI 21-694; OR 1.12 (95% CI 1.01-1.24)).
Conclusions Amitriptyline is less well tolerated than tricyclics/heterocyclics and SSRIs, but slightly more patients treated on it recover than on alternative antidepressants.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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Search strategy
Relevant studies were located by searching the Cochrane Collaboration
Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR). This
specialised register is regularly updated by electronic (Medline, Embase,
PsycINFO, LILACS, Psyndex, CINAHL, SIGLE) and non-electronic literature
searches. The register was searched using the following terms:
AMITRIPTYLIN* or AMITRIL or ELATROL or
ELAVIL or EMITRIP or ENDEP or ENOVIL or
LAROXYL or LENTIZOL or LEVATE or MEVARIL
or NOVOTRIPTYN or SAROTEN or TRYPTAL or
TRYPTIZOL or TRIPTAFEN*. A specific electronic search was
also performed with Medline and Embase from 1966 to 1998. We used the search
term: AMITRIPTYLINE and RANDOMISED CONTROLLED TRIAL or
RANDOM ALLOCATION or DOUBLE-BLIND METHOD. Reference lists of relevant
papers and previous systematic reviews were hand searched for published
reports and citations of unpublished research. Finally, attempts were made to
obtain data through direct contact with the pharmaceutical industry.
Outcomes
Efficacy was evaluated using the following outcome measures:
sberg Depression Scale
(MADRS; Montgomery &
sberg, 1979), or any other
depression scale. Tolerability was evaluated using the following outcome measures:
Data extraction
Using a standard form two reviewers independently extracted information on
the year of publication, concealment of allocation, blindness, length of
treatment, inclusion criteria, age range, country and setting of the study and
type of pharmacological intervention. The number of patients undergoing the
randomisation procedure, the number of patients who failed to complete the
study (drop-outs) and that of patients complaining of side-effects were
recorded. For dichotomous outcomes the number of patients showing a 50%
reduction in score on the HDRS or MADRS scale was extracted; if these figures
were not available, we extracted the number of patients categorised as
‘much improved’ and ‘improved’ on the Clinical Global
Impression scale (CGI; Guy,
1976), or the number of patients in the corresponding categories
of any other rating scale if the CGI was not used. For continuous outcomes the
mean scores at end-point on the HDRS and the number of patients included in
this analysis were recorded. If the HDRS was not employed, we extracted the
mean scores at end-point on the MADRS or on any other rating scale. Mean
scores were recorded with the standard deviation (s.d.) or standard error
(s.e.) of these values. When only the s.e. was reported, it was converted into
s.d. according to Altman & Bland
(1996).
Statistical analysis
Efficacy data were analysed in the following way. Responders to treatment
were calculated on an intention-to-treat (ITT) basis: drop-outs were always
included in this analysis. When data on drop-outs were carried forward and
included in the efficacy evaluation (last observation carried forward, LOCF),
they were analysed according to the primary studies; when drop-outs were
excluded from any assessment in the primary studies they were considered as
‘drug failures’. Scores from continuous outcome scales could not
be analysed on an ITT basis. This approach was not feasible as most studies
performed only an end-point or LOCF analysis, which inevitably excluded most
drop-out patients. Therefore, scores from continuous outcomes were analysed on
an end-point basis, including only patients with a final assessment or with an
LOCF to the final assessment. Tolerability data were analysed by calculating
the proportion of patients who failed to complete the study and who
experienced adverse reactions out of the total number of randomised patients.
For each outcome measure three separate meta-analyses were planned. The first
compared amitriptyline with tricylic/heterocyclic antidepressants, the second
amitriptyline with SSRIs and the third analysis summarised the overall
comparison of amitriptyline with both tricyclic/heterocyclic drugs and
SSRIs.
Dichotomous outcomes were summarised by calculating a Peto-weighted odds
ratio for each study, together with the 95% CI. An overall odds ratio was then
calculated as a summary measure. The number of patients who need to be treated
(NNT) with amitriptyline rather than the control antidepressants for one
additional patient to benefit (NNTB) or be harmed (NNTH) was calculated with
the 95% CI (Altman, 1998).
Heterogeneity of treatment effects between studies was tested using the
2 statistic. Continuous outcomes were analysed by calculating
a standardised weighted mean difference (SMD) for each study. This measure
gives the effect size of an intervention in units of standard deviation so
that scores from different outcome scales can be combined into an overall
estimate of effect. A random effects model, which takes into consideration any
between-study variation, was adopted to combine the effect sizes. Calculations
were performed using the RevMan software provided by the Cochrane
Collaboration (Review Manager,
1999).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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Although all trials reported that patients had been randomly allocated, in six cases the concealment of allocation was inadequate with some bias possible. In four studies only physicians, but not patients, were blind to treatments, in nine cases neither physicians nor patients were blind, while the other 173 studies were double-blind. The median sample size was 50 patients (10% percentile 24, 25% percentile 40, 75% percentile 80, 90% percentile 153; range 10-531). The median length of trials was four weeks (25% percentile 4, 50% percentile 4, 75% percentile 6; range 3-12); the number of studies with more than four weeks of follow-up increased from 28 (30%) to 62 (67%) after 1980. In 67 trials (36%) authors adopted diagnostic criteria and a specification of severity of depression to enrol patients; in 55 trials (30%) authors adopted only a specification of severity, while in the remaining 34% of studies patients were enrolled on the basis of physicians' implicit criteria to define patients with depression or because they were judged to require antidepressant therapy. Fifty-nine per cent of studies published before 1980 used implicit criteria v. 9.6% of those published after this date. Overall, 108 trials (60%) used operational criteria for depression. Nearly half of the studies (47%) provided a comprehensive description of patients' side-effects, while 23 (12%) trials gave inadequate details. The outcome assessment was performed with valid and reliable instruments in 70% of the sample; the use of valid instruments in studies published before and after 1980 increased from 51 (55%) to 81 (86%).
Efficacy of amitriptyline
Data extracted from 82 RCTs showed that the proportion of patients who
responded to amitriptyline was 2.4% higher than for control TCA/heterocyclic
antidepressants (NNTB 42, 95% CI NNTH 357 to 
to NNTB 20) (see
Table 2). This difference
corresponds to an overall odds ratio which favoured amitriptyline (Peto odds
ratio 1.11, 95% CI 0.99-1.25), but with only borderline statistical
significance. The estimate of the efficacy of amitriptyline and control
TCAs/heterocyclic antidepressants on a continuous outcome, performed on 699
and 661 patients respectively, revealed an effect size which also
significantly favoured amitriptyline (SMD=0.177, 95% CI 0.005-0.350).
Head-to-head comparisons indicated that amitriptyline, in comparison with
imipramine, is associated with a greater proportion of responders; in
comparison with dothiepin, however, the proportion of responders was
significantly lower (see Table
2).
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Data from 17 RCTs showed that the proportion of patients who responded to
amitriptyline was 2.8% higher than for SSRIs (NNTB 35, 95% CI NNTH 53 to
to NNTB 13) (see Table
3). This difference corresponded to an overall odds ratio which
favoured amitriptyline (Peto odds ratio 1.14, 95% CI 0.92-1.38), but not
significantly. The estimate of the efficacy of amitriptyline and SSRIs on a
continuous outcome, performed on 1041 and 1061 patients, respectively,
revealed a small effect size which significantly favoured amitriptyline
(SMD=0.106, 95% CI 0.02-0.19). No significant differences emerged from direct
comparisons between amitriptyline and one of the SSRIs (see
Table 3).
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Tolerability of amitriptyline
Data from 125 RCTs showed that 20% of patients treated with amitriptyline
failed to complete the study, in comparison with 21.5% of patients who
received another tricyclic/heterocyclic antidepressant (NNTB=69, 95% CI NNTH
385 to to NNTB 32). This difference corresponded to an overall odds
ratio non-significantly favouring amitriptyline (Peto odds ratio 1.09, 95% CI
0.98-1.22) (see Table 4).
However, the estimate of the proportion of patients who experienced
side-effects during the study was 13% higher for amitriptyline than for
control TCAs/heterocyclic antidepressants (NNTH=7.6, 95% CI NNTH 6 to NNTH 11)
(see Table 4), corresponding to
an odds ratio which significantly favoured the control TCAs/heterocyclic
antidepressants. Head-to-head comparisons failed to detect statistically
significant differences in terms of drop-outs between amitriptyline and one of
the TCA/heterocyclic antidepressants (see
Table 4). However,
amitriptyline was associated with more side-effects than dothiepin,
maprotiline, mianserin, minaprine and nortriptyline (see
Table 4).
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Data from 40 RCTs comparing amitriptyline and SSRIs showed that 29.8% of
patients treated with amitriptyline failed to complete the study, in
comparison with 27.7% of patients treated with SSRIs (NNTH=49, 95% CI NNTB 180
to to NNTH 22). This difference corresponds to an overall odds ratio
of 0.86 (95% CI 0.75-0.98), which significantly favoured SSRIs (see
Table 5). The estimate of the
proportion of patients who experienced side-effects during the study was 11.6%
higher for amitriptyline than for SSRIs (NNTH=8.6, 95% CI NNTH 6 to NNTH 15)
(see Table 5), corresponding to
an odds ratio which significantly favoured the SSRIs.
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Overall efficacy and tolerability of amitriptyline in comparison with
all antidepressant drugs
A funnel plot (Fig. 1)
showed no evidence of publication bias being a problem in the data collected.
The overall estimate of the efficacy of amitriptyline in comparison to
TCAs/heterocyclic drugs and SSRIs showed a 2.5% difference in the proportion
of responders in favour of amitriptyline (NNTB=40, 95% CI NNTB 21 to NNTB 694)
(see Fig. 2), which
corresponded to an intention to treat odds ratio of 1.12 (95% CI 1.01-1.24).
The estimate of the efficacy of amitriptyline and control antidepressants on a
continuous outcome confirmed the slightly superior efficacy profile of
amitriptyline: the estimate of the SMD significantly favours amitriptyline
(see Fig. 2).
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The drop-out rate in patients taking amitriptyline and the control antidepressants was very similar, yielding an overall odds ratio of 0.99 (95% CI 0.91-1.08). However, the estimate of the proportion of patients who experienced side-effects during the study was 13.1% higher for amitriptyline than control antidepressants (NNTH=7.6, 95% CI NNTH 6 to NNTH 10), corresponding to an odds ratio which significantly favoured the control antidepressants (see Fig. 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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Methodological concerns
There are reasons for interpreting these results with caution. Included
studies are heterogeneous in terms of selection criteria, allocation
concealment, setting and out-come measures. A certain variability in the
overall quality of the primary research might therefore have influenced the
overall comparison. This systematic review did not investigate heterogeneity
by grouping trials according to patient characteristics or trial quality and
performing subgroup analyses. This approach was not adopted because it would
have inevitably decreased the power of the analysis, thus providing ambiguous
results; in addition, increasing the number of comparisons would have
increased the possibility of detecting significant differences only by chance.
The present analysis, which pools data from different trials carried out in
many populations, has the advantage of generating information which can be
applied to a very diverse range of patients
(Oxman et al,
1994).
Implications for practice
How should these data be translated into clinical practice? It certainly
seems reasonable to conclude that amitriptyline is as good as — if not
better than — the other TCAs and heterocyclic antidepressants, with the
possible exception of dothiepin (Eccles
et al, 1999). It seems reasonable to suggest that either
amitriptyline or dothiepin should remain the first-line TCA. More
controversial is the role of TCAs alongside SSRIs. The results from randomised
trials suggest that amitriptyline probably has the edge in terms of efficacy
over SSRIs. Given that publication bias is likely to work in favour of newer
compounds, it is possible that unpublished data would further improve
amitriptyline's position. Those who advocate first-line use of an SSRI point
to two additional strands of evidence — the danger of TCAs in overdose
and the fact that they are often in practice prescribed at sub-therapeutic
doses. Although the widespread prescribing of SSRIs has to be viewed as a
public health measure to prevent suicide, it is likely to be prohibitively
expensive; in addition, data showing that the widespread use of SSRIs
decreases suicide rates are lacking (Barbui
et al, 1999). The advice should probably remain that
SSRIs are the first-line treatment to be given to patients at high risk of
committing deliberate self-harm. The problems of TCAs being prescribed in low
doses has attracted considerable attention, as evidence suggests that in real
situations TCAs are rarely taken appropriately. However, the guidelines on
‘adequate’ dosing — which suggest at least 125 mg of
amitriptyline have to be prescribed for it to be effective — are
themselves based on inadequate research. Recent systematic reviews indicate
that low-dose TCAs are as effective as SSRIs in treating depression
(Canadian Coordinating Office for Health
Technology Assessment, 1997a), and studies directly
comparing low- and high-dose TCAs show only very modest benefits of high doses
(Bollini et al,
1999).
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Clinical Implications and Limitations |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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Altman, D. G. (1998) Confidence intervals for
the number needed to treat. British Medical Journal,
317,
1309-1312.
Anderson, I. M. & Tomenson, B. M. (1995)
Treatment discontinuation with selective serotonin reuptake inhibitors
compared with tricyclic antidepressants: a meta-analysis. British
Medical Journal, 310,
1433-1438.
Barbui, C., Campomori, A., D'Avanzo, B., et al (1999) Antidepressant drug use in Italy since the introduction of SSRIs: national trends, regional differences and impact on suicide rates. Social Psychiatry and Psychiatric Epidemiology, 34, 152-156.[CrossRef][Medline]
Bollini, P., Pampallona, S., Tibaldi, G., et al
(1999) Effectiveness of antidepressants. Meta-analysis of
dose-effect relationships in randomised clinical trials. British
Journal of Psychiatry, 174,
297-303.
Canadian Coordinating Office for Health Technology Assessment (1997a) Selective Serotonin Reuptake Inhibitors (SSRIs) for Major Depression. Part I. Evaluation of the Clinical Literature. Ottawa: Canadian Coordinating Office for Health Technology Assessment.
Canadian Coordinating Office for Health Technology Assessment (1997b) Selective Serotonin Reuptake Inhibitors (SSRIs) for Major Depression. Part II. The Cost-Effectiveness of SSRIs in Treatment of Depression. Ottawa: Canadian Coordinating Office for Health Technology Assessment.
Eccles, M., Freemantle, N. & Mason, J.
(1999) North of England Evidence-Based Guideline Development
Project: summary version of guidelines for the choice of antidepressants for
depression in primary care. Family Practice,
16,
103-111.
Garattini, S., Barbui, C. & Saraceno, B. (1998) Antidepressant agents: from tricyclics to serotonin reuptake inhibitors. Psychological Medicine, 28, 1169-1178.[CrossRef][Medline]
Guy, W. (1976) ECDEU Assessment Manual for Psychopharmacology. DHEW Pub. No. (ADM)76-338. Rockville, MD: National Institute of Mental Health.
Hamilton, M. (1960) Arating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56-62.
Hotopf, M., Lewis, G. & Normand, C. (1996)
Are SSRIs a cost-effective alternative to tricyclics? British
Journal of Psychiatry, 168,
404-409.
Hotopf, M., Hardy, R. & Lewis, G. (1997)
Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-analysis
and investigation of heterogeneity. British Journal of
Psychiatry, 170,
120-127.
Montgomery, S. A. & sberg,
M. (1979) A new depression scale designed to be sensitive to
change. British Journal of Psychiatry,
134,
382-389.
Montgomery, S. A. & Kasper, S. (1995) Comparison of compliance between serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. International Clinical Psychopharmacology, 9 (suppl. 4), 33-40.
Oxman, A. D., Cook, D. J. & Guyatt, G. H. (1994) Users' guides to the medical literature. IV. How to use an overview. Journal of the American Medical Association, 272, 1367-1371.[CrossRef][Medline]
Review Manager (RevMan) (1999) Version 4.0 for Windows. Oxford: Cochrane Collaboration.
Song, F., Freemantle, N., Sheldon, T. A., et al (1993) Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. British Medical Journal, 306, 683-687.
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APPENDIX: Potentially relevant studies identified by the electronic search and subsequently excluded from the meta-analysis |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCESAPPENDIX: Potentially relevant...APPENDIX: Randomised controlled... |
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Abram, H. C., Kanter, V. B., Rosen, I., et al (1963) A controlled clinical trial of imipramine (Tofranil) with out-patients. British Journal of Psychiatry, 109, 286-293.
Altamura, A. C., Mauri, M. C., Colacurcio, F., et al (1988) Trazodone in late-life depressive states: a double-blind multicentre study versus amitriptyline and mianserin. Psychopharmacology, 95, S34-S36.
Angst, J. (1963) Vergleich der antidepressiven eigenschaften von amitriptylin und imipramin. Psychopharmacologia, 4, 389-401.[CrossRef]
Anonymous (1971) Multihospital controlled comparison of the therapeutic effects of four antidepressants. Activitas Nervosa Superiora, 13, 166-167.
Anton, R. F. & Burch, E. A. (1993) Response of psychotic depression subtypes to pharmacotherapy. Journal of Affective Disorders, 28, 125-131.[CrossRef][Medline]
Arfwidsson, L., d'Elia, G., Laurell, B., et al (1972) Comparison of chlorimipramine and imipramine in ambulatory treatment of depression. Acta Psychiatrica Scandinavica, 48, 367-376.[Medline]
Bagheri, H., Picault, P., Schmitt, L., et al (1994) Pharmacokinetic study of yohimbine and its pharmacodynamic effects on salivary secretion in patients treated with tricyclic antidepressants. British Journal of Clinical Pharmacology, 37, 93-96.[Medline]
Bagheri, H., Schmitt, L., Berlan, M., et al (1997) A comparative study of the effects of yohimbine and anetholtrihione on salivary secretion in depressed patients treated with psychotropic drugs. European Journal of Clinical Pharmacology, 52, 339-342.[CrossRef][Medline]
Baldini, J. T. & Neary, E. R. (1970) Controlled trials of an amitriptyline—fluphenazine combination in depressive neuroses and psychoses: a collaborative study. Current Therapy Research, 12, 84-93.
Ball, J. R. B. & Kiloh, L. G. (1959) A controlled trial of imipramine in treatment of depressive states. British Medical Journal, 2, 1052-1055.
Ban, T. A., Fujimori, M., Petrie, W. M., et al (1982) Systematic studies with amoxapine, a new anti-depressant. International Pharmacopsychiatry, 17, 18-27.[Medline]
Baumann, U., Eckmann, F. & Stieglitz, R. D. (1985) Self-rating data as a selecting factor in clinical trials of psychotropic drugs. European Archives of Psychiatry and Neurological Sciences, 235, 65-70.[CrossRef][Medline]
Bercel, N. A. (1967) Clinical trial of protriptyline. International Journal of Neuropsychiatry, 3, 365-378.[Medline]
Beresewicz, M., Bidzinska, E., Koszewska, I., et al (1991) Results of using tricyclic antidepressive drugs in the treatment of endogenous depression (comparative analysis of seven drugs). Psychiatria Polska, 25, 13-18.
Bergener, M. (1968) L'application du test de "randomization" en pharmaco-psychiatrie. Evolution Psychiatrique, 33, 707-720.
Bialos, D., Giller, E., Jatlow, P., et al
(1982) Recurrence of depression after discontinuation of
long-term amitriptyline treatment. American Journal of
Psychiatry, 139,
34-38.
Blaine, G. (1975) Double-blind comparison of doxepin and amitriptyline in depressed menopausal outpatients receiving estrogen replacement therapy. In Sinequan (Doxepin HCl) (ed. J. Mendels), pp. 43-50. Amsterdam: Excerpta Medica.
Blashki, T. G., Mowbray, R. & Davies, B. (1971) Controlled trial of amitriptyline in general practice. British Medical Journal, 1, 133-138.
Bolzani, L. & Slivar, G. (1967) Clinical study of an anxiolytic antidepressive drug. Psychiatria et Neurologia, 153, 301-307.[Medline]
Bowden, C. L., Koslow, S., Maas, J. W., et al (1987) Changes in urinary catecholamines and their metabolites in depressed patients treated with amitriptyline or imipramine. Journal of Psychiatry Research, 21, 111-128.
Branconnier, R. J., Cole, J. O. & Ghazvinian, S. (1981) The therapeutic profile of mianserin in mild elderly depressives. Psychopharmacology Bulletin, 17, 129-130.
Brick, H., Doub, W. H. & Perdue, W. C. (1965) A comparison of the effects of amitriptyline and protriptyline on anxiety and depressive states in female prisoners. International Journal of Neuropsychiatry, 1, 325-336.[Medline]
Brown, W. A., Haier, R. J. & Qualls, C. B. (1980) Dexamethasone suppression test identifies subtypes of depression which respond to different antidepressants. Lancet, i, 928-929.
Browne, M. W., Kreeger, L. C. & Kazamias, N. G. (1963) A clinical trial of amitriptyline in depressive patients. British Journal of Psychiatry, 109, 692-694.
Burch, J. E., Ahmed, O., Hullin, R. P., et al (1988) Antidepressive effect of amitriptyline treatment with plasma drug levels controlled within three different ranges. Psychopharmacology Berlin, 94, 197-205.[Medline]
Burgess, C. D., Montgomery, S., Wadsworth, J., et al (1979) Cardiovascular effects of amitriptyline, mianserin, zimelidine and nomifensine in depressed patients. Postgraduate Medical Journal, 55, 704-708.[Abstract]
Casper, R. C. (1994) The pattern of physical symptom changes in major depressive disorder following treatment with amitriptyline or imipramine. Journal of Affective Disorders, 31, 151-164.[CrossRef][Medline]
Chaplan, A. (1975) Doxepin in anxious/depressed outpatients with gastrointestinal symptoms: double-blind comparison of doxepin and perphenazine/amitriptyline. In Sinequan (Doxepin HCl) (ed. J. Mendels), pp. 32-42. Amsterdam: Excerpta Medica.
Charney, D. S., Heninger, G. R. & Sternberg, D. (1984a) Serotonin function and mechanisms of action of antidepressant treatment. Effects of amitriptyline and desimipramine. Archives of General Psychiatry, 41, 359-365.[Abstract]
Charney, D. S., Heninger, G. R. & Sternberg, D.
(1984b) The effect of mianserin on alpha-2
adrenergic receptor function in depressed patients. British Journal
of Psychiatry, 144,
407-416.
Claghorn, J. L., Schroeder, J. & Goldstein, B. J. (1984) Comparison of the electrocardiographic effect of dothiepin and amitriptyline. Journal of Clinical Psychiatry, 45, 291-293.[Medline]
Collard, J., Dufrasne, M., Fraipont, J., et al (1978) Un nouvel agent antidepressif: la dothiepin. Revue Médicale de Liège, XXXIII, 275-279.
Cooke, R. G., Warsh, J. J., Stancer, H. C., et al (1984) The non-linear kinetics of desipramine and 2-hydroxydesipramine in plasma. Clinical Pharmacology and Therapeutics, 36, 343-349.[Medline]
Coppen, A. (1978) Amitriptyline plasma-concentration and clinical effect. A World Health Organization Collaborative Study. Lancet, i, 63-66.[CrossRef]
Coppen, A., Gupta, R., Montgomery, S., et al
(1976) Mianserin hydrochloride: a novel antidepressant.
British Journal of Psychiatry,
129,
342-345.
Coppen, A., Gupta, R., Montgomery, S., et al (1987) A new antidepressant agent. Mianserin hydrochloride. Zeitschrift für Allgemein-medizine, 54, 1569-1573.
Croughan, J. L. (1988) Sociodemographic and prior clinical course characteristics associated with treatment response in depressed patients. Journal of Psychiatry Research, 22, 227-237.
Davidson, J., McLeod, M., LawYone, B., et al (1978) A comparison of electroconvulsive therapy and combined phenelzine—amitriptyline in refractory depression. Archives of General Psychiatry, 35, 639-642.[Abstract]
De Montigny, C., Cournoyer, G., Morissette, R., et al (1983) Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Archives of General Psychiatry, 40, 1327-1334.[Abstract]
Denker, S. J. (1971) Behandlingsforsok med imipramin-N-oxid och amitriptylin-N-oxid. Nordisk Psykiatrisk Tidsskrift, 25, 463-470.
Elwan, O., Taher, Y., Allam, M., et al (1976) A comparative study of antidepressants in the treatment of depressive states. Journal of International Medical Research, 4, 202-210.
Fernstrom, M. H. & Kupfer, D. J. (1988) Antidepressant-induced weight gain: a comparison study of four medications. Psychiatry Research, 26, 265-271.[CrossRef][Medline]
Friedel, R. O., Veith, R. C., Bloom, V., et al (1979) Desipramine plasma levels and clinical response in depressed outpatients. Communications in Psychopharmacology, 3, 81-87.[Medline]
Friedman, J., McCallum, P. & Meares, R. (1980) Stimulus intensity control in depression: a study of the comparative effect of doxepin and amitriptyline on cortical evoked potentials. Australian and New Zealand Journal of Psychiatry, 14, 115-119.[Medline]
Ghose, K., Coppen, A. & Turner, P. (1976) Autonomic actions and interactions of mianserin hydrochloride and amitriptyline in patients with depressive illness. Psychopharmacology, 49, 201-204.[CrossRef][Medline]
Giedke, H., Gaertner, H., Breyer-Pfaff, U., et al (1986) Amitriptyline and oxaprotiline in the treatment of hospitalised depressed patients. Clinical aspects, psychophysiology, and drug plasma level. European Archives of Psychiatry and Neurological Sciences, 235, 329-338.[CrossRef][Medline]
Giedke, H., Heimann, H. & Rein, W. (1987) Changes in slow evoked potentials in depressed patients treated with amitriptyline and oxaprotiline. Review in Electroencephalography and Neurophysiology Clinic, 17, 279-287.
Giller, E., Bialos, D., Harkness, L., et al (1985) Long-term amitriptyline in chronic depression. Hillside Journal of Clinical Psychiatry, 7, 16-33.[Medline]
Glassman, A. H., Perel, J. M., Shostak, M., et al (1977) Clinical implications of imipramine plasma levels for depressive illness. Archives of General Psychiatry, 34, 197-204.[Abstract]
Glatzel, J. (1967) Clinical experiences with a new thymoleptic. Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie, 100, 167-178.
Goldberg, H. L., Rickels, K. & Finnerty, R. (1981) Treatment of neurotic depression with a new antidepressant. Journal of Clinical Psychopharmacology, 1 (suppl. 6), 35S-38S.
Goodwin, F. K., Prange, A. J., Post, R. M., et al (1982) A potentiation of antidepressant effects by L-triiodothyrpsine in tricyclic non responders. American Journal of Psychiatry, 139, 34-38.
Guy, W., Ban, T. A., McEvoy, J. P., et al (1982) A collaborative study of a new antidepressant, viloxezine, in neurotic and endogenous depressives. International Pharmacopsychiatry, 17, 36-42.[Medline]
Hackett, E., Gold, R. L., Kline, N. S., et al
(1967) Controlled evaluation of psychotropic drugs in a
private psychiatric practice. Doxepin vs. amitriptyline (Elavil).
Psychosomatics, 8,
162-165.
Haider, I. (1967) A comparative trial of Ro
4-6270 and amitriptyline in depressive illness. British Journal of
Psychiatry, 113,
993-998.
Hanin, I. (1985) Cerebrospinal fluid levels of amitriptyline, nortriptyline, imipramine and desmethylimipramine. Journal of Affective Disorders, 9, 69-78.[CrossRef][Medline]
Healy, D., Carney, P. A. & Leonard, B. E. (1984) Biochemical correlates of antidepressant response. Results of a trazodone versus amitriptyline trial. Psychopathology, 17 (suppl. 2), 82-87.
Herceg, B. R. L., Prusoff, B. A. & Weissman, M. M. (1979) Pharmacotherapy and psychotherapy in acutely depressed patients: a study of attrition patterns in a clinical trial. Comprehensive Psychiatry, 20, 315-325.[CrossRef][Medline]
Hoenig, J. & Visram, S. (1964) Amitriptyline versus imipramine in depressive psychoses. British Journal of Psychiatry, 110, 840-845.
Hollister, L. E., Overall, J. E., Johnson, M., et al (1964) Controlled comparison of amitriptyline, imipramine and placebo in hospitalised depressed patients. Journal of Nervous and Mental Disease, 139, 370-375.
Horden, A., Holt, N. F., Burt, C. G., et al (1963) Amitriptyline in depressive states. Phenomenology and prognostic considerations. British Journal of Psychiatry, 109, 815-825.
Horden, A., Burt, C. G., Gordon, W. F., et al (1964) Amitriptyline in depressive states: six-month treatment results. British Journal of Psychiatry, 110, 641-647.
Hutchinson, J. T. & Smedberg, D. (1963) Treatment of depression: a comparative study of E.C.T. and six drugs. British Journal of Psychiatry, 109, 536-538.
Jakitowicz, J. (1991) The amitriptyline plasma level and therapeutic response in patients with affective illness. Psychiatria Polska, XXV, 13-20.
Katz, M. M., Koslow, S. H., Maas, J. W., et al (1987) The timing, specificity and clinical prediction of tricyclic drug effects in depression. Psychological Medicine, 17, 297-309.[Medline]
Katz, R. J., Lott, M., Landau, P., et al (1993) A clinical test of noradrenergic involvement in the therapeutic mode of action of an experimental antidepressant. Biological Psychiatry, 33, 261-266.[CrossRef][Medline]
Kieback, D. (1982a) Vergleich der Hamilton Rating Scale for depression (HRS) mit der v. Zerssen-Befindlichkeitsskala (BS) am Beispiel einer klinischen profung von trazodon versus amitriptylin. Pharmacopsychiatry, 15, 97-101.
Kieback, D. (1982b) Zur problematik psychologischer testverfahren in der pharmakopsychiatrie. Pharmacopsychiatry, 15, 175-180.
Kiloh, L. G., Ball, J. R. & Garside, R. F. (1962) Prognostic factors in treatment of depressive states with imipramine. British Medical Journal, 1, 1225-1227.
Klein, R. G., Mannuzza, S., Koplewicz, H. S., et al (1998) Adolescent depression: controlled desimipramine treatment and atypical features. Depression and Anxiety, 7, 15-31.[CrossRef][Medline]
Koch, H. (1990) Steady-state plasma levels during antidepressant therapy with amitriptyline and amitriptylinoxide. Israel Journal of Psychiatry and Related Sciences, 27, 48-56.
Kocsis, J. H. (1990) Response to treatment with
antidepressants of patients with severe or moderate nonpsychotic depression
and of patients with psychotic depression. American Journal of
Psychiatry, 147,
621-624.
Konig, W., Heinrich, T. & Diehl, B. (1994) A double-blind comparison of amitriptylinoxide versus doxepine in the treatment of severe depression. Progress in Neuropsychopharmacology and Biological Psychiatry, 18, 491-496.[CrossRef][Medline]
Kopera, H. (1980) Cardiac effects of mianserin: results of clinical pharmacological investigations. Current Medical Research and Opinion, 6 (suppl. 7), 36-43.
Koszewska, I., Beresewicz, M., Puzynski, S., et al (1994) Psychotropic profile of essential antidepressants (amitriptyline, imipramine, desimipramine, chlorimipramine). Psychiatria Polska, XXVIII, 27-38.
Kowalski, A., Stanley, R. O., Dennerstein, L., et al
(1985) The sexual side-effects of antidepressant medication:
a double-blind comparison of two antidepressants in a non-psychiatric
population. British Journal of Psychiatry,
147,
413-418.
Krakowski, A. J. (1968) Activity study of
doxepin. A new antidepressant. Psychosomatics,
9, 89-95.
Kramer, M. S., Vogel, W. H., DiJohnson, C., et al (1989) Antidepressants in depressed schizophrenic inpatients. A controlled trial. Archives of General Psychiatry, 46, 922-928.[Abstract]
Kupfer, D. J., Hanin, I., Spiker, D. G., et al (1977) Amitriptyline plasma levels and clinical response in primary depression. Clinical Pharmacology and Therapeutics, 22, 904-911.[Medline]
Kupfer, D. J., Coble, P. A. & Rubinstein, D.
(1979) Changes in weight during treatment for depression.
Psychosomatic Medicine,
41,
535-544.
Kuss, H. J., Jungkunz, G. & Holsboer, F. (1984) Amitriptyline: looking through the therapeutic window. Lancet, i, 464-465.
Lambourn, J. & Rees, J. A. (1974) A general practitioner study of dothiepin and amitriptyline. Journal of International Medical Research, 2, 210-213.
Leyburn, P. (1967) A critical look at antidepressant drug trial. Lancet, ii, 1135-1137.
Liisberg, P., Mose, H., Amdisen, A., et al (1978) A clinical trial comparing sustained release amitriptyline and conventional amitriptyline tablets in endogenously depressed patients with simultaneous determination of serum levels of amitriptyline and nortriptyline. Acta Psychiatrica Scandinavica, 57, 426-435.[Medline]
Lloyd, C., Zisook, S., Click, M., et al (1981) Life events and response to antidepressants. Journal of Human Stress, 7, 2-15.
Lyons, J. S., Rosen, A. J. & Dysken, M. W. (1985) Behavioural effects of tricyclic drugs in depressed inpatients. Journal of Consulting and Clinical Psychology, 53, 17-24.[CrossRef][Medline]
Maier, W., Philipp, M., Schlegel, S., et al (1989) Diagnostic determinants of response to treatment with tricyclic antidepressants: a polydiagnostic approach. Psychiatry Research, 30, 83-93.[CrossRef][Medline]
Marey, C., Ganry, H., Delalleau, B., et al (1991) Effects thérapeutiques de la tianeptine chez les patients déprimés et anxieux avec ou sans alcoolisme associé. Presse Médicale, 20, 1828-1836.
Marjerrison, G., Deza, P. C. & Silzer, J. C. K. (1969) Verbal behaviour changes with depression treatment. Canadian Psychiatric Association Journal, 14, 503-508.[Medline]
Martin, I. C. A. & Leahy, M. R. (1968)
Prediction in anti-depressant therapy. British Journal of
Psychiatry, 114,
1289-1291.
Mathur, G. N. (1975) A double-blind comparative clinical trial of maprotiline and amitriptyline. Journal of International Medical Research, 3 (suppl. 2), 71-74.
Mattila, M. J., Liljequist, R. & Seppala, T. (1978) Effects of amitriptyline and mianserin on psychomotor skills and memory in man. British Journal of Clinical Pharmacology, 5, 53S-55S.
McConaghy, N. & Joffe, A. D. (1968)
Correlation of clinical features of depressed out-patients with response to
amitriptyline and protriptyline. British Journal of
Psychiatry, 114,
103-106.
McNair, D. M., Kahn, R. J., Frankenthal, L. M., et al (1984a) Amoxapine and amitriptyline. I. Relative speed of antidepressant action. Psychopharmacology, 83, 129-133.[CrossRef][Medline]
McNair, D. M., Kahn, R. J., Frankenthal, L. M., et al (1984b) Amoxapine and amitriptyline. II. Specificity of cognitive effects during brief treatment of depression. Psychopharmacology, 83, 134-139.[CrossRef][Medline]
Mindham, R. H. S. (1981) Continuation therapy with tricyclic antidepressants in relapsing depressive illness. Bibliotheca Psychiatrica, 160, 49-55.
Montgomery, S., Cronholm, B.,
sberg, M., et al
(1978) Differential effects on suicidal ideation of
mianserin, maprotiline and amitriptyline. British Journal of
Clinical Pharmacology, 5,
77S-80S.
Moyes, I. C. A., Ray, R. L. & Moyes, R. B. (1980) Plasma levels and clinical improvement — a comparative study of clomipramine and amitriptyline in depression. Postgraduate Medical Journal, 56 (suppl. I), 127-129.
Muck-Seler, D., Jakovljevic, M. & Deanovic, Z. (1991) Effect of antidepressant treatment on platelet 5-HT content and relation to therapeutic outcome in unipolar depressive patients. Journal of Affective Disorders, 23, 157-164.[CrossRef][Medline]
Murphy, J. E. (1975) A double-blind general practice trial of maprotiline (Ludiomil) against amitriptyline in the treatment of reactive depression. Journal of International Medical Research, 3 (suppl. 2), 97-100.
Myers, E. D. & Branthwaite, A. (1992)
Out-patient compliance with antidepressant medication. British
Journal of Psychiatry, 160,
83-86.
Myers, E. D. & Calvert, E. J. (1976) The effect of forewarning on the occurrence of side-effects and discontinuance of medication in patients on dothiepin. Journal of International Medical Research, 4, 237-240.
Nahunek, K., Bartova, D. & Ingrova, L. (1964) Endogenic depressive states treated with prothiaden. Activitas Nervosa Superiora (Praha), 4, 178-179.
Oliver-Martin, R., Marzin, D., Buschsenschutz, E., et al (1975) Concentrations plasmatiques de l'imipramine et de la desmethylimipramine et effet anti-depresseur au cours d'un traitement côntrole. Psychopharmacologia, 41, 187-195.[CrossRef]
Oltman, J. E. & Friedman, S. (1963) Evaluation of nortriptyline in the treatment of affective disorders (and comparison with other drugs). American Journal of Psychiatry, 120, 988-989.
Oltman, J. E. & Friedman, S. (1964) Factors influencing results with antidepressant drugs. American Journal of Psychiatry, 121, 895-897.
Ose, E. (1971) Et kontrollert klinsk forsok med det nye antidepressivum noxiptilin sammenlignet med amitriptylin. Nordisk Psykiatrisk Tidsskrift, 25, 382-390.
Pearce, J. B. & Rees, W. L. (1974) A double-blind comparison of three times daily and single night dosage of the tricyclic anti-depressant dothiepin. Journal of International Medical Research, 2, 12-19.
Peet, M. Tienari, P. & Jaskari, M. O. (1977) A comparison of the cardiac effects of mianserin and amitriptyline in man. Pharmacopsychiatry, 10, 309-312.
Pennese, F., Palombo, V., Scurti, R., et al (1993) Post-stroke depression: predictable factors to therapy outcome in a clinical trial comparing dothiepin to amitriptyline. Giornale di Gerontologia, 41, 353-358.
Peselow, E. D., Goldring, N., Stanley, M., et al (1986) The dexamethasone suppression test (DST) in predicting response to desipramine and amitriptyline in depressed outpatients. International Clinical Psychopharmacology, 1, 17-23.[Medline]
Petrie, W. M., Wilson, W. H., Ban, T. A., et al (1980) Mianserin: determination of therapeutic dose range. International Pharmacopsychiatry, 15, 111-117.[Medline]
Post, R. M. & Goodwin, F. K. (1974) Effects of amitriptyline and imipramine on amine metabolites in the cerebrospinal fluid of depressed patients. Archives of General Psychiatry, 30, 234-239.[Medline]
Preskorn, S. H., Othmer, S. C., Lai, C. W., et al (1984) Tricyclic-induced electroencephalogram abnormalities and plasma drug concentrations. Journal of Clinical Psychopharmacology, 4, 262-264.[Medline]
Pressman, M. D. & Weiss, L. B. (1961)
Experiences with elavil: treatment of fifty-one cases of depression.
American Journal of Psychiatry,
118, 74-75.
Prusoff, B. A., Weissman, M. M., Tanner, J., et al (1976) Symptom reduction in depressed outpatients treated with amitriptyline or maprotiline: repeated measurement analysis. Comprehensive Psychiatry, 17, 749-754.[CrossRef][Medline]
Pugh, R. (1983) An association between hostility and poor adherence to treatment in patients suffering from depression. British Journal of Medical Psychology, 56, 205-208.
Rajotte, P., Bordeleau, J. M., Tetreault, L., et al (1966) A double-blind comparative study of opipramol and amitriptyline in neurotic and endogenous depressions. Canadian Psychiatric Association Journal, 11 (suppl.), 159-168.
Rao, M. L., Ruhrmann, S., Retey, B., et al (1996) Low plasma thyroid indices of depressed patients are attenuated by antidepressant drugs and influence treatment outcome. Pharmacopsychiatry, 29, 180-186.[Medline]
Rechlin, T. (1994) The effect of amitriptyline, doxepin, fluvoxamine, and paroxetine treatment on heart rate variability. Journal of Clinical Psychopharmacology, 14, 392-395.[Medline]
Rees, J. A. & Risdall, P. C. (1976) An evaluation of a once daily dosage regime of dothiepin hydrochloride. Journal of International Medical Research, 4, 319-325.
Reisby, N. (1977) Imipramine: clinical effects and pharmacokinetic variability. Psychopharmacology, 54, 263-272.[CrossRef][Medline]
Renfordt, E. & Bush, H. (1976) Neue strategien psychiatrischer urteilsbildung durch anwendung audio-visueller techniken. Pharmakopsychiatrie Nevropsychopharmakologie, 9, 67-75.
Reynolds, E., Craggs, D. F., Joyston-Bechal, M. P., et
al (1969) Physicians' preferences in a blind trial of
imipramine and amitriptyline. British Journal of
Psychiatry, 115,
1175-1179.
Rickels, K., Csanalosi, I., Chung, H. R., et al
(1974) Amitriptyline in anxious—depressed outpatients:
a controlled study. American Journal of Psychiatry,
131, 25-30.
Robinson, D. S., Cooper, T. B., Howard, D., et al (1985) Amitriptyline and hydroxylated metabolite plasma levels in depressed outpatients. Journal of Clinical Psychopharmacology, 5, 83-88.[Medline]
Robinson, S., Dasberg, H. & Winnik, H. Z. (1972) Clinical and electroencephalographic effects of anafranil treatment in depression. Diseases of the Nervous System, 33, 268-272.[Medline]
Rockliff, B. W. (1971) Measurements of drug effects in newly hospitalised depressives. Diseases of the Nervous System, 32, 532-537.[Medline]
Rouillon, F., Phillips, R., Serrurier, D., et al (1989) Recurrence of unipolar depression and efficacy of maprotiline. Encephale, 15, 527-534.[Medline]
Rydzynski, Z. (1966) Badania nad wlasnosciami przeciwdepresyjnymi prothiadenu. Neurologia, Neurochirurgia I Psychiatria Polska, XVI, 1159-1162.
Saletu, B., Marx, B., Grunberger, J., et al (1979) Double-blind clinical and psychological test investigations in depressed out-patient with mianserin and Limbitrol. Excerpta Medica ICS, 462, 8-18.
Sanger, M. D. (1969) The treatment of anxiety and depression in the allergic patient. Annals of Allergy, 25, 506.
Schweizer, E. (1993) The role of antidepressants in the treatment of generalised anxiety disorder (GAD). European Neuropsychopharmacology, 3, 213-214.
Simpson, G. M., Amin, M., Angus, J. W., et al (1972) Role of antidepressants and neuroleptics in the treatment of depression. Archives of General Psychiatry, 27, 337-345.
