Skip to main content Accessibility help

Lithium in Tricyclic-Resistant Depression Correlation of Increased Brain 5-HT Function with Clinical Outcome

  • P. J. Cowen (a1), S. L. McCance (a1), C. J. Ware (a1), P. R. Cohen (a1), J. S. Chalmers (a2) and D. L Julier (a3)...


The addition of lithium to the tricyclic antidepressant medication of 23 patients with major depression resulted in an increase in the prolactin response to intravenous l-tryptophan after both four days and four weeks of treatment. The extent of this increase did not distinguish the ten patients who were classified as clinical responders (> 50% reduction in score on the HRSD). Among the responders there was a modestly significant correlation between the decrease in score on the HRSD and the enhancement of tryptophan-induced prolactin release. Some responders, however, showed very little change in this endocrine response over the four weeks of lithium treatment. Lithium may increase brain 5-HT function in tricyclic-resistant depression but there is only limited support for the hypothesis that changes in brain 5-HT function are involved in the antidepressant effect of this treatment combination.


Corresponding author

Psychopharmacology Research Unit, Littlemore Hospital, Oxford OX4 4XN


Hide All
American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders (3rd edn). Washington DC: APA.
Anderson, I. M. & Cowen, P. J. (1986) Clomipramine enhances prolactin and growth hormone responses to l-tryptophan. Psychopharmacology, 89, 131133.
Blier, P. & de Montigny, C. (1985) Short-term lithium administration enhances serotonergic neurotransmission: electrophysiological evidence in the rat CNS. European Journal of Pharmacology, 113, 6977.
Charig, E. M., Anderson, I. M., Robinson, J. M., et al (1986) l-tryptophan and prolactin release: evidence for interaction between 5-HT, and 5-HT2 receptors. Human Psychopharmacology, 1, 9197.
Charney, D. S., Heninger, G. R. & Sternberg, D. E. (1984) Serotonin function and mechanism of action of antidepressant treatment: effect of amitriptyline and desipramine. Archives of General Psychiatry, 41, 359365.
Coppen, A. J. (1967) The biochemistry of affective disorder. British Journal of Psychiatry, 113, 12371264.
Cowen, P. J. (1987) Psychotropic drugs and human 5-HT neuro-endocrinology. Trends in Pharmacological Sciences, 8, 105108.
Cowen, P. J. (1988) Recent views on the role of 5-hydroxytryptamine in depression. Current Opinion in Psychiatry, 1, 5659.
Cowen, P. J., Geaney, D. P., Schächter, M., et al (1986) Desipramine treatment in normal subjects: effects on neuroendocrine responses to tryptophan and on platelet 5-HT-related receptors. Archives of General Psychiatry, 43, 6167.
Cowen, P. J. & Charig, E. M. (1987) Neuroendocrine responses to tryptophan in major depression. Archives of General Psychiatry, 44, 958966.
Cowen, P. J., McCance, S. L., Cohen, P. R., et al (1989) Lithium increases 5-HT-mediated neuroendocrine responses in tricyclic resistant depression. Psychopharmacology, 99, 230232.
Cowen, P. J., Cohen, P. R., McCance, S. L., et al (1990) 5-HT neuroendocrine responses during psychotropic drug treatment: an investigation of the effects of lithium. Journal of Neuroscience Methods, 34, 201205.
Deakin, J. F. W., Pennell, I., Upadhaya, A. J., et al (1990) A neuroendocrine study of 5-HT function in depression: evidence for biological mechanisms of endogenous and psychosocial causation. Psychopharmacology, 101, 8592.
Finch, E. J. L. & Katona, C. L. E. (1989) Lithium augmentation in the treatment of refractory depression of old age. International Journal of Geriatric Psychiatry, 4, 4146.
Glue, P. W., Cowen, P. J., Nutt, D. J., et al (1986) The effect of lithium on 5-HT-mediated neuroendocrine responses and platelet 5-HT receptors. Psychopharmacology, 90, 398402.
Goodwin, F. K. & Post, R. M. (1983) 5-Hydroxytryptamine and depression. A model for the interaction of normal variance with pathology. British Journal of Clinical Pharmacology, 15, 393S405S.
Goodwin, G. M., De Souza, R. J., Wood, A. J., et al (1986a) Lithium decreases 5-HT1A and 5-HT2 receptor and α-adrenoceptor-mediated function in mice. Psychopharmacology, 91, 500504.
Goodwin, G. M., De Souza, R. J., Wood, A. J., et al (1986b) The enhancement by lithium of the 5-HT1A-mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism. Psychopharmacology, 90, 488493.
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 5662.
Heninger, G. R., Charney, D. S. & Sternberg, D. E. (1983) Lithium carbonate augmentation of antidepressant treatment: an effective prescription for treatment-refactory depression. Archives of General Psychiatry, 40, 13351342.
Heninger, G. R., Charney, D. S. & Sternberg, D. E. (1984) Serotonergic function in depression. Archives of General Psychiatry, 41, 398402.
Hotta, I. & Yamawaki, S. (1988) Possible involvement of presynaptic 5-HT autoreceptors in effect of lithium on 5-HT release in hippocampus of rat. Neuropharmacology, 27, 987992.
Hunter, R., Christie, J. E., Whalley, J. E., et al (1989) Luteinizing hormone responses to luteinizing hormone releasing hormone (LHRH) in acute mania and the effects of lithium on LHRH and thyrotropin releasing hormone tests in volunteers. Psychological Medicine, 19, 6977.
Kramlinger, K. G. & Post, R. M. (1989) The addition of lithium to carbamazepine: antidepressant efficacy in resistant depression. Archives of General Psychiatry, 46, 794800.
McCance, S. L., Cohen, P. R. & Cowen, P. J. (1989) Lithium increases 5-HT-mediated PRL release. Psychopharmacology, 99, 276281.
Meltzer, H. Y., Lowy, M., Robertson, A., et al (1984) Effect of 5-hydroxytryptophan on serum Cortisol levels in major affective disorders — III. Effects of antidepressants and lithium carbonate. Archives of General Psychiatry, 41, 391397.
de Montigny, C. & Aghajanian, G. I. (1978) Tricyclic antidepressants: long term treatment increases responsivity of rat forebrain neurones to serotonin. Science, 202, 13031306.
de Montigny, C., Grunberg, F., Mayer, A., et al (1981) Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. British Journal of Psychiatry, 138, 252256.
de Montigny, C., Cournoyer, G. & Morissette, R. (1983) Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression: correlations with the neurobiological actions of tricyclic drugs and lithium ion on the serotonin system. Archives of General Psychiatry, 40, 13271334.
Muhlbauer, H. D. & Muller-Oerlinghausen, B. (1985) Fenfluramine stimulation of serum Cortisol in patients with major affective disorders and healthy controls: further evidence for a central serotonergic action of lithium in man. Journal of Neural Transmission, 61, 8194.
Peroutka, S. J. (1988) 5-Hydroxytryptamine receptor subtypes: molecular, biochemical and physiological characterization. Trends in Neuroscience, 11, 496500.
Price, L. H., Charney, D. S. & Heninger, G. R. (1986) Variability of response to lithium augmentation in refractory depression. American Journal of Psychiatry, 143, 13871392.
Price, L. H., Charney, D. S., Delgado, P., et al (1989) Lithium treatment and serotonergic function: neuroendocrine and behavioural responses to intravenous tryptophan in affective disorder. Archives of General Psychiatry, 46, 1319.
Price, L. H., Charney, D. S., Delgado, P., et al (1990) Lithium and serotonin function: implications for the serotonin hypothesis of depression. Psychopharmacology, 100, 312.
Quitkin, F. M., Rabkin, J. G., Ross, D., et al (1984) Duration of antidepressant treatment. Archives of General Psychiatry, 41, 238245.
Schöpf, J. (1989) Treatment of depression resistant to tricyclic antidepressants, related drugs or MAO inhibitors by lithium addition: review of the literature. Pharmacopsychiatry, 22, 174182.
Schöpf, J., Baumann, P., Lemarchand, T., et al (1989) Treatment of endogenous depression resistant to tricyclic antidepressants or related drugs by lithium addition: results of a placebo—controlled double-blind study. Pharmacopsychiatry, 22, 183187.
Smith, C. E., Ware, C. J. & Cowen, P. J. (1991) Pindolol decreases prolactin and growth hormone responses to l-tryptophan. Psychopharmacology, 103, 140142.
Swann, A. C., Heninger, G. R., Roth, R. H., et al (1981) Differential effects of short-and long-term lithium on tryptophan uptake and serotonergic function in cat brain. Life Science, 28, 347354.
Treiser, S. L., Cascio, C. S., O'Donohue, T. L., et al (1981) Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science, 213, 15291531.
Upadhaya, A. K., Pennell, I., Cowen, P. J., et al (1990) Blunted growth hormone and prolactin response to L-tryptophan in depression: a state dependent abnormality. Journal of Affective Disorder, 21, 213218.
Wang, H.-Y. & Friedman, E. (1988) Chronic lithium: desensitisation of autoreceptors mediating serotonin release. Psychopharmacology, 94, 312314.
Wood, A. J. & Goodwin, G. M. (1987) A review of the biochemical and neuropharmacological actions of lithium. Psychological Medicine, 17, 579600.


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Lithium in Tricyclic-Resistant Depression Correlation of Increased Brain 5-HT Function with Clinical Outcome

  • P. J. Cowen (a1), S. L. McCance (a1), C. J. Ware (a1), P. R. Cohen (a1), J. S. Chalmers (a2) and D. L Julier (a3)...
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *