The ‘Dalhousie Serotonin cocktail’ for treatment-resistant major depressive disorder

Abstract

We describe the successful treatment of five patients with treatment-resistant major depressive disorder (TR-MDD) with a combination pharmacotherapy of pindolol, tryptophan and nefazodone. Five TR-MDD outpatients who had previously not responded to at least four different antidepressant medication trials were initiated on 300 mg/day of nefazodone, 7.5 mg/day of pindolol and 1 g/day of tryptophan. Pindolol doses remained the same throughout the 20 weeks, while tryptophan and nefazodone dosages were gradually increased to 8 g/day and 450 mg/day, respectively. The Hamilton Depression Rating Scale (HAM-D) was used to evaluate outcome. By week 4, all cases demonstrated at least 50% decrease in HAM-D scores. At the end of the trial, the group mean HAM-D score had significantly decreased from 26.8 (± 1.9) to 1.8 (± 0.8) (p < 0.001). No significant adverse effects were reported. These results suggest that if serotonin availability and release is further enhanced by tryptophan in the presence of nefazodone and pindolol, an antidepressant effect may be produced in patients who are otherwise treatment-resistant. Due to limited sample size, an open design and an ‘unusually’ high successful efficacy rate of this preliminary study, controlled studies are required to confirm the efficacy of this treatment strategy.

Keywords

augmentation strategies major depressive disorder nefazodone pindolol refractory depression treatment-resistant tryptophan

Get full access to this article

View all access options for this article.

References

American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. 4th edn. American Psychiatric Association: Washington, DC

Artigas F , Perez V , Alvarez E (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 51: 248–251

Bakish D , Hooper C L , Thornton M D , Wiens A , Miller C A , Thibaudeau C A (1997) Fast onset: an open study of major depressive disorder with nefazodone and pindolol combination therapy. Int Clin Psychopharmacol 12: 91–97

Blier P , Bergeron R (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol 15: 217–222

Blier P , Bergeron R (1996) Sequential administration of augmentation strategies in treatment resistant obsessive-compulsive disorder: preliminary findings. Int Clin Psychopharmacol 11: 37–44

Chehil S , Devarajan S , Dursun S (2000) Pharmacological strategies for refractory depression. Can Family Physician, 47: 50–52

Cowen P J (1992) New antidepressants: have they superseded tricyclics? In Hawton K , Cowen P J (eds), Practical problems in clinical psychiatry, pp. 23–32. Oxford University Press, Oxford

Cowen P J (1996) Advances in psychopharmacology: mood disorder and dementia. Br Med Bull 52: 539–555

Cowen P J , Anderson I M (1986) 5-HT neuroendocrinology: changes during depressive illness and antidepressant treatment. In Deakin J F W (ed.), The biology of depression, pp. 71–89.Gaskell, London

10.

Deakin J F (1988) 5-HT2 receptors, depression and anxiety. Pharmacol Biochem Behav 29: 819–820

11.

Dursun S M , Handley S L (1993) The effects of alpha-2-adrenoceptor antagonists on the inhibition of DOI-induced head-shakes by 5-HT1A receptor agonists in the mouse. Br J Pharmacol 109: 1046–1052

12.

Dursun S M , Mathew V M , Reveley M A (1993) Toxic serotonin syndrome after fluoxetine plus carbamazepine. Lancet 342: 442–443

13.

Dursun S M , Burke J G , Nielsen F , Mlynik-Szmid A , Reveley M A (1997) SSRI-related toxic serotonin syndrome; improvement by discontinuation of treatment and propranolol. Eur Psychiatry 12: 321–323

14.

Hamilton M A (1960) Rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62

15.

Janicak P G , Davis J M , Preskorn S H , Ayd F J (1997) Principles and practice of psychopharmacotherapy, pp. 270–271. Williams & Williams Co, London

16.

Narayan M , Anderson G , Cellar J , Mallison R T , Price L H , Nelson J C (1998) Serotonin transporter-blocking properties of nefazodone assessed by measurement of platalet serotonin. J Clin Psychopharmacol 18: 67–71

17.

Nelson J C (2000) Augmentation strategies in depression. J Clin Psychiatry 61(Suppl. 2): 13–19

18.

Rabiner E A , Bhapwagar F , Gunn R N , Sargent P A , Bench C J , Cowen P J , Grasby P M (2000a) Pindolol augmentation of SSRIs in depression: PET evidence suggests a higher dose is required. J. Psychopharmacol 14 (Suppl.): A73-A73

19.

Rabiner E A , Gunn R N , Castro M E , Sargent P A , Cowen P J , Koepp M J , Meyer J H , Bench C J , Harrison P J , Pazos A , Sharp T , Grasby P M (2000b) Beta-blocker binding to human 5-HT1A receptors in vivo and in vitro; implications for antidepressant therapy. Neuropsychopharmacology 23: 285–293

20.

Radomski J W , Dursun S M , Reveley M A , Kutcher S P (2000) An exploratory approach to the Serotonin Syndrome: an update of clinical phenomenology and revised diagnopstic criteria. Med Hypoth 55: 218–224

21.

Sargent P , Williamson D J , Pearson G , Odontiadis J , Cowen P J (1997) Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity. Psychopharmacology 132: 296–302

22.

Tricklebank M D , Forler C , Fogard J R (1984) The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioural response to 8-hydroxy-2 (di-npropylamino) tetralin in the rat. Eur J Pharmacol 106: 271–281