Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode
Highlights
► A randomized double blind study to assess efficacy of l-5-HTP as an antidepressant in first depressive episode patients and compare its efficacy with fluoxetine. ► 70 patients of first depressive episode were randomly divided into two groups, receiving l-5-HTP and fluoxetine respectively and observed for a period of 8 weeks. ► HAM-D, BDI and CGI rating scales were administered to assess severity of depression at baseline, 2 weeks, 4 weeks and 8 weeks. ► 22 patients (70.33%) in l-5-HTP group showed positive response compared to 24 patients (80%) in fluoxetine group. ► l-5-HTP showed antidepressant effect in patients of first depressive episode. ► The antidepressant effect of l-5-HTP was as strong as that of fluoxetine.
Introduction
Affective disorders are one of the most common psychiatric disorders and account for nearly 30–40% of the case load at various psychiatric facilities in India (Varma and Das, 1995). There is a marked variability in the prevalence rate of depression across the studies in India which range from 1.5 per 1000 (Sethi and Gupta, 1972) to 37.74 per 1000 (Nandi and Ajmany, 1975). The Epidemiological Catchment Area and National Co morbidity Survey studies suggested that the current rate of major depression is in the realm of 2 − t. It is believed that the true life time rate of major depression is probably in the realm of 10–20 per 100 (Joyce, 2009).
A response to a single antidepressant medication, classically measured as an attenuation of 50% or more in the intensity of depressive symptoms, is generally obtained in about 50–75% of patients with a first trial (Lonnqvist et al., 1994). Remission rates, in contrast are generally around 30% with a single agent (Blier et al., 2010). This is a disappointing result indicating that additional treatment measures must be taken in about two-third of patients after using an antidepressant medication at an adequate dose for a sufficient time.
Tryptophan depletion is widely used paradigm to study the role of the serotonergic system in the pathophysiology and treatment of depression (Neumeister, 2003). There are several reports that plasma tryptophan is significantly lower in patients with major depression than in normal controls or in patients with only minor symptoms of depression (Coppen et al., 1973, Cowen et al., 1989). In humans, several studies have shown that reducing serotonin synthesis (by depriving the brain of tryptophan) can induce depression within hours (Neumeister et al., 1998, Delgado et al., 1990, Lam et al., 1996).
Furthermore, administration of tryptophan has been used as an antidepressant but due to its side effects profile, it was no longer used (Shaw et al., 2002).
l-5-Hydroxytryptophan (l-5-HTP) is an aromatic amino acid naturally produced by the body from the essential amino acid l-tryptophan. Therapeutic use of l-5-HTP bypasses the conversion of l-tryptophan into l-5-HTP by the enzyme tryptophan hydroxylase, which is the rate limiting step in the synthesis of serotonin as shown in Scheme 1 (O’Neil and Moore, 2003). l-5-HTP has been used clinically for over 30 years. In addition to depression, the therapeutic administration of l-5-HTP has been shown to be effective in treating a wide variety of conditions, including fibromyalgia, insomnia, binge eating associated with obesity, cerebellar ataxia, and chronic headaches (Birdsall, 1998).
The first large clinical open trial using l-5-HTP in the treatment of depression was done in 1972 with 107 patients having unipolar or bipolar depression using daily oral dosages of l-5-HTP from 50 to 300 mg. Significant improvement was observed in 74 of the patients (69%), and no significant side effects were reported. The response rate in most of these patients was quite rapid (less than 2 weeks) (Sano, 1972).
After this, many double blind, placebo controlled trials with l-5-HTP showed that l-5-HTP was superior to placebo. A double blind study compared l-tryptophan with amitriptyline over a 3 month period among 115 outpatients diagnosed with mild or moderate depression. Based on scores from the Hamilton Rating Scale for Depression (HAM-D) and a global rating of depression, l-tryptophan at a dose of 3 g per day was more effective than the placebo, as effective as amitriptyline, and produced significantly fewer side effects (Thomson et al., 1982).
Other double blind placebo controlled trials evaluated l-5-HTP in comparison with tryptophan in 15 patients with endogenous unipolar or bipolar depression at a daily oral dosage of 200 mg over 4 weeks. Marked improvement was observed in eight of the patients and l-5-HTP was found more effective than tryptophan or placebo (Van Praag, 1984).
It is amply clear that l-5-HTP has potential for being used as alternative to the traditional forms of therapy in depressive disorder; further work needs to be undertaken because no study has been done in the Indian population till date. This raises the question whether results of a western population could be generalized to the Indian population. Therefore, carrying out such studies in the Indian population is mandatory. The present study aims at comparing the efficacy of l-5-HTP and fluoxetine in patients presenting with first depressive episode.
Section snippets
Sample
This randomized, double-blind, parallel group study was started in May 2009 for 8 weeks in a tertiary center of northern India. The study group consisted of first depressive episode patients attending the Psychiatry Outpatient Department of Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India. Approval from the ethical board of this institute was granted and a sample of 70 outpatients with ICD-10 diagnosis of first depressive episode was recruited. After explaining the purpose and
Socio-demographic profile
The mean age for patients in group A was 38.8 ± 7.04 years, which was comparable to mean age of 34.97 ± 8.59 of group B. No statistical difference was found between the two treatment groups as far as sex distribution was concerned. The majority of patients in both groups were illiterate or had primary education, i.e. 53.3% in the l-5-HTP group as compared to 36.7% in the fluoxetine group with no statistical significant. A majority of the patients belonged to rural background (73.3% in the l-5-HTP
Discussion
Though few studies in the past had examined the role of l-5-HTP in depression and compared it to various antidepressants, no Indian study had assessed its role in depression until now. Most antidepressant trials are scheduled for no longer than 4 weeks, a period not always sufficient to bring out a difference and to permit reliable evaluation (Quitkin and Rabkin, 1981). A difference in efficacy may take as long as 6 weeks of treatment to became apparent (Quitkin et al., 1984). For this reason, a
Conclusion
l-5-HTP definitely plays an antidepressant role in patients of depression. The antidepressant effect is apparent in all degrees of depression including severely depressed. The minimal effective dose of l-5-HTP to produce antidepressant effect is 150 mg/day; a significant number of patients improved with 300 mg of l-5-HTP. The antidepressant effect of l-5-HTP took 2 weeks to start which subsequently continued. l-5-HTP was well tolerated by patients. The antidepressant effect of l-5-HTP was equal to
Limitations
Though the present study was conducted using sound methodology and strict inclusion criteria, there are certain limitations. Small sample size and a single sited study contained to a specific region limits the generalizability of the results to the rest of the Indian population. Lack of a placebo control group is also a limitation of the study. Besides, multicentral studies or metaanalysis studies in different geographical locations can increase accuracy of the results. Dietary intake was not
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