Research on antidepressants in India

Most of the studies done in India have evaluated various antidepressants in depression. There are very few studies which have evaluated antidepressants in conditions other than depressive disorders. In this article, we review studies done in India on various antidepressants. The review ABSTRACT Data suggests that antidepressants are useful in the management of depressive disorders, anxiety disorders, sexual dysfunction, eating disorders, impulse control disorders, enuresis, aggression and some personality disorders. Research focusing on the usefulness of antidepressants in India has more or less followed the trends seen in the West. Most of the studies conducted in India have evaluated various antidepressants in depression. In this article, we review studies conducted in India on various antidepressants. The data suggests that antidepressants have been evaluated mainly in the acute phase treatment and rare studies have evaluated the efficacy in continuation phase treatment.


INTRODUCTION
Antidepressants as a class of drugs are used primarily in the management of depressive disorders and anxiety disorders. However, this class of drugs is also used for the management of sexual dysfunction, eating disorders, impulse control disorders, enuresis, aggression and some personality disorders.
Over the years many classes of antidepressants have become available in India, some of which have stood the test of time and are still in use and some, which are no more marketed or are no more a favorite of clinicians. The research focusing the usefulness of antidepressants in India has more or less followed the trends in the west; however, some of the antidepressants drugs which have been marketed have not been evaluated as thoroughly as others.
Most of the studies done in India have evaluated various antidepressants in depression. There are very few studies which have evaluated antidepressants in conditions other than depressive disorders. In this article, we review studies done in India on various antidepressants. The review

Side-effects
Dube and Narendra [1] Variable N 5 11 IMN 75-225 • Subjects with endogenous depression showed marked improvement or complete recovery, the psychoneurotic variety showed little and no improvement was seen in schiz group • Increase in pulse rate, dryness of mouth, hypotension, dilatation of pupils, stomatitis, constipation, excitement and sinking sensation Davis [2] 3-till needed N 5 30 AMT 75-150 • Sixteen subjects became Sx free; 8 subjects were substantially improved; taken together-77% improved, 3 subjects relapsed, when treatment was discontinued • Dermatitis, constipation, restlessness and panic, dry month Kishore and Murti Rao [3] 3-6 months N 5 10 AMT 75-150 • Two lost on follow-up • One patient improved slightly, 5-considerably improved, 1 -completely free of depression, 1-did not improve (hypochondriasis with sx of depression) • One patient-severe generalized Pruritus. One patient-dizziness, ataxia, drowsiness, blurring of vision, dryness of mouth, nausea, sweating and pains in the knee joints. One patient-took overdose Master, [4] 4 N 5 20 PTP 20-60 • Effective in treatment of depression • Dryness of month Kishore and Sharma [5] 15 N 5 16 TIMN 25-300 • 8/12 subjects who completed the trial showed response. Superior results were observed in endogenous depression and there was little or no effect on reactive neurotic depression • Tension, restlessness, agitation, suicidal tendencies, anxiety, insomnia and somatic complaints were relieved earlier than the depression.
• Dryness of the month, mild drowsiness, dizziness, headache, asthenia Sharma et al. [6] 10 N 5 78 D-IMN 75-300 • D-IMN was found to be effective • Remission rates highest in the retarded and reactive depression; lowest in agitated depression • Dryness of mouth, palpitation, agitation, giddiness, constipation • S/E were of milder severity Shah et al. [7] 6 N 5 104 IMN 1 PRZ 75-225  • Compound proved to be effective in controlling the depression with anxiety • Commonly reported S/E included dry mouth, tremors, giddiness, constipation, difficulty in visual accommodation Boral and Shah [8] 6 N 5 32; DSM-III, HDR AMN 100-200 • AMN was effective as soon as day 7 of treatment and this effect improved continuously throughout the study
The HDRS score showed a steady reduction between day 14 and 42 when the levels of NTZ and desmethyl metabolites were maintained between 176.5 ng/ml to 251 ng/ml • The plasma levels of NTZ (ng/ml) showed a rise from a mean level of 47.0 6 7.3 on day 1 (dose 75 mg) to 129.8 6 24.6 on day 7 (dose 150 mg) (P , 0.01) and remained steady till day 21 • No severe A/E reported Srivastava et al. [10]  trials have evaluated the outcome after six weeks. All these trials have shown that various tricyclic antidepressants, nitroxazepine, centpropazine, amineptine, tianeptine, sertraline, escitalopram and milnacipran are efficacious in treatment of depression. The trial which evaluated the efficacy of sertraline also showed that treatment of depression with sertraline leads to reduction in cardiac events post myocardial infarction. [13] A recently published trial, which evaluated the efficacy of milnacipran, included subjects who had suffered from stroke. [18] It is also one of the few trials which have included subjects more than 65 years of age. The trial done by Margoob et al. [17] in addition to the efficacy of escitalopram, have also shown that gene polymorphism plays an important role in the treatment response to various antidepressants.
• No patient withdrew due to S/E, which were reported in 23 subjects (7.2%).
Pinto et al. [16]   Outcome Side-effects of these trials have been double blind controlled trials, [19][20][21][22] one recruited subjects by consecutive sampling, [23] and one followed cross over design. [24] The duration of these trials has varied from four to eight weeks and these have included 16 to 96 subjects. Of the five trials, one evaluated the efficacy of imipramine in depressive symptoms in schizophrenia [24] and another included subjects with endogenous depression only. [23] Five of these trials showed that amitriptyline, imipramine, protriptyline and trimipramine are better than placebo in the management of depression; [19][20][21][22][23] however, the trial which evaluated the efficacy of imipramine for depressive symptoms in schizophrenia showed negative findings. [24] Active Comparator Group Drug Trials of Efficacy There have been 18 trials which have compared two antidepressants. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] One trial compared amitriptyline with amitriptyline and trifluperazine combination [42] and one trial compared amineptine vs. amineptine with benzodiazepine. [43] In another trial nortriptyline was compared with nortriptyline plus fluphenazine [ Table 3]. [44] The duration of these trials have varied from 10 days to five months; however, most of these have been of four to six weeks duration. Sample size has also varied considerably ranging from 20 to 425 and only four trials have included 100 or more subjects. In terms of study design, 10 trials have followed double blind controlled design; five of these also followed adequate randomization. One trial followed single blind randomized control design and another three trials were open randomized controlled trials. Earlier trials used mixed group of depressive subjects, whereas, recent trials have included subjects with major depressive disorder only. All the trials have used standard doses of antidepressants.
Of the 21 trials, 18 have assessed the outcome of depression at the end of trial on Hamilton depression rating scale. Findings from these trials suggest that imipramine is superior to Nialmide, [25] phenelzine, [25] Go 2998, [24] Go 2330 [26] and moclobemide [37] in the treatment of depression. Antidepressants like noveril, [27] iprindole, [28] trimipramine, [29] dothiepin [31] and centpropazine [34] have efficacy similar to imipramine. Imipramine has been found to be inferior to sintamil. [30] The study which evaluated amitriptyline and trifluperazine combination showed that it was no better than amitriptyline alone. [42] Interestingly, the study which used fluphenazine found it to be as efficacious as • Both the groups showed significant reduction in dep. Sx after 6-week trial and the addition of IMN to CPZ therapy did not have any advantageous or deleterious effect.
• IMN treated group did not exhibit more side-effects than the group receiving PLB   [27] NA N 5 50 NVL vs IMN NA • NVL appears to be a promising and • safe treatment for depression • NVL relatively free of severe S/E • Most common S/E were postural hypotension and coarse tremors of hands, dryness of mouth, sinus tachycardia, drug rash Teja and Bhatia [28] 6 N 5 59; HDRS, DBRCT IPL vs IMN IPL -180 IMN -150 • Out of the 59 subjects, 47 completed the 4 weeks period of trial and 12 dropped out (6 each on IPL and IMN) after taking the drugs for a variable period • In the IMN group 2 subjects were rated as recovered, 5 as markedly improved, 5 as improved and 5 as unchanged where as in the IPL group no subject was rated as recovered, 4 were rated as markedly improved, 5 as improved and 5 as unchanged • On t test-neither at day 0 nor at days 28 and 42 was any significant difference seen in the mean scores of any of the Hamilton's scale Sx between the two drug groups.
• There was no difference in the frequency of observed clinical side-effects between the two groups of subjects • S/E of severe intensity were seen only with IMN Satija et al. [29]   nortriptyline. [44] Nitroxazepine has been shown to be better than doxepin in treatment of depression. [32] The amineptine trial, didn't present data with regard to comparison in efficacy between the various groups of medications. [43] The studies which have compared various selective serotonin reuptake inhibitors have shown that these are equally effective, except for one which showed that citalopram was better than sertraline. [41] The only trial done on mirtazapine suggests that it is better than amitriptyline. [35] Studies have also shown that citalopram [38] and tianeptine [11] are as efficacious as amitriptyline. The trial by Badyal et al. [39] suggests that duloxetine is as efficacious as venlafaxine in the treatment of major depression. One of the recent multicentric trials have shown that escitalopram is superior to investigational drug LY2216684. [41] Active Comparator Group (non-pharmacological treatment/ electroconvulsive therapy) Trials of Efficacy/Effectiveness.
One study has compared the usefulness of antidepressants with respect to non pharmacological treatment [45] and two studies have compared antidepressants with electroconvulsive therapy for treatment of depression. [46,47] Another study compared antidepressants with both electroconvulsive therapy (ECT) and non-pharmacological treatment [ Table  4]. [48] One of these studies has shown that pharmacotherapy is more effective and more economical than non-pharmacological treatment. [45] However, one study showed no difference between ECT, antidepressant and Sudarshan kriya in the management of depression over the period of three weeks. [48] The studies which compared ECT with imipramine didn't find any difference in efficacy between the two; [46,47] however, Gangadhar et al. reported quicker response with ECT compared to imipramine. Table 5] Seven trials have evaluated the different dosing schedules for treatment of depression. [49][50][51][52][53][54][55][56] These studies suggest that parenteral imipramine is better than oral imipramine and possibly the onset of action is also earlier. [49] Studies have evaluated single dosing versus multiple dosing have shown no difference in efficacy [50][51][52]54,55] except for one study, which showed that single dose nitroxazepine was better than divided doses. [53]

Prescription Patterns of Antidepressants in Depression
Chakrabarti and Kulhara [57,58] evaluated the antidepressant prescription pattern in a tertiary care hospital for management of depression during acute and continuation phase. For the evaluation of prescription pattern during the acute phase, case notes of 108 cases fulfilling the ICD-10 criteria of depression or recurrent depression (F32 and F33) were examined. Imipramine was the most commonly prescribed antidepressants followed by Fluoxetine. The authors also observed that pharmacotherapy was often deficient in several areas such as, starting doses, rate of increase in dose, maximum doses used, dose titrations, duration of treatment, change of drugs, recording of side-effects and compliance etc. Results regarding norms for adequate doses and periods of treatment before switching drugs, for the kind of subjects included in this study, were unclear. Regarding the continuation phase treatment, the authors observed that it was deficient in about a third (n 5 24; 34 %) of the cases, on either of the two parameters i.e., dose of drugs or duration of treatment and the outcome was poorer in those treated inadequately.

Efficacy/effectiveness in Disorders Other Than Depression
Obsessive compulsive disorder/symptoms [ Table 6] One double blind controlled trial has evaluated the efficacy of clomipramine in the treatment of OCD and showed that clomipramine was superior to placebo in the management of OCD. [59] This study also showed that male subjects showed better response than female subjects. Another study evaluated the efficacy of clomipramine in late onset OCD with comorbid Parkinsonism and showed that clomipramine can be used in elderly subjects and in the presence of Parkinsonism. [60] A small open label study evaluated the usefulness of neuroleptic and fluoxetine combination for treatment of obsessive compulsive (OC) symptoms occurring during the course of schizophrenia and showed that addition of fluoxetine leads to significant improvement in OC symptoms. [61] Insomnia [ Table 6] One study evaluated the efficacy of antidepressants in insomnia and showed that trimipramine was similar to nitrazepam for treatment of insomnia, especially in the presence of anxiety and depression; however, it had poor tolerability as compared to nitrazepam. [62] Generalized Anxiety Disorder [ Table 6] One trial included subjects with generalized anxiety disorder, mixed anxiety depression and dysthymia and showed that imipramine was as effective as diazepam for anxiety symptoms and better than diazepam for the depressive symptoms. [63] Depressive Symptoms in Schizophrenia [ Table 6] One trial used imipramine in combination of chlorpromazine and compared it with chlorpromazine alone in the treatment of depressive symptoms in schizophrenia and didn't find any benefit of adding imipramine to chlorpromazine in the treatment of treatment of depressive symptoms in schizophrenia. [64] Common Mental Disorders [ Table 6] Two studies have also studied the usefulness of antidepressants in common mental disorders. One study showed that treatment completion rates were higher with fluoxetine than imipramine. [65] The trial by Patel et al. [66] included subjects with common mental disorders and evaluated the outcome at one year. It can be considered the longest study which has evaluated the effectiveness of antidepressant in Indian subjects.

Medication (s) Outcome Side-effects
Balkrishna et al. [45] 2 months N=75 AMT 1 CDP vs PPT • Clinically, drug therapy was found to be more effective and economical. • However, PPT was effective in relieving the anxiety and depression as well as improving social adjustment. Drug therapy was effective only in the relief of depression. Gangadhar et al. [46] [67] compared fluoxetine with yoga for the management of premature ejaculation.
The study included 68 subjects, of whom 38 were in the yoga group and 30 subjects in the fluoxetine group. All 38 subjects (25-65.7% 5 good, 13-34.2% 5 fair) of yoga group and 25 out of 30 of the fluoxetine group (82.3%) had statistically significant improvement in premature ejaculation and the  weeks of treatment and the difference between the two groups was statistically significant • Male subjects improved better than the females (78% vs. 51%), and the difference was statistically significant.
• Statistically significant difference in the mean prolactin level between PLB and CLN at the end of 4 and 8 weeks but not at 12 weeks • Dosage of medication insignificantly correlated with prolactin level at the end of 4, 8 and 12 weeks Agarwal and Agarwal [61]  • Psychiatric outcome was significantly better with FLX than with PLB at 2 months, but not over the 2-12 month period • AD were significantly more cost effective than PLB in the short term and long term (P , 0.05) • Psychological treatment was not more effective than PLB for any outcome during either period Dhikav et al. [67]

Escitalopram
Transvestic fetishism [84] Fluoxetine, Sertraline Trichotillomania in children and adolescent [85] Amitriptyline Clozapine induced sialorrhea [86] difference between the two groups was statistically significant too. In an open clinical study, Prusty and Rath (2000) [68] found clomipramine effective in nocturnal emission. In another open trial, Prusty et al. (2003) [69] found clomipramine 5 mg along with Sildenafil 50 mg was successful in preventing premature ejaculation of 18 men who had erectile dysfunction also. Table 7] Two studies have evaluated imipramine for management of enuresis in children. [70,71] In one of these trials, [71] in addition to enuresis, children had other behavioral abnormalities too. These studies have shown that imipramine is useful for management of enuresis and also for behavioral problems like obstinacy and temper tantrums. It was further seen that compared to subjects with mental retardation, the response to imipramine was better in children with average intelligence.

Antidepressant Withdrawal/Dependence
One case report presented tricyclic withdrawal syndrome with amitriptyline 300 mg/day [121] and another was described by Jhirwal and Chakrabarti [122] with Venlafaxine. Dependence syndrome has been described with dothiepin 450 mg/day. [123] Safety in Overdose In a case report, Gupta et al. [115] described a patient who could tolerate paroxetine 560 mg/day.

Conclusion and Future Directions
Many studies have evaluated the efficacy of antidepressants in depression and have shown that most of the currently marketed antidepressants are useful. In addition, studies also suggest usefulness of antidepressants in generalized anxiety disorder, dysthymia and common mental disorders. Many of the recent studies have been of good design and have followed double blind randomized controlled design and had reasonable sample size. Further, several studies have been carried out at multiple sites throughout the country. The available data also suggest that antidepressants are more costeffective than other modalities of treatment for depression.
In addition, there is some evidence to suggest the usefulness of clomipramine in OCD and that of fluoxetine in management of OC symptoms in schizophrenia. However, some major limitations of the research have been that almost all the data available in relation to treatment of depression pertains to acute phase treatment and rarely studies have evaluated the continuation phase treatment. There is also lack of data with regard to the efficacy and effectiveness in the maintenance phase treatment. Surprisingly, no study has evaluated the efficacy/effectiveness of SSRIs in the management of OCD.
There is a need to conduct studies to evaluate the usefulness of antidepressants in the management of panic disorder and depression in medically ill subjects. Studies are also required to evaluate the efficacy of SSRIs in the management of OCD, and to study the usefulness of polypharmacy in the management of depression and other disorders. Studies are few and sparse and there is a need for multi-centric studies in such a vast country.