VENLAFAXINE - A REVIEW OF ITS PHARMACOLOGY AND THERAPEUTIC POTENTIAL IN VARIOUS PSYCHIATRIC CONDITIONS

DR. P.N. SURESH KUMAR, MD, DPM, DNB (PSYCH), MNAMS 
Senior Lecturer, Department of Psychiatry, Government Medical College, 
 Calicut - 673008, Kerala.
 Major depression, either alone or combined with other psychiatric disorders is one of the most functionally disabling disorder in the community. Despite tremendous strides to wards gaining a better under standing of the disease and its diagnosis as well as improvements pharmacotherapy, major depression and its treatment continues to raise concerns among patients and family. The first class of antidepressants, including the tricyclic antidepressants monoamine oxidase inhibitors were discovered by chance. However, over the 20 Years, in parallel with the under standing of the neurobiology, more and more newer antidepressants have been developed which act at selective sites in brain. Of late, the potential advantages of antidepressant therapy involving more than one putative site of action were recognized. For example, combination of disimipramine a NE reuptake inhibitor with SSRI fluoxetin has shown more rapid on set of neuronal activity and robust response than did either agent alone. Like combination therapy, an antidepressant that has multiple mechanism of action may offer more robust response that do single action agents. For example, a study Clomipramine with SSRI paroxetine showed higher remission rate as well as early and sustained antidepressant effect with clomipramine (Danish study, 1990)  
 Venlafaxine differs from all existing antidepressants in that it exhibits a combined action affect on neuronal reuptake of serotonin and nonepinephrine, thereby prolonging the neurotransmitter action. However, the physician's acceptance of venlafaxine was initially limited by a number of factors unrelated to its phamacologic profile. There are :
  •  Late entry in to market place 
  •  Misperciption that its use was limited to refractory cases of depression only 
  • Poor understanding of pharmacologic profile and the clinical implications, posed by its multiple mechanism of action 
  • Early poor tolerability including nausea and increase in blood pressure  
  •   Need for twice - daily dosing
  • Wide dose - titration range
 However, extensive clinical studies including double - blind, placebo controlled and cross over studies have proved its efficacy and tolerability in various clinical conditions.
 VENLAFAXINE'S UNIQUE CHARACTER PROFILE :
 image  venlafaxine 1
 Dysregulation of serotonin, norepinephrine and dopamine are implicated in various symptomatology of depression.
 Because of venlafaxines, dual reuptake blockade of NE, 5HT and to some extent rotransmitter medicated dysfunctions while shoeing no significant affinity for adrenergic, mucarinic or histamine receptors.
 Velanfaxine     is    a   bycyclic phenythylamine derivative that is chemically distinct from both TCAs and SSRIs
 image  venlafaxine 2
               *chiral centre
 PHARMACOKINETICS
 Following absorption of venlafaxine from the gastrointestinal tract, the drug undergoes extensive first pass metabolism in liver. Food delay the absorption of venlafaxine. The large volume of distribution and its low plasma protein binding of approximately 30% indicate extensive tissue binding. Venlafaxine is metabolised in the liver to a major active metabolite, O-demethyl  venlafaxine, and 2 minor marginally active metabolites, N-demethyl  venlafaxine and N, O-demethyl  venlafaxine . Importantly, non of the metabolites demonstrated appreciable affinity for muscarinic cholinergic, & 1-adrenergic or histamine H1 receptors (Muth et al,1991) 
 Excretion of  venlafaxine and its metabolites is primarily by the renal route with only 4.7% of administered dose appearing in urine as unchanged drug. The elimination half life of O-de-methyl  venlafaxine (= 10 hours) is longer than that of parent drug. The(= 4 hours) There were no apparent differences in steady state pharmacokinetics when 2 and 3 times daily regimen were compared. Therefore, although the majority of published clinical trails used a 3 times daily administration schedule, use of a twice-daily regimen is justified.
 DRUG INTERACTIONS.
 Although  venlafaxine is metabolished by the CYP2D6 isoenzyme it also inhibits this enzyme. However,  venlafaxine is a less potent inhibitor of the CYP2D6 isoenzyme than paroxetine, fluoxetine, sertraline and fluvoxamine (Sellers & Ball, 1993). Hence clinically significant inhibition of CYP2D6 isoenzyme is less likely with  venlafaxine than with SSRIs. Venlafaxine does not have interaction with lithium, diazepam or ethyl alcohol when co-administered. Cimetidine can slightly in crease the blood level of  venlafaxine's active metabolites but this is not clinically significant. Fluoxetin can significantly increase the concentration of  venlafaxine and its active metabolites as well as potentiate side effects. As  venlafaxine inhibits the reuptake of sertonin and norepinephrine, it should not be administered with MAOI (Manely & Wozniak, 1983). When switching from a MAOI to  venlafaxine there should be a 14 day interval between the discontinuation of the MAOI and the initiation of venlafaxine therapy. When switching from  venlafaxine to a MAOI, a 7- day interval is adequate because of  venlafaxines short half life. This time frame is not applicable to reversible MAOI like moclobemide or brofaromine.
 TOLERABILITY :
 Short term treatment (6 weeks) with  venlafaxine upto 450mg/day was generally well tolerated in clinical trials. Most adverse effects are of mild to moderate in severity, tending to occur early in the course of treatment and many resolved with continued therapy. Most commonly reported adverse effects are nausea, headache, sweating, sleeping, dry mouth, deceased appetite, anxiety, dizziness and insomnia 5. The incidents of classical anticholinergic symptoms such as dry mouth and constipation was significantly lower with  venlafaxine than TCAs. There are reports of modest increase in systolic blood pressure, particularly high doses (Fabre & Putamon, 1987). Lethality with suicidal overdose is not reported with  venlafaxine. In comparison with other antidepressant drugs,  venlafaxine was better tolerated than imipramine and clomipramine, at least as well tolerated as trazodone, and fluoxetine. The long term tolerability of  venlafaxine has also been reported to be good (Magni & Hackett, 1992; Tiller et al 1992). Nausea, sweating, headache and anxiety were the common adverse affects reported in 10% of patients in long term trials. Because of its shorter half life,  venlafaxine should be discontinued gradually over at least to weeks. If  venlafaxine is suddenly discontinued, a withdrawal syndrome involving fatigue, nausea, dizziness, headache, insomnia and nervousness may develop.
 Safely and effectiveness of venlafaxine has not been established in individuals below 18 Years. Because of Excretion of its active metabolite    0- de-methyl venlafaxine in breast milk, mothers on this drug are advised not to breast feed their infants. Safely of venlafaxine in pregnancy also has not been established.
 DOSAGE AND ADMINISTRATION
 The recommended starting dose of plain  venlafaxine is 75mg daily administered as 2 or 3 times daily regimen taken with food. The starting dose of XR preparation is once daily. Depending on the tolerability and the need for further clinical effect the dosage may be gradually increased to a maximum of 375 mg daily. When increasing the dose, increments of up to 75mg/day should be made at intervals of not less than 4 days. Regular blood pressure monitoring is recommended when increasing the dose. No dosage adjustment is required in elderly patients who are otherwise healthy. The dosage of  venlafaxine should be reduced by approximately 50% in patients with moderate hepatic impairment and by 20% in patients with mild to moderate renal impairment.
FREQUENCY OF ADMINISTRATION AND ONSET THERAPEUTIC EFFECT
 Pharmacokinetic and clinical data suggest that a twice daily plain venlafaxine regimen is as effective as once daily dosing without compromising the therapeutic efficacy. Limited data suggest that venlafaxine may heve an onset action of about 2 weeks. Khan et al (1998) demonstrated significant improvements in mean depression rating scale scores versus baseline from weeks 2 or 3 onwards in a non-comparative study 10. Comparison with fluoxetine (Clerc et al ,1999) also shows rapid onset of action with venlafaxine. However, this is yet to be confirmed by further clinical trials. 

INDICATIONS
DEPRESSION:
Venlafaxine versus Placebo controlled trials. Rudolph (1998) in a randomised, double blind, placebo-controlled, dose response trial reported that venlafaxine is effective and well tolerated at dose range of 75-375 mg/day. Khan (1998) in double blind, placebo controlled trial reported significant improvement with venlafaxine in doses of 75-200 mg/day with early onset of antidepressant effect within 1-2 weeks. 
Venlafaxine compared with TDAs & SSRIs
 Einarson (19999) in a meta-analysis of randomised controlled trial of venlafaxine XR demonstrated statistically significant greater success rate (73.7%) as compared to SSRIs (61.1%) and TCAs (57.9%). The drugs in cluded in the comparison were the SSRIs such as (citalopram, fluoxetine, fluoxamine and sertraline); and the TCAs such as (amitriptyline, imipramine, desimipramine and nortriptyline). Venlafaxine is reported to be well tolerated and effective in the treatment of dysthymia (Ballus,2000). Venlafaxine has shown beneficial effects in treatment-resistant depression (Poirier, 1999) Zonardi (2000) have reported that venlafaxine is effective in delusional depression. A metanalysis of extension studies (Entsuah,1986) showed a 80% prevention of recurrence in the venlafaxine group indicating that is effective in maintaining the initial response and thereby preventing relapse in major depression.
ANXIETY DISORDERS
 There are many studies showing that venlafaxine is effective and well tolerated in the short term and long treatment if anxiety disorders (Feighner, 200; Lydiard, 2000). The efficacy of venlafaxine in GAD mey be related to the duel inhibition of serotonin and norepinephrine  reuptake as there is evidence that both these neurotransmitters are dysregulated in GAD. For e.g., Norepinephrine may medicate no rewarded behaviours. where as serotonin mey mediate fear induced inhibition of movement and also punishment. There are sporadic reports about the efficacy of venlafaxine in panic disorder. social phobia, obsessive compulsive disorders and trichotillomania (Sheehan, 2000). Venlafaxine's anti-anxiety effects is dependent of antidepressant effect.
OTHERS INDICATIONS
 Venlafaxine is effective in the treatment of anorexia nervosa, borderline personality disorder, adult ADHD, fibromyalgia, chronic fatigue syndrome and not flashes in men and women receiving androgen deprivation therapy for prostate cancer and breast cancer respectively.
COMBINATION TREATMENT
 Bernardo etal (2000) in a small trial of 9 patients reported that combined use of venlafaxine and ECT is sate and well tolerated in depression. Combination of venlafaxine with clomipramine or imipramine who are pertial responders to the later is also reported to be safe and effective in depression (Gomez 2000). Walter (1998) reported that addition of lithium to venlafaxine was rapidly followed by improvement in mood and function in adolescent major depression. 
 In conclusion, this review suggest that both sustained release and plain venlafaxine in a dose range of 75-225 mg/day is an effective, safe and well tolerated antidepressant for all types of depression and so some extant various types of anxiety disorders. The once daily dose also facilitates administration and enhances compliance. However, this newer agents role in psychopharmacologic armamentorium requires further exploration including long term evaluation in India setup.
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