6 1999 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 1999 Volume 3 Pages 17-22
17
Recent advances in antidepressant drug therapy M QUASIM AND ASHOK KUMAR
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
The Medical Centre, Nuneaton, UK
Correspondence Address Dr M Quasim FRCP, FRCPsych, Consultant Psychiatrist, The Medical Centre, 2 Manor Court Avenue, Nuneaton CVl1 5HX, UK
Received 26 March 1998; revised 5 June 1998; accepted for publication 7 July 1998
Many new antidepressants are available for use. The acute effects of administration are mainly manifested as side-effects, whereas the chronic effects take 2-3 weeks to set in and are responsiblefor therapeutic action. Such changes may include formation and release of neurotransmitters, changes in pre-synaptic uptake, and changes in receptor density and sensitivity. The noradrenergic and serotonergic systems are not separate, but are entwined with each other. The newer SSRI citalopram, and drugs from the SNRI, NaSSA and NAN classes, have been shown in controlled trials to be equivalent to, or more efficacious than, TCAs andlor SSRls. They have an improved side-effect profile, especially when compared to TCAs, and hence are better tolerated. (IntJ Psych Clin Pruct 1998; 3: 1722)
Keywords new antidepressants therapeutic effacy
T
he last decade of this millenium has seen a number of new classes of antidepressant drugs becoming available. Most of these agents have a mechanism of action involving two or more neurotransmitter systems especially serotonin (5HT) and noradrenaline (NA). The aim of this ‘designer’ polypharmacy, utilizing rational pharmacological combinations, is to enhance the therapeutic efficacy while minimizing the side-effects.
MECHANISM OF ANTIDEPRESSANT MEDlCATlO N S The actions of antidepressant medication may be broadly categorized as acute and chronic. The former accounts for the majority of side-effects observed early in treatment. This is best exemplified by the blockade of peripheral anticholinergic receptors leading to constipation, urinary retention, tachycardia etc. Chronic changes take about 23 weeks to appear, and are a result of a feedback mechanism that regulates the function of neurotransmitters over time. Such changes may include changes in the formation and release of neurotransmitters, changes in presynaptic uptake, and changes in receptor density and sensitivity. The possible clinical consequences related to specific neurotransmitters and receptors are listed in Table 1.
MONOAMINE THEORYOF DEPRESSION The earliest evidence implicating monoamines in depression was the observation that reserpine-like drugs which
mechanism of action early onset of action
deplete monoamine produce a state somewhat similar to depression.’ This was supplanted by the discovery that treatment with tricyclics (TCA) and monoamine oxidase inhibitors (MAO) results in a transient increase in synaptic levels of monoamines. However, this theory suffered a setback when it was found that depletion of NA or 5HT in normal individuals did not produce depressive symptoms; but those patients whose depressive symptoms had remitted in response to NA or 5HT re-uptake inhibitor drugs were found to be vulnerable to relapse on depletion of corresponding amine~.,-~ Low levels of neurotransmitters lead to secondary changes in receptors, which in turn lead to an increased sensitivity or number of receptors. The onset of depression may occur when post-junctional receptors become supersensitive. The increased level of neurotransmitters in response to antidepressant drug therapy may result in persistent activation of these receptors, which then contribute to the delayed therapeutic response. In the noradrenergic system, NA released in response to TCAs (which have very low affinity for a, and j receptors) acts on these receptors. Thus the inhibitory a2 autoceptors are desensitized over time, resulting in increased release of NA from neurones and gradual loss of post-synaptic j-receptor sensitivity over 2 - 3 weeks, which coincides with the apparent onset of clinical efficacy of antidepressants. This realisation led to the development of the receptor sensitivity hypothesis, which states that the action of antidepressant treatment is dependent on the downregulation of j or 5HT2 receptors, and the enhanced sensitivity of these receptors may lead to depre~sion.*-~ Blier and de Montigny7proposed the 5HT1, hypothesis,
18
M Quasirn and A Kumar
Table 1 Possible clinical consequences of pharmacological properties of antidepressants Phamacological properties
Possible clinical consequences
compounds were rationally designed to be more selective in their action than the older drugs, and as a consequence they have fewer serious side-effects. The broad classes of new antidepressants comprise the SSRIs, SNRIs, NARIS and RlMAs.
SELECTIVE SEROTONIN RE-UPTAKE
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
lnhibition of MA0 lnhibition of NA uptake Inhibition of 5HT uptake
Antagonism of 5HTz receptors Antagonsim at 5HT3 receptors Antagonism at HI receptors
Antagonism at muscrarinic receptors
Antagonism at aI receptors Antagonism at a2 receptors
Alleviation of depression Alleviation of depression Alleviation of depression Sexual dysfunction Anorexia, GIT distress, headache, dizziness Alleviation of depression Weight gain Alleviation of anxiety and psychotic symptoms Potentiation of central depressant drugs Sedation, drowsiness, confusion Blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, mental confusion Postural hypotension, dizziness, reflex tachycardia, sedation, drowsiness Alleviation of depression
INHIBITORS (SSRIs) Five SSRI agents have been introduced since 1987, namely fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram. They differ in chemical structure and pharmacokinetics.’*”’ The main differences between the five agents are listed in Table 2. There have been several direct comprisons of SSRIs but there is no convincing evidence that these compounds differ systematically, either in efficacy or their side-effect profile.” However, some differences are to be expected with respect to receptor blocking and uptake inhibition.” A contentious issue has been the question of a ‘withdrawal syndrome’. Post-marketing investigation of SSRIs (excluding citalopram) in the UK13 found the safety profiles to be similar. However the reported incidence of withdrawal reactions with paroxetine was much greater (5.1%)than with the other three agents (0.06-0.9%). No evidence of physical dependency with paroxetine was seen in the study, and ‘withdrawal symptoms’ such as dizziness, paraesthesia, tremors, anxiety, nausea and palpitations generally lasted for 2- 10 days.
SEROTONIN AND NORADRENALINE according to which there is an increase in the functioning of post-synaptic 5HT1, receptors in the hippocampus following prolonged antidepressant treatment. This could occur as a result of either increased sensitivity of postsynaptic 5HT1, receptors, or desensitization of 5HT autoceptors. Tricyclic and tetracyclic drugs are also potent inhibitors of 5HT re-uptake. They enhance 5-HT-dependent neural transmission by increasing the responsiveness of the postsynaptic receptors. The time course of this development of sensitivity coincides with the onset of therapeutic action.‘ It has been demonstrated that NA and 5HT systems are entwined, and not independent of each other, the septa1 hippocampal region being an important site of 5HT regulation of the NA system. The permissive hypothesis of depression postulates that dysregulation of the serotonergic system is necessary but not sufficient to produce depression. However, in the presence of such a defect, a superimposed insult in the noradrenergic system results in a depressive syndrome.’
NEWER ANTIDEPRESSANTS The range of antidepressant medication available has increased dramatically in the last 10 years. These new
RE-UPTAKE INHIBITORS ( S N R l s ) Venlafaxine, duloxetine and milnacipran belong to this group of drugs. Venlafaxine, a phenylethylamine, blocks synaptosomal uptake of NA and 5HT, and also to a lesser extent dopamine. It has no activity on ul,uz, muscarinic or histaminic receptors. It produces rapid down-regulation of p receptors after both acute and chronic admini~tration,’~ whereas other antidepressants have exhibited this effect only after chronic administration. It also has a low potential for stimulant, sedative and proconvulsant effects,15 and a low risk for drug interactions. Duloxetine is the most potent of the three agents and inhibits the uptake of NA and 5HT equally, whereas venlafaxine is more serotonergic and milnacipran more adrenergic.l6 Venlafaxine has already been introduced in the UK, and milnacipran is in the registration phase, while the clinical development of duloxetine was discontinued in Phase 11. Venlafaxine is well absorbed (about 92%) after oral administration. Peak concentrations are obtained in 2.4 h for the parent drug and 4.3 h for its major metabolite, and the half-lives of the two are 5 h and 11 h respectively. It is metabolized by the hepatic cytochrome P450 2D6 system. In doses of 75 - 375 mg/day venlafaxine has proved as effective as imipramine or fluoxetine in major depression.” Im-
Antidepressant drug therapy
19
Table 2 Pharmacokinetic profile of various SSRls9.”
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
Time of peak plasma concentrations Plasma protein binding Plasma half-life Active metabolite
Inhibition of CYP 2D6 K1 @MI
IC50serotonin
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
6-8 h
2-8 h
2-8 h
6-8 h
94%
77%
95%
99%
1- 3 days Norfluoxetine Equally potent 4=7- 15 days
15 h
20 h
0.60 (norfluoxetine =0.4) 6.8
8.2
0.15
25 h Desmethylsertraline Potency=1/5 4=66 h 0.70
36 h Mono- and dimethylcitalopram Potency=1/4 to 1/13 5.1
3.8
0.29
0.19
1.8
370
620
81
160
6100
54
160
280
840
3400
20
100-300
20 -50
50 - 200
20 - 60
1-2
1 40
-
1
1 40
-
-
Citalopram
(nM) ICm noradrenaline
(nM) Ratio IC50of NNserotonin Therapeutic dose
(mg/day) Doses per day
Max.dose for
1
-
-
elderly patients
provement persists over 12 months of treatment. A rapid onset of action (possibly owing to its property of producing rapid down-regulation of /3 receptors), has been observed, with clinically relevant improvement within the first week of treatment after rapid dose escalation above 200 mglday.” It is better tolerated than TCAs and is comparable to fluoxetine. It appears to be safe in overdose up to 6.75 g. Swings into hypomania have been reported in some patients. One study” has shown efficacy (150 - 375 mglday) in onethird of patients who were considered treatment-resistant (an adequate trial of three different treatments). Milnacipran, another agent of this class, has been shown to be equally potent in inhibiting the reuptake of 5HT and NA and thereby increasing their respective extracellular concentrations, with no effect on dopamine.” It has no action on noradrenergic, muscarinic or histaminic receptors. In doses of 50 mg twice a day, its effectiveness has been shown to be similar to that of TCAs, with response It has rate of 65%,l’.’’ and marginally superior to SSRIS.~’~~’ fewer anticholinergic and cardiac effects than TCAs and fewer gastrointestinal side-effects than SSRIs. However, dysuria and headache are not uncommon.
NORADRENERGIC AND SPECIFIC SEROTONERGIC ANTIDEPRESSANT(NaSSA) Mirtazapine, currently the sole agent of this class, has a unique pharmacological profile. It is an antagonist of
central a2 auto- and heteroceptors, which control NA and 5HT release respectively, and also has a marginal affinity for a, adrenoceptors. The affinity for pre-synaptic a2 autoceptors is much higher than that for central postsynaptic and peripheral pre-synaptic a, autoceptors. Blockade of pre-synaptic inhibitory az autoceptors causes an increase in the release of NA, resulting in stimulation of a1 receptors; the a1 receptors then facilitate 5HT cell firing. Blockade of a2 heteroceptors located on 5HT terminals results in serotonin release. Mirtazapine has a low afinity for 5HT1 receptors, but is a potent blocker of 5HT, and 5HT3 receptor^;^^.'^ hence increased 5HT turnover is mediated only by 5HT, receptors, particularly the 5HT1, sub-type. The resulting increase in both noradrenergic and serotonergic neurotransmission systems is thought to contribute to the antidepressant activity of the drug.26 Mirtazapine exhibits a low affinity for muscarinic, dopaminergic and cholinergic receptors, and high affinity for HI receptor^.^' Long-term administration of mirtazapine in rats has shown that tonic activation of post-synaptic 5HT receptors was probably enhanced as the result of sustained increased in 5HT neuronal activity in the presence of, and due to, inactivated a2 heteroceptors.Z8 Mirtazapine has linear pharmacokinetics, the average half-life of the drug being 22-40 h, so that it need only be given once a day. Its clinical efficacy has been well studied, and being found to be more effective than placebo in
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
20
M Quasim and A Kumar
double-blind controlled s t ~ d i e s . ~ ~Comparisons -~l have shown that its efficacy is similar to that of trazodone,g2 arnit1yptiline,3'*~~ ~lomipramine~~ and d ~ x e p i n A. ~meta~ analysis of all double-blind randomized studies comparing mirtazapine with amitryptiline demonstrated equivalent improvements in Hamilton Depression Scores, and the percentage of patients showing improvement was similar for both the drugs (70% for mirtazapine and 73% for amitr~ptiline).~~ It has also been shown to be as effective as amitryptiline in elderly depressed patients.37 Mirtazapine has a favourable safety profile. The occurrence of adverse anticholinergic and cardiac effects, and of vertigo and tremor, is One out of five patients may become sleepy, while seronotin-related symptoms occur in fewer than 5% of patients.39The side-effects seen are typically mild and transient and disappear after a few days, even when the dose is being escalated.
SELECTIVE NORADRENALINE RE-UPTAKE INHIBITOR Reboxetine belongs to this group of drugs, which are highly selective in re-uptake inhibition of NA. The potential antidepressant activity of the drug has been seen in two animal models: antagonism of reserpine-induced hypothermia and blepharospasm, and antagonism of clonidineinduced hypothermia, in mice.40 Reboxetine has linear pharmacokinetics. Peak values in plasma following oral ingestion are achieved in 2 h, and the elimination half-life is 13 h. Ingestion with high fat meals delays the time required for achieving peak plasma concentrations, with slightly lowered maximum plasma values but no effect on bi~availability.~~ Pharmacokinetic studies have shown that there is no need to reduce doses in patients with liver impairment, but renally impaired patients do require lower Reboxetine undergoes oxidative metabolism in the liver by CYP enzymes, but does not produce any alterations in their activity. Reboxetine has been found to be an effective antidepressant. In a 6-week randomized double-blind study with i m i ~ r a r n i n eboth , ~ ~ drugs were equally efficacious as measured by the Hamilton Depression Rating Scale. The response rate has been seen to range from 56% to 74%,* and the drug was effective in ameliorating depression in both adult and elderly patients. Evaluated against fluoxetine, reboxetine has been shown to be similarly* or marginally more45efficacious. Reboxetine has fewer anticholinergic side-effects than tricyclic drugs. In a review of studies,46the discontinuation rate due to adverse events was shown to be comparable to that of placebo-about 8%.The total frequency of adverse events was similar in both reboxetine and fluoxetinetreated groups-about 65%. The drug has a favourable effect on cognitive function^,^' and at doses below 4 mg does not cause disruption in cognitive functioning or psychomotor performan~e.~~
NEFAZODONE Although chemically related to trazodone, nefazodone has a distinct pharmacological profile. It exhibits a dual action on the serotonergic system, as it is a relatively weak re-uptake inhibitor but a potent 5HT2 receptor antagonist. This combination enhances 5HT1,-mediated neurotransmission which may be beneficial in the treatment of depression. Nefazodone seems as effective as TCAs and superior to placebo in doses of 200 - 600 mg daily.49Efficacy seems to be maintained over at least one year of treatment. There have been no reports of priapism (a recognised side-effect of trazodone) in clinical trials with nefazodone. Furthermore, sexual dysfunction was reported much less frequently than with other antidepre~sants.~'This might be related to 5HT2, receptor blockade. Nefazodone seems to be moderately sedating (less so than TCAs or trazodone). Postural hypotension is reported but other cardiovascular effects seem rare and weight gain is not a major problem.
REVERSIBLEINHIBITORSOF MONOAMINE OXIDASE TYPE A (RIMA) The new generation MAOIs, such as moclobemide, have the advantage that they are selective in inhibition of MAO; they inhibit the activity of MAO-A but not MAO-B, and the inhibition is reversible. Selectivity significantly reduces the possibility of side-effects, while efficacy remains the same. Tyramine is metabolized by both MAO-A and MAO-B, and by inhibiting only one enzyme sub-type the potential for the 'cheese reaction' is significantly reduced. The reversibility of action on enzyme inhibition allows the monoamine oxidase to free itself promptly after treatment is stopped, with no need for lengthy wash-out periods. The potential for serotonin syndrome, however, is not reduced and concomitant administration with an SSRI should be avoided. A number of studies have shown moclobemide to be as efficacious as SSRIs, the therapeutic dose range being 150- 600 mg/day. Moclobemide has also been shown to produce a significant and rapid improvement in quality of life and social f u n ~ t i o n i n g . ~ ~
TRICYCLIC AGENTS (TCA) Lofepramine is the only new TCA available. It has fewer cardiac side-effects and is safe in overdose. It has no sedative properties and produces minimal psychomotor side-effects, while its efficacy is similar to that of other TCAs.
CONCLUSION Research has identified a role for specific receptor subtypes in the pathophysiology of depression and the mechanism of response to antidepressants. New antidepressants are more specific in their action at particular neurotransmitters;
Antidepressant drug therapy
consequently, their side-effect profile is more favourable than that of the older drugs. They are, however, only as effective as TCAs and/or SSRIs. There is a need for further comparisons between these newer drugs.
KEY POINTS 0
0
0
0 0
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
21
Downregulation of fl or 5HT2receptors is probably required for antidepressant efficacy All antidepressants are similarly effective, when compared to TCA or SSRI New antidepressant drugs have different sideeffect profiles, which seem to improve overall tolerability Some newer drugs may start acting sooner The major advantage of newer drugs is in their greater safety in overdose
REFERENCES 1. Healy D, Savage M (1998) Reserpine exhumed. BrJ Psychiatry 172: 376-8. 2. Shopsin B, Gershon S, Goldstein M (1975) Use of synthetic inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun 1: 239-49. 3. Delgado PI, Price LH, Miller HL, Salomon RM (1994) Serotonin and the neurobiology of depression. Arch Gen Psychiatry 51: 865 - 74. 4. Miller HI, Delgado PL, Salomon RM (1996) Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry 53: 117-28. 5 . Sulser F, Ventulani J, Mobley P (1978) Mode of action of antidepressant drugs. Biochem Pharmacol, 27: 257 - 61. 6. Charney DS, Menkes DB, Heninger GR (1981) Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and therapy of depression. Arch Gen Psychiatry 38: 1160-80. 7. Blier P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15: 220-6. 8. Kessel JB, Simpson GM (1995) Tricyclic and tetracyclic drugs. In: Comprehensive Textbook of Psychiatry. 6th edn Vol 11: (eds HI Kaplan, BJ Sadock) 2096 - 21 11. Williams & Wilkins, Baltimore. 9. Van Harten J (1993) Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet 24: 203 220. 10. Taylor D, Lader M (1996) Selective Serotonin Reuptake Inhibitors. In: Formulary Focus, 3- 11. A & M Publishing Ltd, Guildford. 11. Aguglia E, Casachia M, Casano GB et a1 (1993) Double blind study of efficacy and safety of sertraline vs fluoxetine in major depression. Jnt Clin Psychopharmacol 8: 197- 202. 12. Hyttel J (1993) Comparative pharmacology of selective serotonin reuptake inhibitors. Nord J Psychiatry 47 (suppl): 305- 12. 13. Price JS, Waller PC, Wood SM, Mackay AP (1996) A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occuring on withdrawal. Br J Clin Pharmacol 42: 757 - 63. 14. Mendlewicz J (1994) Pharmacologic profile and efficacy of venlafaxine. Int Clin Psychopharmacol 10 (suppl 2): 5- 14.
15. Moyer JA, Andree TH, Haskins JT (1992) The preclinical pharmacological profile of venlafaxine: a novel antidepressant agent. Clin Neuropharmacol 15 (suppl B): 435B. 16. Pinder RM (1997) Designing a new generation of antidepressant drugs. Acta Psychiatr Scand 96 (suppl 391): 7- 13. 17. Holliday SH, Benfield P (1995) Venlafaxine. A review of its pharmacology and therapeutic potential in depression. Drugs 49: 280 - 294. 18. GuelfiJD, White C, Guichoux JY, Magni G (1995) Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J Clin Psychiatry 56: 450-8. 19. Nierenberg AA, Feighner JP, Rudolph R (1994) Venlafaxine for treatment-resistant unipoplar depression. J Clin Psychopharmacol 14: 419- 23. 20. Briley M, Prost JF, Moret C (1996) Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol 11 (Suppl 4): 9- 14. 21. Montgomery SA, Prost JF, Scolles A, Briley M (1996) Efficacy and tolerability of milnacipran: an overview. Int Clin Psychopharmacol 11 (suppl 4): 47 - 5 1. 22. Kasper S, Pletan Y, Solles A, Tournoux A (1996) Comparative studies with milnacipran and tricyclic antidepressant drugs in patients with major depression: a summary of clinical trials. Int Clin Psychopharmacol 11 (suppl 4): 35-9. 23. Lopez-Ibor J, Guelfi JD, Pletan Y et a1 (1996) Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 11 (suppl 4): 41-6. 24. De Boer T, Nefkens F, van Helvoirt A (1994) The ct2adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 253: R5 - R6. 25. Clement HH, Gemsa D, Weseman W (1992) The effect of adrenergic drugs on serotonin metabolism in the nucleus raphe dorsalis of the rat. Studied by in vitro voltametry. Eur J Pharmacol 217: 43-8. 26. De Boer TH, Ruigt G (1995) The selective a12 agonist Org 3770 enhances noradrenergic and serotonin la-mediated serotonergic neurotransmission. CNS Drugs 41 (suppl 1):29 38. 27. De Boer TH, Maura G, Raiteri M (1988) Neurochemical and autonomic pharmacological properties of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropsychopharmacol 27: 399 - 408.
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
22
M Quasim and A Kumar
28. Haddjeri N, Blier P, de Montigny C (1995) Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine. Int Clin Psychopharmacol 10 (SUPPI 4): 11 - 17. 29. Claghom JL (1995) A double-blind, placebo controlled study of Org 3770 in depressed 0utpatients.J Affect Disord 34: 167-71. 30. Smith WT, Glaudin V, Panagides J, Gilvary E (1990) Mirtazapine vs amitriptiline vs placebo in the treatment of major depressive episode. Psychopharmacol Bull 26: 191 -6. 31. Vartiainen H, Leinonen E (1994) Double-blind study of mirtazapine and placebo in hospitalized patients with major depression. Eur Neuropsychopharmacol 4: 145 - 50. 32. Van Moffaert M, de Wilde D, Vereecken A et a1 (1995) Mirtazapine is more effective than trazodone. A controlled study in hospitalized patients with major depression. Znt Clin Psychopharmacol 10: 3 - 9. 33. Zivkov M, de Jongh GD (1995) Org 3770 vs amitriptiline: 6week randomised double-blind multicentre trial in hospitalised depressed patients. Hum Psychopharmacol 10: 173 -80. 34. Richou H, Ruimy P, Charbaut J et a1 (1995) A multicenter double-blind, clomipramine controlled efficacy and safety study of Org 3770. Hum Psychopharmacol 10: 263- 71. 35. Martilla M, Jaaskelainen J, Jarvi R et a1 (1995) A double-blind study comparing the efficacy and tolerability of Org 3770 and doxepin in patients with major depression. Eur Neuropsychopharmacol 5: 441 -6. 36. Kasper S (1995) Clinical efficacy of mirtazapine: a review of meta-analyses of pooled data. Znt Clin Psychopharmacol 10 (suppl 4): 25-35. 37. Hoyberg OJ, Maragakis B, Mullin J et a1 (1996) A double blind multicentre comparison of mirtazapine and amitriptyline in elderly depressed patients. Acta Psychiatr Scand 93: 184-90. 38. Sisten AMJ, Zivkov M (1995) Mirtazapine: clinical profile. CNS Drugs 41 (SUPPI 1): 39-48. 39. Montgomery S (1995) Safety of mirtazapine: a review. Znt Clin Psychopharmacol 10 (suppl4): 37-45. 40. Melloni P, Carnie1 G, Della Toree A et a1 (1984) Potential antidepressive agents. a-Aryloxy-benzyl derivatives of ethnolamine and morpholine. Ewr J Med Chem Chim Ther 19: 235 - 42.
41. Pellizzoni C, Strolin Benedetti M, Poggesi M et a1 (1995) Pharmacokinetics of reboxetine in healthy volunteers: relative bioavailability and food effect. Pharmacol Res 31: 41. 42. Dostert P, Benedetti MS, Poggesi 1 (1997) Review of pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol7 (Suppl 1): 523-5. 43. Berezweski H, Van Moffaert M, Gagiano CA (1997) Efficacy and tolerability of reboxetine compared with impramine in a double-blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacol 7 (suppl 1): S37-47. 44. Montgomery SA (1997) Reboxetine: additional benefits to depressed patients. J Psychopharmacol 11 (suppl 4): S9- 15. 45. Dubini A, Bosc M, Polin V (1997) Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning. Psychopharmacol 11 (suppl 4): S17-23. 46. Mucci M (1997) Reboxetine: a review of antidepressant tolerability. J Psychopharmacol 11 (suppl 4): 533-37. 47. Hindmarch 1 (1997) The effects of antidepressants on psychomotor function with particular reference to reboxetine. Eur Neuropsychopharmacol 7 (suppl 1): 517-21. 48. Kerr JS, Powell J, Hindmarch I (1996). The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance. Br J Clin Pharmacol 42: 239-41. 49. Rickels K, Robinson DS, Schweizer E et a1 (1995) Nefazodone: aspects of efficacy. J Clin Psychiatry 56 (suppl 6): 43 - 6. 50. Baldwin DS, Thomas JC, Birtwistle J (1997) Effect of antidepressant drugs on sexual function. Int J Psych Clin Pract 1: 47-58. 51. Lorinquivst J, Sintonen H, Syvalati H et a1 (1994) Antidepressant efficacy and quality of life in depression: a double-blind study with moclobemide and fluoxetine. Acta Psychiatr Scand 89: 363-9.
International Journal of Psychiatry in Clinical Practice 1999 Volume 3 Pages 17-22
17
Recent advances in antidepressant drug therapy M QUASIM AND ASHOK KUMAR
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
The Medical Centre, Nuneaton, UK
Correspondence Address Dr M Quasim FRCP, FRCPsych, Consultant Psychiatrist, The Medical Centre, 2 Manor Court Avenue, Nuneaton CVl1 5HX, UK
Received 26 March 1998; revised 5 June 1998; accepted for publication 7 July 1998
Many new antidepressants are available for use. The acute effects of administration are mainly manifested as side-effects, whereas the chronic effects take 2-3 weeks to set in and are responsiblefor therapeutic action. Such changes may include formation and release of neurotransmitters, changes in pre-synaptic uptake, and changes in receptor density and sensitivity. The noradrenergic and serotonergic systems are not separate, but are entwined with each other. The newer SSRI citalopram, and drugs from the SNRI, NaSSA and NAN classes, have been shown in controlled trials to be equivalent to, or more efficacious than, TCAs andlor SSRls. They have an improved side-effect profile, especially when compared to TCAs, and hence are better tolerated. (IntJ Psych Clin Pruct 1998; 3: 1722)
Keywords new antidepressants therapeutic effacy
T
he last decade of this millenium has seen a number of new classes of antidepressant drugs becoming available. Most of these agents have a mechanism of action involving two or more neurotransmitter systems especially serotonin (5HT) and noradrenaline (NA). The aim of this ‘designer’ polypharmacy, utilizing rational pharmacological combinations, is to enhance the therapeutic efficacy while minimizing the side-effects.
MECHANISM OF ANTIDEPRESSANT MEDlCATlO N S The actions of antidepressant medication may be broadly categorized as acute and chronic. The former accounts for the majority of side-effects observed early in treatment. This is best exemplified by the blockade of peripheral anticholinergic receptors leading to constipation, urinary retention, tachycardia etc. Chronic changes take about 23 weeks to appear, and are a result of a feedback mechanism that regulates the function of neurotransmitters over time. Such changes may include changes in the formation and release of neurotransmitters, changes in presynaptic uptake, and changes in receptor density and sensitivity. The possible clinical consequences related to specific neurotransmitters and receptors are listed in Table 1.
MONOAMINE THEORYOF DEPRESSION The earliest evidence implicating monoamines in depression was the observation that reserpine-like drugs which
mechanism of action early onset of action
deplete monoamine produce a state somewhat similar to depression.’ This was supplanted by the discovery that treatment with tricyclics (TCA) and monoamine oxidase inhibitors (MAO) results in a transient increase in synaptic levels of monoamines. However, this theory suffered a setback when it was found that depletion of NA or 5HT in normal individuals did not produce depressive symptoms; but those patients whose depressive symptoms had remitted in response to NA or 5HT re-uptake inhibitor drugs were found to be vulnerable to relapse on depletion of corresponding amine~.,-~ Low levels of neurotransmitters lead to secondary changes in receptors, which in turn lead to an increased sensitivity or number of receptors. The onset of depression may occur when post-junctional receptors become supersensitive. The increased level of neurotransmitters in response to antidepressant drug therapy may result in persistent activation of these receptors, which then contribute to the delayed therapeutic response. In the noradrenergic system, NA released in response to TCAs (which have very low affinity for a, and j receptors) acts on these receptors. Thus the inhibitory a2 autoceptors are desensitized over time, resulting in increased release of NA from neurones and gradual loss of post-synaptic j-receptor sensitivity over 2 - 3 weeks, which coincides with the apparent onset of clinical efficacy of antidepressants. This realisation led to the development of the receptor sensitivity hypothesis, which states that the action of antidepressant treatment is dependent on the downregulation of j or 5HT2 receptors, and the enhanced sensitivity of these receptors may lead to depre~sion.*-~ Blier and de Montigny7proposed the 5HT1, hypothesis,
18
M Quasirn and A Kumar
Table 1 Possible clinical consequences of pharmacological properties of antidepressants Phamacological properties
Possible clinical consequences
compounds were rationally designed to be more selective in their action than the older drugs, and as a consequence they have fewer serious side-effects. The broad classes of new antidepressants comprise the SSRIs, SNRIs, NARIS and RlMAs.
SELECTIVE SEROTONIN RE-UPTAKE
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
lnhibition of MA0 lnhibition of NA uptake Inhibition of 5HT uptake
Antagonism of 5HTz receptors Antagonsim at 5HT3 receptors Antagonism at HI receptors
Antagonism at muscrarinic receptors
Antagonism at aI receptors Antagonism at a2 receptors
Alleviation of depression Alleviation of depression Alleviation of depression Sexual dysfunction Anorexia, GIT distress, headache, dizziness Alleviation of depression Weight gain Alleviation of anxiety and psychotic symptoms Potentiation of central depressant drugs Sedation, drowsiness, confusion Blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, mental confusion Postural hypotension, dizziness, reflex tachycardia, sedation, drowsiness Alleviation of depression
INHIBITORS (SSRIs) Five SSRI agents have been introduced since 1987, namely fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram. They differ in chemical structure and pharmacokinetics.’*”’ The main differences between the five agents are listed in Table 2. There have been several direct comprisons of SSRIs but there is no convincing evidence that these compounds differ systematically, either in efficacy or their side-effect profile.” However, some differences are to be expected with respect to receptor blocking and uptake inhibition.” A contentious issue has been the question of a ‘withdrawal syndrome’. Post-marketing investigation of SSRIs (excluding citalopram) in the UK13 found the safety profiles to be similar. However the reported incidence of withdrawal reactions with paroxetine was much greater (5.1%)than with the other three agents (0.06-0.9%). No evidence of physical dependency with paroxetine was seen in the study, and ‘withdrawal symptoms’ such as dizziness, paraesthesia, tremors, anxiety, nausea and palpitations generally lasted for 2- 10 days.
SEROTONIN AND NORADRENALINE according to which there is an increase in the functioning of post-synaptic 5HT1, receptors in the hippocampus following prolonged antidepressant treatment. This could occur as a result of either increased sensitivity of postsynaptic 5HT1, receptors, or desensitization of 5HT autoceptors. Tricyclic and tetracyclic drugs are also potent inhibitors of 5HT re-uptake. They enhance 5-HT-dependent neural transmission by increasing the responsiveness of the postsynaptic receptors. The time course of this development of sensitivity coincides with the onset of therapeutic action.‘ It has been demonstrated that NA and 5HT systems are entwined, and not independent of each other, the septa1 hippocampal region being an important site of 5HT regulation of the NA system. The permissive hypothesis of depression postulates that dysregulation of the serotonergic system is necessary but not sufficient to produce depression. However, in the presence of such a defect, a superimposed insult in the noradrenergic system results in a depressive syndrome.’
NEWER ANTIDEPRESSANTS The range of antidepressant medication available has increased dramatically in the last 10 years. These new
RE-UPTAKE INHIBITORS ( S N R l s ) Venlafaxine, duloxetine and milnacipran belong to this group of drugs. Venlafaxine, a phenylethylamine, blocks synaptosomal uptake of NA and 5HT, and also to a lesser extent dopamine. It has no activity on ul,uz, muscarinic or histaminic receptors. It produces rapid down-regulation of p receptors after both acute and chronic admini~tration,’~ whereas other antidepressants have exhibited this effect only after chronic administration. It also has a low potential for stimulant, sedative and proconvulsant effects,15 and a low risk for drug interactions. Duloxetine is the most potent of the three agents and inhibits the uptake of NA and 5HT equally, whereas venlafaxine is more serotonergic and milnacipran more adrenergic.l6 Venlafaxine has already been introduced in the UK, and milnacipran is in the registration phase, while the clinical development of duloxetine was discontinued in Phase 11. Venlafaxine is well absorbed (about 92%) after oral administration. Peak concentrations are obtained in 2.4 h for the parent drug and 4.3 h for its major metabolite, and the half-lives of the two are 5 h and 11 h respectively. It is metabolized by the hepatic cytochrome P450 2D6 system. In doses of 75 - 375 mg/day venlafaxine has proved as effective as imipramine or fluoxetine in major depression.” Im-
Antidepressant drug therapy
19
Table 2 Pharmacokinetic profile of various SSRls9.”
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
Time of peak plasma concentrations Plasma protein binding Plasma half-life Active metabolite
Inhibition of CYP 2D6 K1 @MI
IC50serotonin
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
6-8 h
2-8 h
2-8 h
6-8 h
94%
77%
95%
99%
1- 3 days Norfluoxetine Equally potent 4=7- 15 days
15 h
20 h
0.60 (norfluoxetine =0.4) 6.8
8.2
0.15
25 h Desmethylsertraline Potency=1/5 4=66 h 0.70
36 h Mono- and dimethylcitalopram Potency=1/4 to 1/13 5.1
3.8
0.29
0.19
1.8
370
620
81
160
6100
54
160
280
840
3400
20
100-300
20 -50
50 - 200
20 - 60
1-2
1 40
-
1
1 40
-
-
Citalopram
(nM) ICm noradrenaline
(nM) Ratio IC50of NNserotonin Therapeutic dose
(mg/day) Doses per day
Max.dose for
1
-
-
elderly patients
provement persists over 12 months of treatment. A rapid onset of action (possibly owing to its property of producing rapid down-regulation of /3 receptors), has been observed, with clinically relevant improvement within the first week of treatment after rapid dose escalation above 200 mglday.” It is better tolerated than TCAs and is comparable to fluoxetine. It appears to be safe in overdose up to 6.75 g. Swings into hypomania have been reported in some patients. One study” has shown efficacy (150 - 375 mglday) in onethird of patients who were considered treatment-resistant (an adequate trial of three different treatments). Milnacipran, another agent of this class, has been shown to be equally potent in inhibiting the reuptake of 5HT and NA and thereby increasing their respective extracellular concentrations, with no effect on dopamine.” It has no action on noradrenergic, muscarinic or histaminic receptors. In doses of 50 mg twice a day, its effectiveness has been shown to be similar to that of TCAs, with response It has rate of 65%,l’.’’ and marginally superior to SSRIS.~’~~’ fewer anticholinergic and cardiac effects than TCAs and fewer gastrointestinal side-effects than SSRIs. However, dysuria and headache are not uncommon.
NORADRENERGIC AND SPECIFIC SEROTONERGIC ANTIDEPRESSANT(NaSSA) Mirtazapine, currently the sole agent of this class, has a unique pharmacological profile. It is an antagonist of
central a2 auto- and heteroceptors, which control NA and 5HT release respectively, and also has a marginal affinity for a, adrenoceptors. The affinity for pre-synaptic a2 autoceptors is much higher than that for central postsynaptic and peripheral pre-synaptic a, autoceptors. Blockade of pre-synaptic inhibitory az autoceptors causes an increase in the release of NA, resulting in stimulation of a1 receptors; the a1 receptors then facilitate 5HT cell firing. Blockade of a2 heteroceptors located on 5HT terminals results in serotonin release. Mirtazapine has a low afinity for 5HT1 receptors, but is a potent blocker of 5HT, and 5HT3 receptor^;^^.'^ hence increased 5HT turnover is mediated only by 5HT, receptors, particularly the 5HT1, sub-type. The resulting increase in both noradrenergic and serotonergic neurotransmission systems is thought to contribute to the antidepressant activity of the drug.26 Mirtazapine exhibits a low affinity for muscarinic, dopaminergic and cholinergic receptors, and high affinity for HI receptor^.^' Long-term administration of mirtazapine in rats has shown that tonic activation of post-synaptic 5HT receptors was probably enhanced as the result of sustained increased in 5HT neuronal activity in the presence of, and due to, inactivated a2 heteroceptors.Z8 Mirtazapine has linear pharmacokinetics, the average half-life of the drug being 22-40 h, so that it need only be given once a day. Its clinical efficacy has been well studied, and being found to be more effective than placebo in
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
20
M Quasim and A Kumar
double-blind controlled s t ~ d i e s . ~ ~Comparisons -~l have shown that its efficacy is similar to that of trazodone,g2 arnit1yptiline,3'*~~ ~lomipramine~~ and d ~ x e p i n A. ~meta~ analysis of all double-blind randomized studies comparing mirtazapine with amitryptiline demonstrated equivalent improvements in Hamilton Depression Scores, and the percentage of patients showing improvement was similar for both the drugs (70% for mirtazapine and 73% for amitr~ptiline).~~ It has also been shown to be as effective as amitryptiline in elderly depressed patients.37 Mirtazapine has a favourable safety profile. The occurrence of adverse anticholinergic and cardiac effects, and of vertigo and tremor, is One out of five patients may become sleepy, while seronotin-related symptoms occur in fewer than 5% of patients.39The side-effects seen are typically mild and transient and disappear after a few days, even when the dose is being escalated.
SELECTIVE NORADRENALINE RE-UPTAKE INHIBITOR Reboxetine belongs to this group of drugs, which are highly selective in re-uptake inhibition of NA. The potential antidepressant activity of the drug has been seen in two animal models: antagonism of reserpine-induced hypothermia and blepharospasm, and antagonism of clonidineinduced hypothermia, in mice.40 Reboxetine has linear pharmacokinetics. Peak values in plasma following oral ingestion are achieved in 2 h, and the elimination half-life is 13 h. Ingestion with high fat meals delays the time required for achieving peak plasma concentrations, with slightly lowered maximum plasma values but no effect on bi~availability.~~ Pharmacokinetic studies have shown that there is no need to reduce doses in patients with liver impairment, but renally impaired patients do require lower Reboxetine undergoes oxidative metabolism in the liver by CYP enzymes, but does not produce any alterations in their activity. Reboxetine has been found to be an effective antidepressant. In a 6-week randomized double-blind study with i m i ~ r a r n i n eboth , ~ ~ drugs were equally efficacious as measured by the Hamilton Depression Rating Scale. The response rate has been seen to range from 56% to 74%,* and the drug was effective in ameliorating depression in both adult and elderly patients. Evaluated against fluoxetine, reboxetine has been shown to be similarly* or marginally more45efficacious. Reboxetine has fewer anticholinergic side-effects than tricyclic drugs. In a review of studies,46the discontinuation rate due to adverse events was shown to be comparable to that of placebo-about 8%.The total frequency of adverse events was similar in both reboxetine and fluoxetinetreated groups-about 65%. The drug has a favourable effect on cognitive function^,^' and at doses below 4 mg does not cause disruption in cognitive functioning or psychomotor performan~e.~~
NEFAZODONE Although chemically related to trazodone, nefazodone has a distinct pharmacological profile. It exhibits a dual action on the serotonergic system, as it is a relatively weak re-uptake inhibitor but a potent 5HT2 receptor antagonist. This combination enhances 5HT1,-mediated neurotransmission which may be beneficial in the treatment of depression. Nefazodone seems as effective as TCAs and superior to placebo in doses of 200 - 600 mg daily.49Efficacy seems to be maintained over at least one year of treatment. There have been no reports of priapism (a recognised side-effect of trazodone) in clinical trials with nefazodone. Furthermore, sexual dysfunction was reported much less frequently than with other antidepre~sants.~'This might be related to 5HT2, receptor blockade. Nefazodone seems to be moderately sedating (less so than TCAs or trazodone). Postural hypotension is reported but other cardiovascular effects seem rare and weight gain is not a major problem.
REVERSIBLEINHIBITORSOF MONOAMINE OXIDASE TYPE A (RIMA) The new generation MAOIs, such as moclobemide, have the advantage that they are selective in inhibition of MAO; they inhibit the activity of MAO-A but not MAO-B, and the inhibition is reversible. Selectivity significantly reduces the possibility of side-effects, while efficacy remains the same. Tyramine is metabolized by both MAO-A and MAO-B, and by inhibiting only one enzyme sub-type the potential for the 'cheese reaction' is significantly reduced. The reversibility of action on enzyme inhibition allows the monoamine oxidase to free itself promptly after treatment is stopped, with no need for lengthy wash-out periods. The potential for serotonin syndrome, however, is not reduced and concomitant administration with an SSRI should be avoided. A number of studies have shown moclobemide to be as efficacious as SSRIs, the therapeutic dose range being 150- 600 mg/day. Moclobemide has also been shown to produce a significant and rapid improvement in quality of life and social f u n ~ t i o n i n g . ~ ~
TRICYCLIC AGENTS (TCA) Lofepramine is the only new TCA available. It has fewer cardiac side-effects and is safe in overdose. It has no sedative properties and produces minimal psychomotor side-effects, while its efficacy is similar to that of other TCAs.
CONCLUSION Research has identified a role for specific receptor subtypes in the pathophysiology of depression and the mechanism of response to antidepressants. New antidepressants are more specific in their action at particular neurotransmitters;
Antidepressant drug therapy
consequently, their side-effect profile is more favourable than that of the older drugs. They are, however, only as effective as TCAs and/or SSRIs. There is a need for further comparisons between these newer drugs.
KEY POINTS 0
0
0
0 0
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
21
Downregulation of fl or 5HT2receptors is probably required for antidepressant efficacy All antidepressants are similarly effective, when compared to TCA or SSRI New antidepressant drugs have different sideeffect profiles, which seem to improve overall tolerability Some newer drugs may start acting sooner The major advantage of newer drugs is in their greater safety in overdose
REFERENCES 1. Healy D, Savage M (1998) Reserpine exhumed. BrJ Psychiatry 172: 376-8. 2. Shopsin B, Gershon S, Goldstein M (1975) Use of synthetic inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun 1: 239-49. 3. Delgado PI, Price LH, Miller HL, Salomon RM (1994) Serotonin and the neurobiology of depression. Arch Gen Psychiatry 51: 865 - 74. 4. Miller HI, Delgado PL, Salomon RM (1996) Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry 53: 117-28. 5 . Sulser F, Ventulani J, Mobley P (1978) Mode of action of antidepressant drugs. Biochem Pharmacol, 27: 257 - 61. 6. Charney DS, Menkes DB, Heninger GR (1981) Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and therapy of depression. Arch Gen Psychiatry 38: 1160-80. 7. Blier P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15: 220-6. 8. Kessel JB, Simpson GM (1995) Tricyclic and tetracyclic drugs. In: Comprehensive Textbook of Psychiatry. 6th edn Vol 11: (eds HI Kaplan, BJ Sadock) 2096 - 21 11. Williams & Wilkins, Baltimore. 9. Van Harten J (1993) Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet 24: 203 220. 10. Taylor D, Lader M (1996) Selective Serotonin Reuptake Inhibitors. In: Formulary Focus, 3- 11. A & M Publishing Ltd, Guildford. 11. Aguglia E, Casachia M, Casano GB et a1 (1993) Double blind study of efficacy and safety of sertraline vs fluoxetine in major depression. Jnt Clin Psychopharmacol 8: 197- 202. 12. Hyttel J (1993) Comparative pharmacology of selective serotonin reuptake inhibitors. Nord J Psychiatry 47 (suppl): 305- 12. 13. Price JS, Waller PC, Wood SM, Mackay AP (1996) A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occuring on withdrawal. Br J Clin Pharmacol 42: 757 - 63. 14. Mendlewicz J (1994) Pharmacologic profile and efficacy of venlafaxine. Int Clin Psychopharmacol 10 (suppl 2): 5- 14.
15. Moyer JA, Andree TH, Haskins JT (1992) The preclinical pharmacological profile of venlafaxine: a novel antidepressant agent. Clin Neuropharmacol 15 (suppl B): 435B. 16. Pinder RM (1997) Designing a new generation of antidepressant drugs. Acta Psychiatr Scand 96 (suppl 391): 7- 13. 17. Holliday SH, Benfield P (1995) Venlafaxine. A review of its pharmacology and therapeutic potential in depression. Drugs 49: 280 - 294. 18. GuelfiJD, White C, Guichoux JY, Magni G (1995) Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J Clin Psychiatry 56: 450-8. 19. Nierenberg AA, Feighner JP, Rudolph R (1994) Venlafaxine for treatment-resistant unipoplar depression. J Clin Psychopharmacol 14: 419- 23. 20. Briley M, Prost JF, Moret C (1996) Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol 11 (Suppl 4): 9- 14. 21. Montgomery SA, Prost JF, Scolles A, Briley M (1996) Efficacy and tolerability of milnacipran: an overview. Int Clin Psychopharmacol 11 (suppl 4): 47 - 5 1. 22. Kasper S, Pletan Y, Solles A, Tournoux A (1996) Comparative studies with milnacipran and tricyclic antidepressant drugs in patients with major depression: a summary of clinical trials. Int Clin Psychopharmacol 11 (suppl 4): 35-9. 23. Lopez-Ibor J, Guelfi JD, Pletan Y et a1 (1996) Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 11 (suppl 4): 41-6. 24. De Boer T, Nefkens F, van Helvoirt A (1994) The ct2adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 253: R5 - R6. 25. Clement HH, Gemsa D, Weseman W (1992) The effect of adrenergic drugs on serotonin metabolism in the nucleus raphe dorsalis of the rat. Studied by in vitro voltametry. Eur J Pharmacol 217: 43-8. 26. De Boer TH, Ruigt G (1995) The selective a12 agonist Org 3770 enhances noradrenergic and serotonin la-mediated serotonergic neurotransmission. CNS Drugs 41 (suppl 1):29 38. 27. De Boer TH, Maura G, Raiteri M (1988) Neurochemical and autonomic pharmacological properties of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropsychopharmacol 27: 399 - 408.
Int J Psych Clin Pract Downloaded from informahealthcare.com by Chulalongkorn University on 12/27/14 For personal use only.
22
M Quasim and A Kumar
28. Haddjeri N, Blier P, de Montigny C (1995) Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine. Int Clin Psychopharmacol 10 (SUPPI 4): 11 - 17. 29. Claghom JL (1995) A double-blind, placebo controlled study of Org 3770 in depressed 0utpatients.J Affect Disord 34: 167-71. 30. Smith WT, Glaudin V, Panagides J, Gilvary E (1990) Mirtazapine vs amitriptiline vs placebo in the treatment of major depressive episode. Psychopharmacol Bull 26: 191 -6. 31. Vartiainen H, Leinonen E (1994) Double-blind study of mirtazapine and placebo in hospitalized patients with major depression. Eur Neuropsychopharmacol 4: 145 - 50. 32. Van Moffaert M, de Wilde D, Vereecken A et a1 (1995) Mirtazapine is more effective than trazodone. A controlled study in hospitalized patients with major depression. Znt Clin Psychopharmacol 10: 3 - 9. 33. Zivkov M, de Jongh GD (1995) Org 3770 vs amitriptiline: 6week randomised double-blind multicentre trial in hospitalised depressed patients. Hum Psychopharmacol 10: 173 -80. 34. Richou H, Ruimy P, Charbaut J et a1 (1995) A multicenter double-blind, clomipramine controlled efficacy and safety study of Org 3770. Hum Psychopharmacol 10: 263- 71. 35. Martilla M, Jaaskelainen J, Jarvi R et a1 (1995) A double-blind study comparing the efficacy and tolerability of Org 3770 and doxepin in patients with major depression. Eur Neuropsychopharmacol 5: 441 -6. 36. Kasper S (1995) Clinical efficacy of mirtazapine: a review of meta-analyses of pooled data. Znt Clin Psychopharmacol 10 (suppl 4): 25-35. 37. Hoyberg OJ, Maragakis B, Mullin J et a1 (1996) A double blind multicentre comparison of mirtazapine and amitriptyline in elderly depressed patients. Acta Psychiatr Scand 93: 184-90. 38. Sisten AMJ, Zivkov M (1995) Mirtazapine: clinical profile. CNS Drugs 41 (SUPPI 1): 39-48. 39. Montgomery S (1995) Safety of mirtazapine: a review. Znt Clin Psychopharmacol 10 (suppl4): 37-45. 40. Melloni P, Carnie1 G, Della Toree A et a1 (1984) Potential antidepressive agents. a-Aryloxy-benzyl derivatives of ethnolamine and morpholine. Ewr J Med Chem Chim Ther 19: 235 - 42.
41. Pellizzoni C, Strolin Benedetti M, Poggesi M et a1 (1995) Pharmacokinetics of reboxetine in healthy volunteers: relative bioavailability and food effect. Pharmacol Res 31: 41. 42. Dostert P, Benedetti MS, Poggesi 1 (1997) Review of pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol7 (Suppl 1): 523-5. 43. Berezweski H, Van Moffaert M, Gagiano CA (1997) Efficacy and tolerability of reboxetine compared with impramine in a double-blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacol 7 (suppl 1): S37-47. 44. Montgomery SA (1997) Reboxetine: additional benefits to depressed patients. J Psychopharmacol 11 (suppl 4): S9- 15. 45. Dubini A, Bosc M, Polin V (1997) Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning. Psychopharmacol 11 (suppl 4): S17-23. 46. Mucci M (1997) Reboxetine: a review of antidepressant tolerability. J Psychopharmacol 11 (suppl 4): 533-37. 47. Hindmarch 1 (1997) The effects of antidepressants on psychomotor function with particular reference to reboxetine. Eur Neuropsychopharmacol 7 (suppl 1): 517-21. 48. Kerr JS, Powell J, Hindmarch I (1996). The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance. Br J Clin Pharmacol 42: 239-41. 49. Rickels K, Robinson DS, Schweizer E et a1 (1995) Nefazodone: aspects of efficacy. J Clin Psychiatry 56 (suppl 6): 43 - 6. 50. Baldwin DS, Thomas JC, Birtwistle J (1997) Effect of antidepressant drugs on sexual function. Int J Psych Clin Pract 1: 47-58. 51. Lorinquivst J, Sintonen H, Syvalati H et a1 (1994) Antidepressant efficacy and quality of life in depression: a double-blind study with moclobemide and fluoxetine. Acta Psychiatr Scand 89: 363-9.
