# 2003 Taylor & Francis
International Journal of Psychiatry in Clinical Practice 2003 Volume 7 (Suppl 1) Pages 3 /8
3
Essential considerations when choosing a modern antidepressant DAVID BALDWIN
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 12/01/14 For personal use only.
University of Southampton, UK
Correspondence Address D. Baldwin, Community Clinical Sciences Research Division, Faculty of Medicine, Health and Biological Sciences, University of Southampton, UK Tel: /(44) 2380 825533 Fax: /(44) 2380 234243 E-mail: [email protected]
The man-years of disability produced by depression in industrialised nations is second only to that caused by ischaemic heart disease. One in ten patients seen by a primary care physician is suffering from depressive symptoms (but neither of them may recognise it). Depression is clearly a major health problem, which can, however, be successfully treated by modern antidepressants in the overwhelming majority of cases. The problem for the primary care physician is not whether to treat but how to treat major depression. The increasing number of antidepressants from different families with different mechanisms has become an embarrassment of riches. When choosing an antidepressant, efficacy, adverse effects, safety in overdose, potential drug interactions and withdrawal effects are among the principal criteria. Although all antidepressants may appear to be equivalent in efficacy, in more severely depressed patients it has been demonstrated that dual action antidepressants, acting on both serotonin and noradrenaline, have superior efficacy to compounds acting on a single neurotransmitter. In addition certain types of depressive symptoms may respond better to one antidepressant than to another. The importance of adverse effects goes beyond patient safety and comfort and has a major influence on efficacy. If, due to adverse effects, an antidepressant is prescribed at sub-optimal doses or the patient is not compliant, even the most effective antidepressant will perform badly. The risk of suicide is inherent to depression, and to prescribe a drug which if taken in overdose can be fatal if used in a suicide attempt, is clearly unacceptable. Similarly certain antidepressants have a far greater potential for interactions with other drugs with potentially toxic effects and should be avoided in patients taking several medications. Applying these criteria globally will not designate a single ‘‘best antidepressant’’ but consideration of the importance of each criteria for an individual patient will help the clinician to find the antidepressant best adapted to each patient. (Int J Psych Clin Pract 2003; 7 (Suppl 1): 3 8) /
Keywords antidepressant criteria serotonin
INTRODUCTION
D
epression is a chronic and usually recurrent illness that is associated with significant morbidity and mortality. Despite the highly prevalent nature of the disease, depression is frequently unrecognised and undertreated. The majority of cases of depression are managed solely within primary care, but there is ample evidence that general practice management may not change with guidelines and education about
choice noradrenaline
depression. Patients frequently experience recurrent depressive episodes characterised by a longer duration and a greater severity than the initial episode. In addition, the efficacy of antidepressants tends to decline with each successive episode. To prevent relapse and recurrence, treatment needs to be continued for a long period of time, so optimising compliance with antidepressant medication is essential. However, compliance is known to be generally poor. Thus, these considerations explain why it is difficult, for many DOI: 10.1080/13651500310000825
4
D Baldwin
primary care physicians, to diagnose and manage the illness effectively. This paper reviews the most important criteria for choosing an antidepressant.
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 12/01/14 For personal use only.
DIFFERENT TYPES OF ANTIDEPRESSANTS The monoamine hypothesis of depression, which dates from the mid 1960s1 is still the most widely accepted, even though it has undergone a series of minor modifications over the years. The symptoms of depression are generally considered to be related to a decreased content and/or activity of cerebral monoamines, particularly serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA).2 The discovery of the antidepressant properties of the monoamine oxidase inhibitors (MAOI) and the tricyclic antidepressants (TCA) which both increase concentrations of both monoamines in the brain, gave further credibility to the hypothesis. MAOI and TCA, however, have considerable side effects. The MAOI interact with foodstuffs which contain tyramine, causing a dramatically increased release of NA leading to potentially dangerous increases in blood pressure. Reversible MAOI, such as moclobemide, are displaced at this enzyme by large amounts of tyramine and thus do not require the dietary restrictions of the first generation of MAOI which are irreversible. Apart from blocking monoamine reuptake, TCA interact directly with various synaptic receptors, notably the cholinergic muscarinic receptor, a1-adrenoceptors, and histamine H1 receptors.3 These interactions are responsible for the major side effects of these compounds: dry mouth, constipation, blurred vision and other cholinergic side effects, orthostatic hypotension, and sedation. In addition to the discomfort they cause, these side effects diminish antidepressant efficacy either by causing treatment to be abandoned or by reducing compliance and encouraging the use of low, therapeutically suboptimal doses. Considerable research efforts over the last few decades have thus centred on the search for compounds devoid of these receptor interactions and their associated side effects. The first major advance since TCA, the selective serotonin reuptake inhibitors (SSRI), in fact went one step further, because they are not only devoid of direct receptor interactions, but also the ability to inhibit the reuptake of noradrenaline. There are now six well-established agents in this group, fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram and escitalopram. The advantages conferred by the specificity of their action and their lack of TCA-like receptor blocking include lack of cardiotoxicity in overdose and a different more benign side effect profile. The major side effects are mediated via stimulation of 5-HT2 receptors (agitation, anxiety, panic attacks, insomnia and sexual dysfunction) and 5-HT3 receptors (nausea, gastrointestinal upset, diarrhoea and headache). There is considerable evidence to suggest that increasing NA function has an antidepressant effect.4 Relatively selective
NA reuptake inhibitors, such as desipramine and lofepramine, have clear antidepressant efficacy. More recently another NA-specific agent, reboxetine, has been introduced. This is the prototypical agent of a new class of antidepressants called NA reuptake inhibitors (NARI). Mirtazapine, which increases noradrenergic and serotonergic neurotransmission through blockade of a2-adrenoceptors while blocking 5-HT2 and 5-HT3 receptors, improves depressive symptoms. Mirtazapine5,6 has been termed the first noradrenergic and specific serotonergic antidepressant (NaSSA). Evidence that simultaneous stimulation of the 5-HT and NA systems are probably complementary is provided by combination studies with SSRI and NARI.7,8 Consequently, there has been a recent tendency toward the development of new antidepressants that selectively and simultaneously inhibit the reuptake of both 5-HT and NA, with no affinity for the synaptic receptors responsible for the adverse effects of TCA. These compounds, such as venlafaxine, milnacipran and duloxetine, are referred to as the specific serotonin and noradrenaline reuptake inhibitors (SNRI). The situation of venlafaxine is complex since at low doses it is essentially a SSRI and only inhibits NA reuptake at higher doses. In contrast, milnacipran has a dual action on 5-HT and NA neurotransmission at all doses. Duloxetine is expected to become available in 2003 and also has a dual action at all doses, but there is limited published data. In addition to these different classes of antidepressants, most of which are already marketed, there is a list of potential new antidepressants with different mechanisms, such as the substance P (NK-1) receptor antagonists, corticotrophinreleasing factor receptor antagonists, glucocorticoid receptor antagonists, vasopressin receptor antagonists, and melatonin receptor agonists (see Baldwin and Thompson9). Since the actions of these compounds are more or less indirectly linked to the functioning of the 5-HT system, it remains to be seen whether they will represent any major clinical advantage over existing drugs.
WHICH ANTIDEPRESSANT? EFFICACY Many studies have compared the efficacy of the different antidepressants, and the results of meta-analyses10 12 show that, when all studies are considered, TCA, SSRI and SNRI have essentially equivalent efficacy. However, in hospitalised patients TCA and SNRI tend to be superior to SSRI. Interestingly, in these more seriously depressed patients, dual action TCA are superior to SSRI, whereas TCA acting on a single neurotransmitter, such as desipramine, have been shown to be equivalent to SSRI. In moderate to severe depression for example, a metaanalysis of studies comparing the SNRI, milnacipran (100 mg/day), with different TCA (150 mg/day), has shown similar results in terms of responses and remissions in both groups (Table 1).
Essential considerations when choosing a modern antidepressant
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Table 1 Effect of treatment with milnacipran or TCA at doses, indicated in mg/ day, on the percentage of responders and remissions in moderate to severe depression. TCA, tricyclic antidepressants. Responders are patients who respond by a decrease of 50% or more from baseline in scores on the Hamilton Depression Rating Scale (HDRS) to treatment. Remission is defined as a lack of depressive symptoms and with HDRS equal or less than 8. Taken from Kasper et al.25 Milnacipran, 100 mg/day (%)
TCA, 150 mg/day (%)
64 39
67 42
Responders Remissions
Figure 1 Monoamine systems implicated in depressive symptoms
Sechter et al13 and Clerc14 have compared milnacipran with some SSRI in mild to moderate and moderate to severe depression, respectively (Table 2). Table 2 shows that in mild to moderate depression milnacipran is equipotent to the SSRI, paroxetine, using MADRS (Montgomery Asberg Depression Rating Scale). But in moderate to severe depression, milnacipran has shown a larger decrease in MADRS at endpoint (42 days) and a greater effect size than the SSRI, fluvoxamine (Table 2).13,14
SUITABILITY Figure 1 summarises the different depressive symptoms and the monoamine systems that are thought to be principally implicated. As already mentioned above, 5-HT and NA play key roles in the pathophysiology of depression, but dopamine is also clearly involved. Some symptoms are controlled principally by a single neurotransmitter, although most of them are regulated by two or even three monoamine systems, predicting that an antidepressant acting on more than one neurotransmitter would be more efficacious in treating depression. Retardation is an example of a symptom which is probably determined by NA function. As such it would be expected to respond more readily to an antidepressant acting on NA and 5-HT (such as milnacipran) than to a SSRI.
Retardation is characterised by a slowness of thought and speech, an impaired ability to concentrate and a decreased motor activity. The antidepressant response has been studied in patients with moderate to severe psychomotor retardation (3 or 4 on item 8 of HDRS (Hamilton Depression Rating Scale). This investigation led by Sechter et al13 showed that 98% of these patients responded (CGI (clinical global impression) improvement scale) to milnacipran, while only 50% responded to the SSRI, paroxetine. The NA system targeted by milnacipran but not by paroxetine is the probable explanation for the better response obtained with the SNRI.
ADVERSE EFFECTS An interesting study by Dunn et al15 showed that only a minority of patients take antidepressants at the recommended dose and for the recommended duration (Figure 2). With SSRI, just over 30% took the antidepressant according to current recommendations while for about 10% the duration was too short. Less than 10% of patients took TCA according to the recommendations, while over 60% took an insufficient dose for an inadequate duration.
Table 2 Comparison of efficacy between milnacipran and two SSRI on the severity of depression, at baseline and end-point (42 days) in two independent studies. MADRS, Montgomery Asberg depression rating scale. n / number of patients. **P /0.007. Taken from Sechter et al13 and Clerc14 MADRS Moderate/severe
N Baseline End-point (42 days) Effect size
Mild/moderate
Milnacipran
Fluvoxamine
Milnacipran
Paroxetine
57 37.1 12.9**
56 35.5 18.1
148 28.9 13.6
151 29.6 12.8
24.2**
17.4
15.3
16.8
Figure 2 Dosage and duration of antidepressant treatments. The ordinate represents the percentage of patients taking a SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant). Horizontal lines column / percentage of patients taking the recommended dose; white column / percentage of patients taking the drug for insufficient duration; striped columns /percentage of patients taking an inadequate dose; dotted column /percentage of patients taking an inadequate dose and for insufficient duration. Taken from Dunn et al.15
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D Baldwin
Clearly, the impact of the unpleasant side effects influences the dose of TCA administered. This overwhelming majority of patients taking antidepressants for an insufficient duration is, however, independent of the drug prescribed. This is probably more related to a lack of education of both doctors and patients about the value of continuation treatment. Figure 3 shows a comparison of the principal undesirable side effects between TCA, SSRI and the SNRI, milnacipran. Only nausea occurs more frequently (20%) following treatment with SSRI compared with TCA and milnacipran. All other side effects reported occur more frequently with TCAs in contrast to SSRI and milnacipran.16 The tolerability of milnacipran is comparable with that of the SSRI. Most adverse events associated with milnacipran or SSRI treatment are of mild to moderate severity, occurring early in treatment, and tending to either diminish or resolve with continuing therapy. In particular, anticholinergic side effects, such as dry mouth, constipation and tremor are greatly reduced with SSRI and milnacipran. Sweating, tiredness and somnolence, which are due to the blockade of noradrenergic receptors, occur in less than 5% of patients treated with SSRI or milnacipran. Secondary adverse events due to TCA, SSRI and milnacipran are included in Table 3. With the exception of dysuria, probably related to increased noradrenergic stimulation of the urinary tract, which occurs with TCA and milnacipran, no side effect appears more common with the SNRI. In contrast to the two other classes of antidepressants, an improvement of cognition and a calming effect but no sedation are frequently observed. Fukuchi and Kanemoto17 have compared milnacipran with fluvoxamine in 202 depressed outpatients in a case / control study and found, by a global analysis, an overall similar efficacy. In moderate to severely depressed individuals with a mean HDRS17 of 24.4, however, the percentage of remissions was 42% with milnacipran and 23% with fluvoxamine. Moreover the patients with insomnia, agitation
Table 3 Secondary adverse events of antidepressants. TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor. * /improvement; # / calming effect. x, xx, xxx indicate the level of frequency TCA
SSRI
xxx xxx xxx x xx? x
0* x? 0? xxx varies 0
Cognition Sedation Effects on driving Sexual dysfunction Weight gain Dysuria
Milnacipran 0* 0# 0 0 0 x
or predominant somatic symptoms showed a significantly (P B/0.05) better response to milnacipran than fluvoxamine. These findings thus confirm the data described above13 and support the calming effect of the SNRI. Therefore, taken together these results indicate that globally milnacipran is better tolerated than TCA and is more efficacious and possibly better tolerated than SSRI.
SAFETY
IN
OVERDOSE
TCA can be lethal in overdose from five times the daily dose which means that a month’s prescription for a TCA puts a potentially fatal ‘‘weapon’’ into the patients’ hands. SSRIs are non-lethal, and serious events are rare even at a dose of 30 times the daily dose. Similarly, milnacipran is non-lethal: no serious adverse events have been seen at 30 times the daily dose. In Table 4, the fatal toxicity index (deaths per million prescriptions) for the different types of antidepressants, shows that the most toxic are TCA followed by MAOI, atypical and SSRI. Given that self-poisoning is the most frequently used means of attempting suicide, the safety of an antidepressant in case of an overdose is an essential safety element. Milnacipran can thus be considered as a secure alternative to TCA when extra efficacy is required without sacrificing safety in overdose.
POTENTIAL DRUG INTERACTIONS Depressed patients, particularly the elderly, often take concomitant medication with an antidepressant. The possibility of adverse events resulting from drug interactions is Table 4 Antidepressant fatal toxicity index (FTI). Values of FTI represent the UK deaths per million prescriptions, from 1987 to 1992. Cl, confidence limits. Taken from Henry et al26 Class Figure 3 Principal adverse events of TCA, SSRI and SNRI. TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor. Taken from Puech et al.16
TCA MAOI Atypical SSRI
FTI
95% Cl
P
34.14 13.48 6.19 2.02
32.47 /38.86 6.93 /22.19 4.04 /8.80 0.64 /4.17
B/0.001 B/0.001 B/0.001 B/0.001
Essential considerations when choosing a modern antidepressant
Table 5 Cytochrome P450 enzymes and SSRI. SSRI, serotonin and noradrenaline reuptake inhibitors; TCA, tricyclic antidepressants; NSAID, non-steroid anti-inflammatory drugs Enzyme
SSRI
7
there is no significant interaction with psychotropic drugs, such as lithium, benzodiazepines, levomepromazine, and carbamazepine.21
Substrates
CONCLUSIONS
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1A2
Fluvoxamine
2C19
Fluoxetine, fluvoxamine, paroxetine
2C9
Fluvoxamine, paroxetine, sertraline Fluoxetine, paroxetine
2D6
3A4
Theophylline, TCA, melatonin, clozapine, haloperidol Benzodiazepines, propranolol, TCA, proton pump inhibitor NSAIDs
TCA, antipsychotics, b-blockers, antiarrhythmics Fluvoxamine, norfluoxetine Very many including antibiotics, antivirals, benzodiazepines, Ca antagonists, etc.
therefore a major consideration. Stanton et al18 and Classen et al19 give some interesting figures concerning these drug interactions. Up to 11% of all patients suffer from undesirable side effects produced by drug /drug interactions. In addition, drug interaction-related adverse effects account for one in 50 of all hospital admissions. TCA are metabolised by various liver cytochrome P450 (mainly 2D6) enzymes commonly associated with the metabolism of psychotropic drugs.20 In addition, in vitro they inhibit the 2D6 isoenzyme but not at clinical concentrations. Many SSRI inhibit several cytochrome P450 enzymes at clinical doses. Table 5 lists the different P450 enzymes inhibited by SSRI and the substrates for these isoenzymes, indicating the likely interactions with SSRI. Milnacipran is excreted essentially as the parent compound and the inactive glucuronic acid conjugate.21 The liver and kidney are similarly involved in its elimination.22 Since there is no hepatic metabolism, no dose adjustment is necessary in hepatically impaired patients (e.g. in alcohol dependence). Milnacipran is not metabolised by, and does not inhibit, any cytochrome P450 isoenzyme,23 consequently there is no risk of pharmacokinetic interaction with coprescribed medication. Specific studies have confirmed that
There is no overall ‘‘best antidepressant’’ and the existing drugs are still far from ideal.9 Depression is not due to a malfunction of a single neurotransmitter system, and its treatment is difficult because of its multi-faceted picture. Yet depression is treatable and the goal of physicians is to find an antidepressant that is most suitable for an individual patient. Each criteria must be weighed in relation to the patient’s situation in order to select a medication the mostly adapted for him. Clinical outcomes in depression can be improved by public education and professional training. A good relationship between the clinician and the patient is essential, in fact ineffective patient /physician communication may be largely responsible for patients’ discontinuation or switching of antidepressants before completion of the recommended treatment period.24 Improvements to existing antidepressant drugs and new targets for antidepressant pharmacotherapy will result in better depression outcomes. Adjunctive and psychological treatments are helpful to achieve a complete remission and an efficacious prevention of relapse. But, finally, the skill of the clinician in choosing the right antidepressant for the right patient remains the key to effective therapy.
KEY POINTS . Depression is a major health problem but can be successfully treated . Many antidepressants are available and the choice from the different classes of drugs and, in the same class from the different drugs, is difficult . Efficacy, suitability, adverse effects, safety in overdose and potential drug interactions are the most important criteria which might help choosing the best antidepressant for an individual patient
REFERENCES 1.
2.
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122: 509 /22. Asnis GM, Wetzler S, Sanderson WC, Kahn RS, van Praag HM (1992) Functional interrelationship of serotonin and norepinephrine: cortisol response to MCPP and DMI in patients with panic
3. 4.
disorder, patients with depression, and normal control subjects. Psychiatry Res 43: 65 /76. Richelson E (1994) Pharmacology of antidepressants /characteristics of the ideal drug. Mayo Clinic Proc 69: 1069 /81. Potter WZ, Manji HK (1994) Catecholamines in depression: an update. Clin Chem 40: 279 /87.
8
5. 6. 7.
8.
9.
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 12/01/14 For personal use only.
10.
11.
12.
13.
14.
15.
D Baldwin
Sitsen JMA, Zivkov M (1995) Mirtazapine: clinical profile. CNS Drugs 4 (Suppl 1): 39 /48. Holm KJ, Markham A (1999) Mirtazapine: a review of its use in major depression. Drugs 57: 607 /31. Nelson JC, Mazure CM, Bowers MB, Jatlow PI (1991) A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 48: 303 /7. Seth R, Jennings AL, Bindman J, Phillips J, Bergmann K (1992) Combination treatment with noradrenalin and serotonin reuptake inhibitors in resistant depression. Br J Psychiatry 161: 562 /5. Baldwin D, Thompson C (2003) The future of antidepressant pharmacotherapy. World Psychiatry (in press). Anderson IM, Tomenson BM (1994) The efficacy of selective serotonin re-uptake inhibitors in depression: A meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol 8: 238 /49. Anderson IM (1998) SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety 7 (Suppl 1): 11 /7. Anderson IM, Nutt DJ, Deakin JF (2000) Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. J Psychopharmacol 14: 3 /20. Sechter D, Weiller E, Pezous N, Bisserbe JC (2003) Psychomotor retardation as a predictive factor favouring a positive clinical response to milnacipran. Int Clin Psychopharmacol (in press). Clerc G, the Milnacipran/Fluvoxamine Study group (2001) Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenaline reuptake inhibitor: a comparison with fluvoxamine. Int Clin Psychopharmacol 16: 145 /51. Dunn RL, Donoghue JM, Ozminkowski RJ, Stephenson D, Hylan TR (1999) Cross-sectional database analysis of antidepressant prescribing in general practice in the United Kingdom. J Psychopharmacol 13: 136 /43.
16.
17.
18.
19.
20.
21.
22.
23. 24.
25.
26.
Puech A, Montgomery SA, Prost JF, Solles A, Briley M (1997) Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 12: 99 /108. Fukuchi T, Kanemoto K (2002) Differential effects of milnacipran and fluvoxamine, especially in patients with severe depression and agitated depression: a case-control study. Int Clin Psychopharmacol 17: 53 /8. Stanton LA, Peterson GM, Rumble RH, Cooper GM, Polack AE (1994) Drug-related admissions to an Australian hospital. J Clin Pharm Ther 19: 341 /7. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP (1997) Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. J Am Med Assoc 277: 301 / 6. Nemeroff CB, DeVane CL, Pollock BG (1996) Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153: 311 /20. Puozzo C, Leonard BE (1996) Pharmacokinetics of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 11 (Suppl 4): 15 /27. Briley M, Moret C (1997) Antidepressant properties of specific serotonin-noradrenaline reuptake inhibitors. In: Skolnick P (ed.) Antidepressants: New Pharmacological Strategies . Totowa, NJ: Humana Press: 35 /52. Sawada Y, Ohtani H (2001) Pharmacokinetics and drug interactions of antidepressive agents. Nippon Rinsho 59: 1539 /45. Bull SA, Hu XH, Hunkeler EM, Lee JY, Ming EE, Markson LE, Fireman B (2002) Discontinuation of use and switching of antidepressants: influence of patient /physician communication. J Am Med Assoc 288: 1403 /9. Kasper S, Pletan Y, Solles A, Tournoux A (1996) Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results. Int Clin Psychopharmacol 11 (Suppl 4): 35 /9. Henry JA, Alexander CA, Sener EK (1995) Relative mortality from overdose of antidepressants. Br Med J 310: 221 /4.
International Journal of Psychiatry in Clinical Practice 2003 Volume 7 (Suppl 1) Pages 3 /8
3
Essential considerations when choosing a modern antidepressant DAVID BALDWIN
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 12/01/14 For personal use only.
University of Southampton, UK
Correspondence Address D. Baldwin, Community Clinical Sciences Research Division, Faculty of Medicine, Health and Biological Sciences, University of Southampton, UK Tel: /(44) 2380 825533 Fax: /(44) 2380 234243 E-mail: [email protected]
The man-years of disability produced by depression in industrialised nations is second only to that caused by ischaemic heart disease. One in ten patients seen by a primary care physician is suffering from depressive symptoms (but neither of them may recognise it). Depression is clearly a major health problem, which can, however, be successfully treated by modern antidepressants in the overwhelming majority of cases. The problem for the primary care physician is not whether to treat but how to treat major depression. The increasing number of antidepressants from different families with different mechanisms has become an embarrassment of riches. When choosing an antidepressant, efficacy, adverse effects, safety in overdose, potential drug interactions and withdrawal effects are among the principal criteria. Although all antidepressants may appear to be equivalent in efficacy, in more severely depressed patients it has been demonstrated that dual action antidepressants, acting on both serotonin and noradrenaline, have superior efficacy to compounds acting on a single neurotransmitter. In addition certain types of depressive symptoms may respond better to one antidepressant than to another. The importance of adverse effects goes beyond patient safety and comfort and has a major influence on efficacy. If, due to adverse effects, an antidepressant is prescribed at sub-optimal doses or the patient is not compliant, even the most effective antidepressant will perform badly. The risk of suicide is inherent to depression, and to prescribe a drug which if taken in overdose can be fatal if used in a suicide attempt, is clearly unacceptable. Similarly certain antidepressants have a far greater potential for interactions with other drugs with potentially toxic effects and should be avoided in patients taking several medications. Applying these criteria globally will not designate a single ‘‘best antidepressant’’ but consideration of the importance of each criteria for an individual patient will help the clinician to find the antidepressant best adapted to each patient. (Int J Psych Clin Pract 2003; 7 (Suppl 1): 3 8) /
Keywords antidepressant criteria serotonin
INTRODUCTION
D
epression is a chronic and usually recurrent illness that is associated with significant morbidity and mortality. Despite the highly prevalent nature of the disease, depression is frequently unrecognised and undertreated. The majority of cases of depression are managed solely within primary care, but there is ample evidence that general practice management may not change with guidelines and education about
choice noradrenaline
depression. Patients frequently experience recurrent depressive episodes characterised by a longer duration and a greater severity than the initial episode. In addition, the efficacy of antidepressants tends to decline with each successive episode. To prevent relapse and recurrence, treatment needs to be continued for a long period of time, so optimising compliance with antidepressant medication is essential. However, compliance is known to be generally poor. Thus, these considerations explain why it is difficult, for many DOI: 10.1080/13651500310000825
4
D Baldwin
primary care physicians, to diagnose and manage the illness effectively. This paper reviews the most important criteria for choosing an antidepressant.
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 12/01/14 For personal use only.
DIFFERENT TYPES OF ANTIDEPRESSANTS The monoamine hypothesis of depression, which dates from the mid 1960s1 is still the most widely accepted, even though it has undergone a series of minor modifications over the years. The symptoms of depression are generally considered to be related to a decreased content and/or activity of cerebral monoamines, particularly serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA).2 The discovery of the antidepressant properties of the monoamine oxidase inhibitors (MAOI) and the tricyclic antidepressants (TCA) which both increase concentrations of both monoamines in the brain, gave further credibility to the hypothesis. MAOI and TCA, however, have considerable side effects. The MAOI interact with foodstuffs which contain tyramine, causing a dramatically increased release of NA leading to potentially dangerous increases in blood pressure. Reversible MAOI, such as moclobemide, are displaced at this enzyme by large amounts of tyramine and thus do not require the dietary restrictions of the first generation of MAOI which are irreversible. Apart from blocking monoamine reuptake, TCA interact directly with various synaptic receptors, notably the cholinergic muscarinic receptor, a1-adrenoceptors, and histamine H1 receptors.3 These interactions are responsible for the major side effects of these compounds: dry mouth, constipation, blurred vision and other cholinergic side effects, orthostatic hypotension, and sedation. In addition to the discomfort they cause, these side effects diminish antidepressant efficacy either by causing treatment to be abandoned or by reducing compliance and encouraging the use of low, therapeutically suboptimal doses. Considerable research efforts over the last few decades have thus centred on the search for compounds devoid of these receptor interactions and their associated side effects. The first major advance since TCA, the selective serotonin reuptake inhibitors (SSRI), in fact went one step further, because they are not only devoid of direct receptor interactions, but also the ability to inhibit the reuptake of noradrenaline. There are now six well-established agents in this group, fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram and escitalopram. The advantages conferred by the specificity of their action and their lack of TCA-like receptor blocking include lack of cardiotoxicity in overdose and a different more benign side effect profile. The major side effects are mediated via stimulation of 5-HT2 receptors (agitation, anxiety, panic attacks, insomnia and sexual dysfunction) and 5-HT3 receptors (nausea, gastrointestinal upset, diarrhoea and headache). There is considerable evidence to suggest that increasing NA function has an antidepressant effect.4 Relatively selective
NA reuptake inhibitors, such as desipramine and lofepramine, have clear antidepressant efficacy. More recently another NA-specific agent, reboxetine, has been introduced. This is the prototypical agent of a new class of antidepressants called NA reuptake inhibitors (NARI). Mirtazapine, which increases noradrenergic and serotonergic neurotransmission through blockade of a2-adrenoceptors while blocking 5-HT2 and 5-HT3 receptors, improves depressive symptoms. Mirtazapine5,6 has been termed the first noradrenergic and specific serotonergic antidepressant (NaSSA). Evidence that simultaneous stimulation of the 5-HT and NA systems are probably complementary is provided by combination studies with SSRI and NARI.7,8 Consequently, there has been a recent tendency toward the development of new antidepressants that selectively and simultaneously inhibit the reuptake of both 5-HT and NA, with no affinity for the synaptic receptors responsible for the adverse effects of TCA. These compounds, such as venlafaxine, milnacipran and duloxetine, are referred to as the specific serotonin and noradrenaline reuptake inhibitors (SNRI). The situation of venlafaxine is complex since at low doses it is essentially a SSRI and only inhibits NA reuptake at higher doses. In contrast, milnacipran has a dual action on 5-HT and NA neurotransmission at all doses. Duloxetine is expected to become available in 2003 and also has a dual action at all doses, but there is limited published data. In addition to these different classes of antidepressants, most of which are already marketed, there is a list of potential new antidepressants with different mechanisms, such as the substance P (NK-1) receptor antagonists, corticotrophinreleasing factor receptor antagonists, glucocorticoid receptor antagonists, vasopressin receptor antagonists, and melatonin receptor agonists (see Baldwin and Thompson9). Since the actions of these compounds are more or less indirectly linked to the functioning of the 5-HT system, it remains to be seen whether they will represent any major clinical advantage over existing drugs.
WHICH ANTIDEPRESSANT? EFFICACY Many studies have compared the efficacy of the different antidepressants, and the results of meta-analyses10 12 show that, when all studies are considered, TCA, SSRI and SNRI have essentially equivalent efficacy. However, in hospitalised patients TCA and SNRI tend to be superior to SSRI. Interestingly, in these more seriously depressed patients, dual action TCA are superior to SSRI, whereas TCA acting on a single neurotransmitter, such as desipramine, have been shown to be equivalent to SSRI. In moderate to severe depression for example, a metaanalysis of studies comparing the SNRI, milnacipran (100 mg/day), with different TCA (150 mg/day), has shown similar results in terms of responses and remissions in both groups (Table 1).
Essential considerations when choosing a modern antidepressant
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Table 1 Effect of treatment with milnacipran or TCA at doses, indicated in mg/ day, on the percentage of responders and remissions in moderate to severe depression. TCA, tricyclic antidepressants. Responders are patients who respond by a decrease of 50% or more from baseline in scores on the Hamilton Depression Rating Scale (HDRS) to treatment. Remission is defined as a lack of depressive symptoms and with HDRS equal or less than 8. Taken from Kasper et al.25 Milnacipran, 100 mg/day (%)
TCA, 150 mg/day (%)
64 39
67 42
Responders Remissions
Figure 1 Monoamine systems implicated in depressive symptoms
Sechter et al13 and Clerc14 have compared milnacipran with some SSRI in mild to moderate and moderate to severe depression, respectively (Table 2). Table 2 shows that in mild to moderate depression milnacipran is equipotent to the SSRI, paroxetine, using MADRS (Montgomery Asberg Depression Rating Scale). But in moderate to severe depression, milnacipran has shown a larger decrease in MADRS at endpoint (42 days) and a greater effect size than the SSRI, fluvoxamine (Table 2).13,14
SUITABILITY Figure 1 summarises the different depressive symptoms and the monoamine systems that are thought to be principally implicated. As already mentioned above, 5-HT and NA play key roles in the pathophysiology of depression, but dopamine is also clearly involved. Some symptoms are controlled principally by a single neurotransmitter, although most of them are regulated by two or even three monoamine systems, predicting that an antidepressant acting on more than one neurotransmitter would be more efficacious in treating depression. Retardation is an example of a symptom which is probably determined by NA function. As such it would be expected to respond more readily to an antidepressant acting on NA and 5-HT (such as milnacipran) than to a SSRI.
Retardation is characterised by a slowness of thought and speech, an impaired ability to concentrate and a decreased motor activity. The antidepressant response has been studied in patients with moderate to severe psychomotor retardation (3 or 4 on item 8 of HDRS (Hamilton Depression Rating Scale). This investigation led by Sechter et al13 showed that 98% of these patients responded (CGI (clinical global impression) improvement scale) to milnacipran, while only 50% responded to the SSRI, paroxetine. The NA system targeted by milnacipran but not by paroxetine is the probable explanation for the better response obtained with the SNRI.
ADVERSE EFFECTS An interesting study by Dunn et al15 showed that only a minority of patients take antidepressants at the recommended dose and for the recommended duration (Figure 2). With SSRI, just over 30% took the antidepressant according to current recommendations while for about 10% the duration was too short. Less than 10% of patients took TCA according to the recommendations, while over 60% took an insufficient dose for an inadequate duration.
Table 2 Comparison of efficacy between milnacipran and two SSRI on the severity of depression, at baseline and end-point (42 days) in two independent studies. MADRS, Montgomery Asberg depression rating scale. n / number of patients. **P /0.007. Taken from Sechter et al13 and Clerc14 MADRS Moderate/severe
N Baseline End-point (42 days) Effect size
Mild/moderate
Milnacipran
Fluvoxamine
Milnacipran
Paroxetine
57 37.1 12.9**
56 35.5 18.1
148 28.9 13.6
151 29.6 12.8
24.2**
17.4
15.3
16.8
Figure 2 Dosage and duration of antidepressant treatments. The ordinate represents the percentage of patients taking a SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant). Horizontal lines column / percentage of patients taking the recommended dose; white column / percentage of patients taking the drug for insufficient duration; striped columns /percentage of patients taking an inadequate dose; dotted column /percentage of patients taking an inadequate dose and for insufficient duration. Taken from Dunn et al.15
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D Baldwin
Clearly, the impact of the unpleasant side effects influences the dose of TCA administered. This overwhelming majority of patients taking antidepressants for an insufficient duration is, however, independent of the drug prescribed. This is probably more related to a lack of education of both doctors and patients about the value of continuation treatment. Figure 3 shows a comparison of the principal undesirable side effects between TCA, SSRI and the SNRI, milnacipran. Only nausea occurs more frequently (20%) following treatment with SSRI compared with TCA and milnacipran. All other side effects reported occur more frequently with TCAs in contrast to SSRI and milnacipran.16 The tolerability of milnacipran is comparable with that of the SSRI. Most adverse events associated with milnacipran or SSRI treatment are of mild to moderate severity, occurring early in treatment, and tending to either diminish or resolve with continuing therapy. In particular, anticholinergic side effects, such as dry mouth, constipation and tremor are greatly reduced with SSRI and milnacipran. Sweating, tiredness and somnolence, which are due to the blockade of noradrenergic receptors, occur in less than 5% of patients treated with SSRI or milnacipran. Secondary adverse events due to TCA, SSRI and milnacipran are included in Table 3. With the exception of dysuria, probably related to increased noradrenergic stimulation of the urinary tract, which occurs with TCA and milnacipran, no side effect appears more common with the SNRI. In contrast to the two other classes of antidepressants, an improvement of cognition and a calming effect but no sedation are frequently observed. Fukuchi and Kanemoto17 have compared milnacipran with fluvoxamine in 202 depressed outpatients in a case / control study and found, by a global analysis, an overall similar efficacy. In moderate to severely depressed individuals with a mean HDRS17 of 24.4, however, the percentage of remissions was 42% with milnacipran and 23% with fluvoxamine. Moreover the patients with insomnia, agitation
Table 3 Secondary adverse events of antidepressants. TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor. * /improvement; # / calming effect. x, xx, xxx indicate the level of frequency TCA
SSRI
xxx xxx xxx x xx? x
0* x? 0? xxx varies 0
Cognition Sedation Effects on driving Sexual dysfunction Weight gain Dysuria
Milnacipran 0* 0# 0 0 0 x
or predominant somatic symptoms showed a significantly (P B/0.05) better response to milnacipran than fluvoxamine. These findings thus confirm the data described above13 and support the calming effect of the SNRI. Therefore, taken together these results indicate that globally milnacipran is better tolerated than TCA and is more efficacious and possibly better tolerated than SSRI.
SAFETY
IN
OVERDOSE
TCA can be lethal in overdose from five times the daily dose which means that a month’s prescription for a TCA puts a potentially fatal ‘‘weapon’’ into the patients’ hands. SSRIs are non-lethal, and serious events are rare even at a dose of 30 times the daily dose. Similarly, milnacipran is non-lethal: no serious adverse events have been seen at 30 times the daily dose. In Table 4, the fatal toxicity index (deaths per million prescriptions) for the different types of antidepressants, shows that the most toxic are TCA followed by MAOI, atypical and SSRI. Given that self-poisoning is the most frequently used means of attempting suicide, the safety of an antidepressant in case of an overdose is an essential safety element. Milnacipran can thus be considered as a secure alternative to TCA when extra efficacy is required without sacrificing safety in overdose.
POTENTIAL DRUG INTERACTIONS Depressed patients, particularly the elderly, often take concomitant medication with an antidepressant. The possibility of adverse events resulting from drug interactions is Table 4 Antidepressant fatal toxicity index (FTI). Values of FTI represent the UK deaths per million prescriptions, from 1987 to 1992. Cl, confidence limits. Taken from Henry et al26 Class Figure 3 Principal adverse events of TCA, SSRI and SNRI. TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor. Taken from Puech et al.16
TCA MAOI Atypical SSRI
FTI
95% Cl
P
34.14 13.48 6.19 2.02
32.47 /38.86 6.93 /22.19 4.04 /8.80 0.64 /4.17
B/0.001 B/0.001 B/0.001 B/0.001
Essential considerations when choosing a modern antidepressant
Table 5 Cytochrome P450 enzymes and SSRI. SSRI, serotonin and noradrenaline reuptake inhibitors; TCA, tricyclic antidepressants; NSAID, non-steroid anti-inflammatory drugs Enzyme
SSRI
7
there is no significant interaction with psychotropic drugs, such as lithium, benzodiazepines, levomepromazine, and carbamazepine.21
Substrates
CONCLUSIONS
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1A2
Fluvoxamine
2C19
Fluoxetine, fluvoxamine, paroxetine
2C9
Fluvoxamine, paroxetine, sertraline Fluoxetine, paroxetine
2D6
3A4
Theophylline, TCA, melatonin, clozapine, haloperidol Benzodiazepines, propranolol, TCA, proton pump inhibitor NSAIDs
TCA, antipsychotics, b-blockers, antiarrhythmics Fluvoxamine, norfluoxetine Very many including antibiotics, antivirals, benzodiazepines, Ca antagonists, etc.
therefore a major consideration. Stanton et al18 and Classen et al19 give some interesting figures concerning these drug interactions. Up to 11% of all patients suffer from undesirable side effects produced by drug /drug interactions. In addition, drug interaction-related adverse effects account for one in 50 of all hospital admissions. TCA are metabolised by various liver cytochrome P450 (mainly 2D6) enzymes commonly associated with the metabolism of psychotropic drugs.20 In addition, in vitro they inhibit the 2D6 isoenzyme but not at clinical concentrations. Many SSRI inhibit several cytochrome P450 enzymes at clinical doses. Table 5 lists the different P450 enzymes inhibited by SSRI and the substrates for these isoenzymes, indicating the likely interactions with SSRI. Milnacipran is excreted essentially as the parent compound and the inactive glucuronic acid conjugate.21 The liver and kidney are similarly involved in its elimination.22 Since there is no hepatic metabolism, no dose adjustment is necessary in hepatically impaired patients (e.g. in alcohol dependence). Milnacipran is not metabolised by, and does not inhibit, any cytochrome P450 isoenzyme,23 consequently there is no risk of pharmacokinetic interaction with coprescribed medication. Specific studies have confirmed that
There is no overall ‘‘best antidepressant’’ and the existing drugs are still far from ideal.9 Depression is not due to a malfunction of a single neurotransmitter system, and its treatment is difficult because of its multi-faceted picture. Yet depression is treatable and the goal of physicians is to find an antidepressant that is most suitable for an individual patient. Each criteria must be weighed in relation to the patient’s situation in order to select a medication the mostly adapted for him. Clinical outcomes in depression can be improved by public education and professional training. A good relationship between the clinician and the patient is essential, in fact ineffective patient /physician communication may be largely responsible for patients’ discontinuation or switching of antidepressants before completion of the recommended treatment period.24 Improvements to existing antidepressant drugs and new targets for antidepressant pharmacotherapy will result in better depression outcomes. Adjunctive and psychological treatments are helpful to achieve a complete remission and an efficacious prevention of relapse. But, finally, the skill of the clinician in choosing the right antidepressant for the right patient remains the key to effective therapy.
KEY POINTS . Depression is a major health problem but can be successfully treated . Many antidepressants are available and the choice from the different classes of drugs and, in the same class from the different drugs, is difficult . Efficacy, suitability, adverse effects, safety in overdose and potential drug interactions are the most important criteria which might help choosing the best antidepressant for an individual patient
REFERENCES 1.
2.
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122: 509 /22. Asnis GM, Wetzler S, Sanderson WC, Kahn RS, van Praag HM (1992) Functional interrelationship of serotonin and norepinephrine: cortisol response to MCPP and DMI in patients with panic
3. 4.
disorder, patients with depression, and normal control subjects. Psychiatry Res 43: 65 /76. Richelson E (1994) Pharmacology of antidepressants /characteristics of the ideal drug. Mayo Clinic Proc 69: 1069 /81. Potter WZ, Manji HK (1994) Catecholamines in depression: an update. Clin Chem 40: 279 /87.
8
5. 6. 7.
8.
9.
Int J Psych Clin Pract Downloaded from informahealthcare.com by The University of Manchester on 12/01/14 For personal use only.
10.
11.
12.
13.
14.
15.
D Baldwin
Sitsen JMA, Zivkov M (1995) Mirtazapine: clinical profile. CNS Drugs 4 (Suppl 1): 39 /48. Holm KJ, Markham A (1999) Mirtazapine: a review of its use in major depression. Drugs 57: 607 /31. Nelson JC, Mazure CM, Bowers MB, Jatlow PI (1991) A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 48: 303 /7. Seth R, Jennings AL, Bindman J, Phillips J, Bergmann K (1992) Combination treatment with noradrenalin and serotonin reuptake inhibitors in resistant depression. Br J Psychiatry 161: 562 /5. Baldwin D, Thompson C (2003) The future of antidepressant pharmacotherapy. World Psychiatry (in press). Anderson IM, Tomenson BM (1994) The efficacy of selective serotonin re-uptake inhibitors in depression: A meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol 8: 238 /49. Anderson IM (1998) SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety 7 (Suppl 1): 11 /7. Anderson IM, Nutt DJ, Deakin JF (2000) Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. J Psychopharmacol 14: 3 /20. Sechter D, Weiller E, Pezous N, Bisserbe JC (2003) Psychomotor retardation as a predictive factor favouring a positive clinical response to milnacipran. Int Clin Psychopharmacol (in press). Clerc G, the Milnacipran/Fluvoxamine Study group (2001) Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenaline reuptake inhibitor: a comparison with fluvoxamine. Int Clin Psychopharmacol 16: 145 /51. Dunn RL, Donoghue JM, Ozminkowski RJ, Stephenson D, Hylan TR (1999) Cross-sectional database analysis of antidepressant prescribing in general practice in the United Kingdom. J Psychopharmacol 13: 136 /43.
16.
17.
18.
19.
20.
21.
22.
23. 24.
25.
26.
Puech A, Montgomery SA, Prost JF, Solles A, Briley M (1997) Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol 12: 99 /108. Fukuchi T, Kanemoto K (2002) Differential effects of milnacipran and fluvoxamine, especially in patients with severe depression and agitated depression: a case-control study. Int Clin Psychopharmacol 17: 53 /8. Stanton LA, Peterson GM, Rumble RH, Cooper GM, Polack AE (1994) Drug-related admissions to an Australian hospital. J Clin Pharm Ther 19: 341 /7. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP (1997) Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. J Am Med Assoc 277: 301 / 6. Nemeroff CB, DeVane CL, Pollock BG (1996) Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153: 311 /20. Puozzo C, Leonard BE (1996) Pharmacokinetics of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol 11 (Suppl 4): 15 /27. Briley M, Moret C (1997) Antidepressant properties of specific serotonin-noradrenaline reuptake inhibitors. In: Skolnick P (ed.) Antidepressants: New Pharmacological Strategies . Totowa, NJ: Humana Press: 35 /52. Sawada Y, Ohtani H (2001) Pharmacokinetics and drug interactions of antidepressive agents. Nippon Rinsho 59: 1539 /45. Bull SA, Hu XH, Hunkeler EM, Lee JY, Ming EE, Markson LE, Fireman B (2002) Discontinuation of use and switching of antidepressants: influence of patient /physician communication. J Am Med Assoc 288: 1403 /9. Kasper S, Pletan Y, Solles A, Tournoux A (1996) Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results. Int Clin Psychopharmacol 11 (Suppl 4): 35 /9. Henry JA, Alexander CA, Sener EK (1995) Relative mortality from overdose of antidepressants. Br Med J 310: 221 /4.
