sign in sign up
<<
Home , Astemizole, Bromocriptine, Cisapride, Dosulepin, Lofepramine, Setiptiline

Drug Therapy for in

JMAJ 45(1): 28–33, 2002

Makoto KAMIMURA* and Anri AOBA**

Assistant Professor*, Professor**, Department of Neuropsychiatry, St. Marianna University School of

Abstract: Drug therapy for depression fails in more than half of the patients receiving it because inadequate doses are given. It must be explained before starting drug therapy that its effects only appear after 2Ð4 weeks, but side-effects develop immediately and then begin to subside after 1 week. As a rule, a single is administered. SSRIs are as effective as , but their adverse effects are far weaker than those of the older drugs. This is an advantage of SSRIs over tricyclic antidepressants. According to the American version of the therapeutic algorithm for depression (1995), the first-line drugs for moderate depression are SSRIs. For servere depression, however, tricyclic anti- are more effective than SSRIs. To prevent the relapse of acute depres- sion, drug therapy should be continued for 4Ð6 months at the same dose. When the patients have had two or more depressive episodes in the last 5 years, drug therapy must be continued without changing the dose for 2Ð3 years, or for 5 years if possible, to prevent recurrence. Key words: Depression; Drug therapy; Evidence-based medicine (EBM); Selective inhibitor (SSRI)

Introduction use in Japan in 1999. Subsequently, another SSRI (paroxetin) and the first serotonin nor- In recent years, drug therapy for depression (SNRI, milnaci- has been undergoing the transition from expe- pran) have been successively released in Japan. rience-based medicine to evidence-based medi- Thus, all the types of new-generation antide- cine (EBM) utilizing the findings of random- pressants have now become clinically available ized controlled trials. To cope with the transi- in Japan, as in many other countries. These tion, the investigation of algorithms for EBM- changes have propelled drug therapy for depres- oriented drug therapy is underway. Although it sion in Japan to a new level. was far later than in many other countries, The prevalence of depression in the general fluvoxamin was introduced as the first selective population is 2–7%, with a lifetime prevalence serotonin reuptake inhibitor (SSRI) for clinical of 4–19%, indicating that it is a very common

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 124, No. 1, 2000, pages 33–37).

28 JMAJ, January 2002—Vol. 45, No. 1 DRUG THERAPY FOR DEPRESSION IN JAPAN

Table 1 List of Antidepressants Clinically Available in Japan and Their Daily Doses

Nonproprietary name Daily dose (mg) Tricyclic antidepressants 25Ð300 30Ð300 50Ð300 20Ð150 50Ð225 25Ð300 20Ð150 75Ð150 antidepressants 30Ð150 30Ð60 3Ð6 Others 75Ð200 150Ð600 Selective serotonin reuptake inhibitors (SSRIs) 50Ð150 (2001ϳ) 20Ð40 Serotonine noradrenaline reuptake inhibitors (SNRIs) (2001ϳ) 50Ð100

disease. Among all patients, about one third seek reuptake of monoamines such as serotonin and attention at psychiatric clinics, with another noradrenaline at the synapses and the other is one third being seen at other types of clinics. tricyclic and tetracyclic antidepressants, which The remaining one third do not seek any medi- not only inhibit the reuptake of monoamines cal assistance. Even at psychiatric clinics, depres- but also block various neurotransmitter recep- sion is often overlooked. In addition, drug tors such as ␣1 and ␣2, muscarinic therapy fails to control depression in more than (), H1 and D2 half of the patients receiving it because of inad- receptors. Antidepressants of the former class equate doses. In the end, only one tenth of all can be further divided into two subclasses, patients with depression receive appropriate which are selective serotonin reuptake inhibi- drug therapy.1,2) tors that have a much stronger inhibitory effect This article provides an outline of drug ther- on the reuptake of serotonin than that of nor- apy for depression following the introduction adrenaline (SSRIs) and drugs that inhibit the of the first SSRI in Japan, with the factors reuptake of both serotonin and noradrenaline described above being taken into consideration. (SNRIs). Selective monoamine reuptake inhibitors have Pharmacology of Antidepressants as strong an antidepressant action as tricyclic or (Tables 1Ð3) tetracyclic antidepressants, but cause much less severe side-effects. This is an advantage over Antidepressants can be divided into two major the older antidepressants, particularly during classes: one is drugs that selectively inhibit the long-term treatment to prevent relapse or recur-

JMAJ, January 2002—Vol. 45, No. 1 29 M. KAMIMURA and A. AOBA

Table 2 In vitro Short-term Biochemical Activities of Selected Older and Newer Antidepressants. Adapted from Potter et al. (1991) and Pirmohamed et al. (1992), plus data from Richelson & Nelson (1984) and Lancaster & Gonzalez (1989a,b)

Reuptake inhibition affinity Drug NA 5-HT D ␣1 ␣2 H1 MUSC D2 Older drugsa 0 ¿¿ ע ÷ 0 ? ע Amitriptyline ??/ 0 ? 0 ÷ ע Clomipramine 0 / ע ÷ 00/ 0 0 ÷÷ 0 ע 0 עע Dothiepin ?/ 0 ÷ 0 ¿? 0 Imipramine // 0 ? 0 /? 0 0 ?/ 0 ? 0 ע ? Nortriptyline ??¿ ע ÷Trimipramine / 00 Newer drugs 00000 ? 0 ע (Amfebutamone ( Amoxapine ? 00? 0 / 0 ? 0 ÷ 000000 Fluoxetineb 0 ÷ 000000 Fluvoxamine 0 ÷ 000000 Lofepramine ÷ 00/ 0 /? Maprotiline ? 00? 0 ÷// Mianserin 0 0 0 ÷?¿ 00 0 עParoxetineb 0 ¿ 0000 Sertralineb 0 ÷ 000000 00 עע ÷ Trazodone 0 / 0 a: Tricyclic antidepressants. b: Selective serotonin reuptake inhibitors. ;(5-hydroxytryptamine (serotoninסnoradrenaline (); 5-HTסAbbreviations and symbols: NA ;2-; H1 = H1 ␣ס1-adrenergic receptor; ␣2␣סdopamine; ␣1סD ;equivocal effectסע ;no effectסD2 ; 0סmuscarinic (cholinergic) receptor; D2סMUSC .maximal effectס¿ ;large effectס÷ ;moderate effectס? ;small effectס/ Source: Rudorfer, M.V. et al.: Comparative tolerability profiles of the newer versus older antidepressants. Source: Drug Saf 1994; 10(1): 18Ð46.

rence, because poor compliance can be avoided. effects. The co-administration of drugs to poten- In addition, because of adverse effects on the tiate gastric defensive factors may be effective central nervous system and cardiovascular sys- in preventing the gastrointestinal side-effects tem, these drugs are relatively safe even for of fluvoxamine, although the value of such com- elderly and/or debilitated patients. Unlike tri- binations is largely unproven. Care must be cyclic antidepressants, these drugs are rarely taken when fluvoxamine is used because it is a lethal even when an overdose is taken for potent inhibitor of cytochrome P-450(CYP)1A2 attempted suicide. and thus blocks the of , Fluvoxamine may cause side-effects such theophylline, and warfarin. It also causes mod- as gastrointestinal disorders (including erate inhibition of CYP3A4, and hence blocks and decreased appetite), and irritation, the metabolism of antiallergic drugs (such as , impaired ejaculation, and the seroto- or ) and (a nin syndrome. Therefore, this drug should be gastrointestinal prokinetic drug). Fluvoxamine used with careful consideration of such side- should not be used in combination with any of

30 JMAJ, January 2002—Vol. 45, No. 1 DRUG THERAPY FOR DEPRESSION IN JAPAN

Table 3 Antidepressants Side-effects and Possible Clinical Consequences of Neurotransmitter Receptor Blockade by Antidepressants

Antihistamine H1 Potentiation of central drugs Sedation, drowsiness Weight gain Hypotension Antimuscarinic Blurred vision Dry mouth Sinus Memory dysfunction

Anti-␣1-Adrenergic Potentiation of the antihypertensive effect of (Minipress) Postural hypotension, dizziness Reflex tachycardia

Anti-␣2-Adrenergic Blockade of the antihypertensive effects of (Catapress) and ␣- (Aldomet) Anti- effects Extrapyramidal movement disorders: , , , Endocrine effects: increase of (, , and menstrual changes) Source: Kanba, S. and Richelson, E.: Antidepressant interactions with neurotransmitter receptors in vitro; Prediction of potential side effects. Ed. O’Brien, R.A. In Receptor Binding in Drug Research. Mircel Dekker Inc., New York, Basel, 1986; pp.429Ð477

these drugs because the inhibition of metabo- after about 1 week. In order to assess the effec- lism may result in QT prolongation and ven- tiveness of drug therapy, a single antidepres- tricular . sant is usually administered. In the case of antidepressants, combined drug therapy has Acute Therapy rarely evidenced an increase in efficacy. When the treatment of moderate depression As a rule, acute therapy of depression is is tried from the perspective of EBM, there is treated at outpatient clinics. When anxiety, irri- no evidence that one antidepressant is superior tation, or suicidal ideation is severe or the to another in effectiveness. On the basis of anti- patient is unable to eat, hospitalization is nec- depressant activity, consequently, drug therapy essary. Before starting drug therapy, it should can be started with any antidepressant, but it is be carefully explained to the patient and the better for one having minimal side-effects be family that: 1) depression is a brain disease that selected. According to the American version of can be cured by drug therapy and rest, 2) the the therapeutic algorithm (1995), the first-line family should make allowance for the disease drugs for initiating therapy are SSRIs.3) Based and should not encourage the patient to do too on this policy, fluvoxamine and paroxetine be- much, 3) drug therapy begins to have an effect come the drug of choice in Japan. According to after 2 to 4 weeks, and 4) side-effects develop the Japanese algorithm (1998) produced before immediately, but begin to subside gradually the introduction of fluvoxamine, sulpiride and

JMAJ, January 2002—Vol. 45, No. 1 31 M. KAMIMURA and A. AOBA

the tricyclic or tetracyclic antidepressants are all total. Depression resolves completely within regarded as first-line drugs.4) 6 months after the start of drug therapy in Fluvoxamine is initially administered at a 79% of all patients treated. During the sub- dose of 25–50 mg/day, which is increased to sequent 12 months, remission is only achieved 75–100 mg/day after 1–2 weeks, if necessary. in 2%.5) If depression is associated with psy- If the condition shows a tendency to improve chotic features, the remission rate is even lower. after 2–3 weeks, treatment is continued without For depression of this category, a combination a further increase of the dose. If not, the dose of antidepressants and antipsychotic drugs is can be increased to 150 mg. If the drug is inef- effective. fective despite administration at a higher dose When depression is associated with , for 4–6 weeks, fluvoxamine should be replaced anxiety, and irritation, the combination of an with another antidepressant. If the alternative antidepressant with a is effec- drug is one of the tricyclic antidepressants, the tive, particularly soon after the introduction of initial dose should be 75–100 mg/day. The dose antidepressant therapy. When the response is is increased gradually once every two weeks if inadequate, however, treatment should not be there is no response and an absence of side- continued for more than 2–4 weeks. Generally, effects or tolerable side-effects. It is desirable drug therapy is discontinued step-wise when for the drug to be administered for 4–6 weeks the symptoms have been stabilized.4) or longer at an adequately high dose exceeding 150 mg or around 250 mg, if possible (see Table Continuation Therapy and 1). Because antidepressants can lower the thresh- Maintenance Therapy old for tremor at high doses, the patients should undergo and electroenceph- 1. Continuation therapy: To prevent relapse alography. When an antidepressant is given at before the termination of a depressive such a high dose and fails to elicit any effect, it episode can be regarded as having failed and an alter- Drug therapy for a first episode is continued native antidepressant should be used. for 4–6 months without changing the dose. For For severe depression, tricyclic antidepres- second and subsequent episodes of depression, sants are more effective than SSRIs.3) Ami- treatment is continued the same period as for triptyline and clomipramine are the drugs of the previous episode.6-9) choice. Intravenous infusion of clomipramine and electroconvulsive therapy are used in some 2. Maintenance therapy: Prevention of cases. recurrence and new depressive episodes When depression is refractory to antidepres- After a first depressive episode, depression sant monotherapy, the drugs are administered will recur within one, five, and ten years in in combination with , thyroid hormone, 28%, 68%, and 75% of patients, respectively.10) or (an antiparkinson agent) for Among patients receiving long-term drug ther- potentiation of efficacy. The effectiveness of apy with fluvoxamine at an average dose of such combinations has been documented.3,4) 100 mg/day for 2 years, the recurrence rate was Remission is achieved with first-line drugs in 20%.11) The rate for patients receiving imipra- 38% of patients. This rate increases to 61% and mine at a dose of 200 mg/day for three and five then 77% when therapy is continued by replac- years was 21%12) and 9%,13) respectively. If a ing the first-line drug with a second-line and patient has had two or more depressive epi- then third-line drug, respectively. If fourth-line sodes in the previous five years, it is desirable drugs and alternatives are given subsequently, for prophylactic therapy to be continued for 2– remission is only achieved in another 9% in 3 years at the same dose as that used during

32 JMAJ, January 2002—Vol. 45, No. 1 DRUG THERAPY FOR DEPRESSION IN JAPAN

acute treatment and for 5 years, if possible.11,13) Edited by Sato, K., Higuchi, T. and Yamawaki, N.: Therapeutic Procedures for and Mood Disorders. Seiwa Shoten, Tokyo, Conclusion 1998; pp.63–74. (in Japanese) 5) Naganuma, H.: Outcomes of drug therapy for Drug therapy for depression fails to work in acute phase mood disorders. No to Seishin no more than half of the patients receiving it. In Igaku (Brain and Mind Medicine) 1999; 10: 1–8. particular, tricyclic antidepressants are very (in Japanese) likely to cause adverse events, and have failed 6) Frank, E., Kupfer, D.J., Perel, J.M., Cornes, C. to elicit a sufficient clinical response in patients et al.: Comparison of full-dose versus half-dose receiving these drugs at inadequate doses be- pharmacotherapy in the maintenance treat- cause of such adverse effects. This has been ment of recurrent depression. J Affect Disord partly responsible for the frequent occurrence 1993; 27(3): 139–145. of therapeutic failure. Because two SSRI drugs 7) Furukawa, J.: Drug therapy for major depres- sion. Edited by Otsuka, T., Kazamatsuri, H., (fluvoxamin and paroxetine) and an SNRI Kitamura, T. et al.: Evidence-Based Psychiatric (milnacipran) have now become clinically Therapy, Nippon Hyoron Sha, Tokyo, 1998; available in Japan, more patients with depres- pp.17–29. (in Japanese) sion can receive adequate doses of antidepres- 8) American Psychiatric Association: Practice sants at present. With the advent of this new guideline for major depressive disorder in stage in the treatment of depression, it is hoped adults. Am J Psychiatry 1993; 150 (4 Suppl): that psychiatrists will not overlook depression 1–26. and depressive states that can easily be im- 9) Task Force of the Collegium Internationale Neuro-Psychopharmacologicum (CINP): Im- proved by drug therapy, even if the response is pact of neuropharmacology in the 1990—Strat- not perfect. In other words, it is important to egies for the therapy of depressive illness. Eur identify patients with the indications for ag- Neuropsychopharmacol 1993; 3(2): 153–156. gressive drug therapy as completely as possible. 10) Lavori, P.W., Keller, M.B., Scheftner, W.A. et al.: Recurrence after recovery in unipolar MDD: REFERENCES An observation follow-up study of clinical predictors in somatic treatment as a mediating 1) Shapiro, S., Skinner, E.A., Kessler, L.G. et al.: factor. Int J Methods in Psychiatr Res 1994; 4: Utilization of health and mental health ser- 211–229. vices. Three epidemiologic catchment area 11) Franchini, L., Gasperini, M., Perez, J. et al.: sites. Archi Gen Psychiatry 1984; 41(10): 971– A double-blind study of long-term treatment 978. with or fluvoxamine for prevention 2) Katon, W., von Korff, M., Lin, E. et al.: of highly recurrent unipolar depression. J Clin Adequacy and duration of antidepressant Psychiatry 1997; 58(3): 104–107. treatment in primary care. Med Care 1992; 12) Frank, E., Kupfer, D.J., Perel, J.M. et al.: Three- 30(1): 67–76. year outcomes for maintenance therapies in 3) Nelson, J.C., Docherty, J.P., Henschen, G.M. recurrent depression. Arch Gen Psychiatry et al.: Algorithms for the treatment of sub- 1990; 47(12): 1093–1099. types of unipolar major depression. Psycho- 13) Kupfer, D.J., Frank, E., Perel, J.M. et al.: Five- pharmacol Bull 1995; 31(3): 475–482. year outcome for maintenance therapies in 4) Shioe, K., Kubota, M., Shinohara, M. et al.: recurrent depression. Arch Gen Psychiatry Therapeutic algorithms for major depression. 1992; 49(10): 769–773.

JMAJ, January 2002—Vol. 45, No. 1 33