Clin Drug Investig 2011; 31 (10): 675-689 REVIEW ARTICLE 1173-2563/11/0010-0675/$49.95/0 ª 2011 Adis Data Information BV. All rights reserved. Pirlindole in the Treatment of Depression and Fibromyalgia Syndrome Jaime C. Branco,1,2 Ana Maria Tome´,3,4 Manuel R. Cruz5 and Augusto Filipe3 1 CEDOC, Faculdade de Cieˆncias Me´dicas da Universidade Nova de Lisboa, Lisbon, Portugal 2 Servic¸o de Reumatologia do CHLO, EPE/Hospital Egas Moniz, Lisbon, Portugal 3 Medical Department, Grupo Tecnimede, Sintra, Portugal 4 Faculty of Life Sciences, University of Hertfordshire, Hatfield, UK 5 Centro Hospitalar Psiquia´trico de Lisboa, Lisbon, Portugal Contents Abstract. 675 1. Introduction . 676 2. Literature Search Methodology . 676 3. Burden of Disease and Current Pharmacological Treatment Options . 677 3.1 Depression . 677 3.2 Fibromyalgia Syndrome . 677 4. Pirlindole in the Treatment of Depression and Fibromyalgia Syndrome . 678 4.1 Pharmacological Characteristics . 679 4.1.1 Pharmacokinetics in Humans . 679 4.1.2 Pharmacodynamics in Humans . 679 4.2 Clinical Experience in Depression . 680 4.2.1 Placebo-Controlled Studies . 680 4.2.2 Active Comparator-Controlled Studies . 680 4.2.3 Non-Comparative Studies. 684 4.3 Clinical Experience in Fibromyalgia Syndrome . 684 4.4 Safety and Tolerability. 685 4.4.1 Drug Interactions . 686 5. Conclusions. 686 Abstract Depression and fibromyalgia syndrome are debilitating chronic condi- tions that impose a significant burden on individuals, families and society. Both depression and fibromyalgia have many overlapping symptoms, and antidepressants of several classes are among recommended treatment options for patients with fibromyalgia syndrome. Pirlindole is a selective and re- versible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A) that is approved in some European and non-European countries for the treatment of depression. The antidepressant efficacy and safety of pirlindole have been demonstrated in a number of placebo- and active comparator-controlled studies and are supported by many years of clinical experience in the treat- ment of depression. The drug’s efficacy and safety have also been demon- strated, more recently, in the treatment of fibromyalgia syndrome. Pirlindole 676 Branco et al. has a favourable tolerability profile, with no deleterious effect on cardio- vascular dynamics. The effect of pirlindole on sensorimotor performance relevant to driving a motor vehicle is similar to that of placebo, as pirlindole appears to have an activating rather than a sedating antidepressant profile. Because of its specific and reversible inhibition of MAO-A and relatively short elimination half-life, no tyramine or ‘cheese’ effect is likely after short- or long-term administration. The available evidence supports pirlindole as a safe and effective treatment option for the management of depression and fibromyalgia syndrome. 1. Introduction pirlindole is approved in Portugal and other coun- tries for the treatment of depression. This review Depression is a mood disorder characterized summarizes the evidence for the efficacy and by persistent episodes of loss of interest or plea- tolerability of pirlindole in the management of sure in ordinary activities, and experiences and depression and fibromyalgia syndrome. feelings of helplessness, hopelessness and worth- lessness, accompanied by additional symptoms 2. Literature Search Methodology such as changes in sleep, appetite or weight, and decreased energy, feelings of inadequacy, and Articles included in the current review were difficulty concentrating or making decisions.[1] all randomized, placebo- or active comparator- Fibromyalgia syndrome is a debilitating chronic controlled trials or systematic reviews published medical condition that causes diffuse and/or spe- in English between January 1970 and January cific pain throughout the soft tissues that support 2011 and identified via a search of MEDLINE and move the bones and joints.[2] Associated so- and EMBASE using the keywords (‘pirlindole’ matic and psychological symptoms include fa- OR ‘pirlindol’ OR ‘pyrazidol’) AND (‘depression’ tigue, sleep disturbances, cognitive impairment, OR ‘depressive disorder’ OR ‘antidepressant’ OR nervousness, depression and headaches.[2,3] Both ‘fibromyalgia’ OR ‘fibromyalgia syndrome’). This depression and fibromyalgia syndrome are dis- literature search was supplemented by AdisBase, tressing and common disorders that impose a a proprietary database of Wolters Kluwer Health/ considerable burden on individuals, their families Adis. Additional references were identified from and society.[4-10] the reference lists of published articles and sup- Fibromyalgia syndrome and depression have plied on request from the reference files of Grupo many overlapping symptoms and often occur to- Tecnimede, Sintra, Portugal. The inclusion of gether.[2,3,11] In fibromyalgia syndrome, a psychic placebo-controlled trials in the current review co-morbidity with variables such as anxiety and may provide further insight into the efficacy of depression adversely affects the perception of dis- pirlindole not necessarily provided by analysis of ease severity, functional capacity, and the experi- trials comparing pirlindole with other active ence and tolerance of pain.[12] Furthermore, there agents. In clinical trials of patients with psychia- is emerging evidence that similar candidate genes tric disorders, placebo response rates are often high, may be implicated in both fibromyalgia syndrome and vary considerably;[15,16] the average placebo and depression, with polymorphisms of genes response rate in trials of patients with depression involved in the serotonergic, dopaminergic and has been estimated at 35–45%.[15] Consequently, catecholaminergic systems contributing to the placebo-controlled trials are important to dem- aetiology of fibromyalgia syndrome.[13,14] onstrate the efficacy of a drug,[16] as many trials The selective and reversible inhibitor of mono- of psychiatric disorders fail to confirm superi- amine oxidase (MAO) subtype A (MAO-A) [RIMA] ority of a drug over placebo.[15] ª 2011 Adis Data Information BV. All rights reserved. Clin Drug Investig 2011; 31 (10) Pirlindole in Depression and Fibromyalgia 677 3. Burden of Disease and Current comparable between and within classes.[21,22] How- Pharmacological Treatment Options ever, as the likely adverse events profiles of anti- depressant medications differ, the selection of an 3.1 Depression antidepressant should take tolerability, safety and cost into consideration, as well as patient pref- Depression has been identified by the WHO as erence and the previous treatment response to a [17] a leading cause of global burden of disease. particular drug.[1,21,22] While newer classes of anti- Worldwide, between 4% and 10% of the popula- depressants, such as selective serotonin reuptake tion is likely to experience major depression during inhibitors (SSRIs), noradrenergic reuptake in- [1] their lifetime, and population-based systematic hibitors and serotonin-norepinephrine reuptake reviews of the global burden of mental disorders inhibitors are considered first-line choices, the estimate a median 1-year rate of major depressive use of non-selective MAO inhibitors (MAOIs) [18] disorder of 5.3%. A recent survey-based study has declined because of the necessity for dietary of general medical practices in six European restrictions, adverse events related to their non- countries (UK, Spain, Portugal, Slovenia, Estonia selective and irreversible binding profile, and the and the Netherlands) found a prevalence rate of potential for drug-drug interactions.[1,21-23] The major depressive disorder of 12.2% in consecutive limitations of non-selective MAOIs, which irre- [19] practice attendees. Depression was more than versibly bind to both MAO-A and MAO-B iso- 60% more prevalent in women than in men, with enzymes, led to the development of RIMAs with the highest overall prevalence for women being improved tolerability and safety profiles; these observed in Spain, Portugal and the UK (18.4%, include pirlindole and moclobemide. As MAO-A [19] 17.8% and 13.2%, respectively). The impact of preferentially deaminates norepinephrine and major depression on functioning and quality of serotonin, inhibition of MAO-A is recognized as life (QOL) is illustrated in figure 1. a key factor for antidepressant effect.[28] Choosing an effective treatment strategy for patients with depression is guided by the duration 3.2 Fibromyalgia Syndrome and severity of the condition.[1,21-23] A wide range of effective pharmacological treatment options is The recent European League Against Rheu- available for depression (summarized in table I). matism (EULAR) multidisciplinary taskforce Although there are some suggestions of the su- described fibromyalgia syndrome as a common periority of one mechanism of antidepressant rheumatological condition characterized by chron- action over another, for the majority of patients ic widespread pain and reduced pain threshold, the effectiveness of antidepressants is generally with hyperalgesia and allodynia.[2] The prevalence Depressed mood Emotional pain Loss of interest Loss of pleasure Feelings of guilt Pessimistic feelings Physical pain Depression Low self-worth Poor concentration Sleep disorders Appetite loss/gain Fatigue Atypical physical Clinically significant complaints distress or impairment of functioning Fig. 1. Impact of major depression on functioning and quality of life including symptoms identified in the Diagnostic and Statistical