Long-term Treatment Of Depression Research Articles

Safety of Repeated Administration of Parenteral Ketamine for Depression

The objective of this study was to investigate the safety of repeated parenteral ketamine for depression. An electronic survey inquiring about the frequency of adverse events was distributed to providers of parenteral ketamine for depression. In addition, the investigators conducted a search of published studies describing six or more repeated parenteral ketamine treatments administered to individuals for depression, and extracted reported adverse events. The survey was sent to 69 providers, of which 36 responded (52% response rate); after eliminating those that were incomplete, 27 were included in the analysis. The providers in the analysis collectively reported treating 6630 patients with parenteral ketamine for depression, one-third of whom received more than 10 treatments. Only 0.7% of patients experienced an adverse effect that required discontinuation of ketamine. Psychological distress during the treatment was the most frequent cause. Other adverse events were extremely rare (such as bladder dysfunction (0.1%), cognitive decline (0.03%) and psychotic symptoms (0.03%)). Among the 20 published reports of repeated parenteral ketamine treatments, rates of significant adverse events resulting in discontinuation were low (1.2%). The rate of adverse effects reported in the survey and the published literature is low, and suggests that long-term treatment of depression with ketamine is reasonably safe.

A network meta-analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression.

No network meta-analysis has examined the relative effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression, while this is a very important clinical issue. We conducted systematic searches in bibliographical databases to identify randomized trials in which a psychotherapy and a pharmacotherapy for the acute or long-term treatment of depression were compared with each other, or in which the combination of a psychotherapy and a pharmacotherapy was compared with either one alone. The main outcome was treatment response (50% improvement between baseline and endpoint). Remission and acceptability (defined as study drop-out for any reason) were also examined. Possible moderators that were assessed included chronic and treatment-resistant depression and baseline severity of depression. Data were pooled as relative risk (RR) using a random-effects model. A total of 101 studies with 11,910 patients were included. Depression in most studies was moderate to severe. In the network meta-analysis, combined treatment was more effective than psychotherapy alone (RR=1.27; 95% CI: 1.14-1.39) and pharmacotherapy alone (RR=1.25; 95% CI: 1.14-1.37) in achieving response at the end of treatment.No significant difference was found between psychotherapy alone and pharmacotherapy alone (RR=0.99; 95% CI: 0.92-1.08). Similar results were found for remission. Combined treatment (RR=1.23; 95% CI: 1.05-1.45) and psychotherapy alone (RR=1.17; 95% CI: 1.02-1.32) were more acceptable than pharmacotherapy. Results were similar for chronic and treatment-resistant depression. The combination of psychotherapy and pharmacotherapy seems to be the best choice for patients with moderate depression. More research is needed on long-term effects of treatments (including cost-effectiveness), on the impact of specific pharmacological and non-pharmacological approaches, and on the effects in specific populations of patients.

Unconventional side effects of antidepressants: Focus on emotional blunting

ObjectivesThe aim of this study was to investigate the unconventional side-effects of selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs) antidepressants during long-term treatment of depression, with a special focus on emotional blunting and, in particular, on the possible changes of some features of loving relationships.MethodsTwo hundred outpatients (130 women and 70 men, mean age ± SD: 43.4 ± 11.1 years) were enrolled. They were suffering from mild or moderate depression, according to DSM–5 criteria, treated with one antidepressant for at least six months and involved in a long-term loving relationship. A specifically designed test, the so-called “sex, attachment, love” (SALT) questionnaire was built to assess the possible changes of the loving relationship.ResultsThe results showed differences between the two genders, in particular women taking TCAs reported more sexual side effects than men, whereas men taking SSRIs complained a reduction of the feelings of love and attachment towards the partner.ConclusionsAntidepressants seem to have a dimorphic effect on some elements of loving relationships, however these results need to be further explored.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Ketamine users have high rates of psychosis and/or depression.

Ketamine has been linked to psychosis and used in the treatment of depression. However, no study has examined the prevalence of psychotic and depressive disorders in dependent ketamine users. This study aimed to examine the frequency of various psychopathologies among a series of patients seeking treatment for ketamine use in Hong Kong, China. The case records of 129 patients with a history of ketamine use receiving treatment at three substance use clinics between January 2008 and August 2012 were retrieved for data collection. Patients' demographic data, patterns of substance misuse, and comorbid psychiatric diagnoses were recorded and entered into analyses. The mean age of onset and length of ketamine use were 17.7 ± 4.4 and 8.7 ± 5.7 years, respectively. All patients were dependent on ketamine at the time of data collection. Multiple substance misuse was common. Eighty-four of the 129 (65.1%) patients were found to have comorbid psychiatric disorders, most commonly substance-induced psychotic disorder (31.8%) followed by depressive disorder (27.9%). Psychosis and/or depression were common in ketamine-dependent patients referred to a psychiatric substance use clinic. The findings provide evidence of an association between chronic ketamine use and the presence of psychosis and/or depression. The results raise the issue of safety when using ketamine in the long-term treatment of depression.

EPA-1129 – Efficacy of different antidepressants in long-term treatment of major depressive disorder: A comparative study

Introduction Few studies have compared the available antidepressants in terms of effectiveness in long-term treatment of Major Depressive Disorder (MDD) (Furukawa et al., 2007; Hansen et al., 2008). Objectives Long-term prevention of relapses/recurrence should be the main goal of maintenance MDD treatment. Aims Purpose of the present study was to compare the different antidepressants in terms of retention in treatment (no discontinuation for relapses, hospitalizations or side effects). Methods 150 outpatients with a MDD diagnosis and treated with antidepressants in mono-therapy have been included. Follow-up period was defined in 24 months and information have been obtained from charts, interviews with patients and their relatives and from the Lombardy regional database. A survival analysis (Kaplan-Meier) was performed, considering recurrences, hospitalizations or discontinuation due to side effects as ’death’ events. Results 48.7% out of patients presented a recurrence within the first two years after the beginning of antidepressant treatment. With the exception of Fluoxetine (p=0.09), Amitriptiline (p=0.13), Fluvoxamine (p=0.83), Venlafaxine (p=0.5) and Trazodone (p=0.58), Bupropione appears to be less effective in long-term treatment of MDD compared to other antidepressants. Fluvoxamine appears to be less effective compared to Citalopram (p=0.036), Paroxetine (p=0.037), Clomipramine (p=0.05), Sertraline (p=0.011) and Duloxetine (p=0.024). Conclusions Bupropione and Fluvoxamine would be less effective in long-term treatment of depression. These data should be confirmed by prospective studies with large samples.

On ‘polypharmacy’ and multi-target agents, complementary strategies for improving the treatment of depression: a comparative appraisal

Major depression is a heterogeneous disorder, both in terms of symptoms, ranging from anhedonia to cognitive impairment, and in terms of pathogenesis, with many interacting genetic, epigenetic, developmental and environmental causes. Accordingly, it seems unlikely that depressive states could be fully controlled by a drug possessing one discrete mechanism of action and, in the wake of disappointing results with several classes of highly selective agent, multi-modal treatment concepts are attracting attention. As concerns pharmacotherapy, there are essentially two core strategies. First, multi-target antidepressants that act via two or more complementary mechanisms and, second, polypharmacy, which refers to co-administration of two distinct drugs, usually in separate pills. Both multi-target agents and polypharmacy ideally couple a therapeutically unexploited action to a clinically established mechanism in order to enhance efficacy, moderate side-effects, accelerate onset of action and treat a broader range of symptoms. The melatonin MT1/MT2 agonist and 5-HT(2C) antagonist, agomelatine, which is effective in the short- and long-term treatment of depression, exemplifies the former approach, while evidence-based polypharmacy is illustrated by the adjunctive use of second-generation antipsychotics with serotonin reuptake inhibitors for treatment of resistant depression. Histone acetylation and methylation, ghrelin signalling, inflammatory modulators, metabotropic glutamate-7 receptors and trace amine-associated-1 receptors comprise attractive substrates for new multi-target and polypharmaceutical strategies. The present article outlines the rationale underpinning multi-modal approaches for treating depression, and critically compares and contrasts the pros and cons of established and potentially novel multi-target vs. polypharmaceutical treatments. On balance, the former appear the most promising for the elaboration, development and clinical implementation of innovative concepts for the more effective management of depression.

S03-02 - Prediction and Prevention of Suicide in Elderly Depressives

In the majority of countries, suicide rates increase progressively with age, the highest suicide rates occurring in men above 75 years. Given the progressive aging of population in industrialized countries, old age suicide is one of the greatest public health problems. Although suicide attempt, and particularly completed suicide are relatively rare events in the community, they are very common among older psychiatric patients who contact different levels of health care system, particularly some weeks or months before the suicide event. More than one-third of suicide victims have at least one prior suicide attempt, which significantly increases the risk of future attempts and completed suicide. However, the rate of attempted to completed suicide decreases with increasing age indicating that the lethality of suicidal behaviour is much higher in older persons. Suicide is a very complex, multifactorial human behaviour with several biological and psychosocial components, associated with a number of 1/ Psychiatric (e.g., major mental disorders),2/ Psycho-social (e.g., adverse life situations), and3/ Demographic (e.g., male gender) suicide risk factors.Although depressive disorders and substance-use disorders are the two most common diagnoses among suicide victims, depression is more common and substance abuse is less prevalent in later-life suicide victims. Beside depression and prior suicide attempt, social isolation, loss of relatives/friends and physical illnesses are the most important risk factors for suicide in this age-range. Available studies suggest that appropriate acute and long-term treatment of depression in combination with psychosocial interventions reduces suicide mortality even in this very high-risk population.

Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials.

Selective serotonin reuptake inhibitors are increasingly used in the long-term treatment of depression. Much of the supporting evidence about the effects of these drugs comes from discontinuation trials, a variant of randomized controlled trials whose design is problematic to interpret. We conducted a systematic review to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of unipolar depression. We identified placebo-controlled randomized trials with a treatment duration of at least 6 months by searching MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to update a recently published systematic review. Efficacy was defined in terms of response to treatment (50% improvement in depression score relative to baseline) and remission (score of 7 or below on the Hamilton rating scale for depression). Key secondary outcomes included quality of life, return to work, need for additional treatment and self-harm. Overall acceptability was defined in terms of dropouts for any reason over a course of treatment. Of the 2693 records identified initially, we included 6 randomized controlled trials that met our eligibility criteria. These studies had a moderate risk of bias, had assigned a total of 1299 participants with depression to either treatment or placebo and had followed both groups for 6-8 months. We observed statistically significant improvements in response to treatment (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.12-2.48), but not in remission (OR 1.46, 95% CI 0.92-2.32) or acceptability (OR 0.87, 95% CI 0.67-1.14). The effects appeared greater among patients without comorbidities. There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors lasting more than 1 year for the treatment of depression. The results of our systematic review support current recommendations for 6-8 months of antidepressant treatment following initial recovery but provide no guidance for longer treatment.

Long-term treatment of depression, when is monotherapy used?

Long-term treatment of depression, when is monotherapy used?

Authors' Response to Hockey and Reidak

Because the increased prescriptions of antidepressants are correlated to increased medical visits, it is tempting to conclude, as Hockey did [1], that decreased suicides are a function of greater recognition of depression. It should be noted that the biggest cause of suicide is clinical major depression and increased visits do not treat that; antidepressants do. In a comprehensive review of the literature on the role of long-term antidepressant use to prevent relapse of major depression, Geddes et al. [2] reported that “data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62–78; 2p<0.00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment”. We therefore conclude that just seeing a doctor is in the long term not protective against major depression and its consequences, such as suicide. The weight of existing data supports a positive effect of antidepressants. It is plausible that effective long-term treatment of depression by other methods might also be beneficial. In response to the query from Reidak regarding Eli Lilly, I must say that I completely disclose all my activities, and that is why Aasa Reidak was able to write her letter [3]. I had published before on this topic in Nature Reviews Drug Discovery and had data (which were widely known to all in the field, including Eli Lilly) that since fluoxetine was introduced, prescriptions had gone up and suicide rates had gone down. There is nothing really conceptually new there. That was what was presented at one of Eli Lilly’s regular weekly scientific sessions, which exist at most research institutions, including Lilly Research Laboratories. The paper published here is on the modelling of suicide rates using pre-1988 data to estimate what suicide rates would be now and therefore to predict a potential putative effect of fluoxetine and other selective serotonin reuptake inhibitors [4] . These mathematical modelling data are new to this paper, and that entire analysis and manuscript content took place without the knowledge, support, or input of Eli Lilly. The work reported in the article was done in the absence of any conflict of interest or pharmaceutical industry support. After the paper was submitted for publication in PLoS Medicine, I agreed to provide consultations for Eli Lilly, the manufacturer of fluoxetine. This has been a minor, occasional role, with very limited compensation. Such a relationship did not exist and was not planned when the work was done or the article written and submitted, and it is being disclosed here in the interests of transparency.

Psicoterapia interpersonal en el tratamiento de la depresión mayor

Introducction. Interpersonal psychotherapy (IPT), a time-limited psychotherapy, was developed in the 1970s as a treatment for outpatient adults with major depression. It has been subsequently modified for different age groups and types of mood and non mood disorders and for use as a long-term treatment. It has grown since in its range of research applications and in its clinical accessibility. Method. Review of recent research and educational developments on IPT. Results. IPT has demonstrated efficacy in several randomized controlled trials for acute major depression, for other psychiatric conditions and for long-term treatment of depression. Conclusions. By enhancing interpersonal functioning of the depressed patient IPT initiates the reduction of depressive symptomatology and helps solving current life problems as dual goal of therapy. The publication of efficacy data and the appearance of two North American practice guidelines that include IPT among validated treatments for depression have increased the interest among clinicians in many countries

Cohort Experience in 39 Psychiatric Outpatients with High Doses of an Enteric-Coated Weekly Formulation of Fluoxetine

Background: A new formulation of enteric-coated oral fluoxetine given at a dose of 90mg once weekly has been shown in clinical trials to be well tolerated, safe, effective and associated with very high compliance. It has been approved by regulatory agencies for marketing in the continuation phase of antidepressant therapy. However, literature reports on experience with the once-weekly formulation in clinical practice, especially in patients with substantial medical and psychiatric co-morbidities, are sparse. Methods: Enteric-coated fluoxetine 90mg was provided in a clinic setting to 39 psychiatric outpatients (aged 18 to 78 years) with a confirmed diagnosis of major depression. A co-morbid medical or psychiatric condition was present in 45.8% of the women and 42.9% of the men; most of these patients were on concomitant medication. Seven patients were previously untreated for depression. The tolerability, efficacy and compliance of once-weekly fluoxetine (90 to 540mg) were evaluated in this patient population utilising data from patient charts. Results: Of the 32 patients already receiving fluoxetine, 31 were successfully converted from a single daily dose to a single weekly dose (90 to 540mg) and one patient was converted to a divided dosage (twice weekly). The remaining seven patients were started on weekly fluoxetine administration de novo. Presently, all 39 remain in remission from depression, with no changes in affect, co-morbid conditions or compliance. After dosage adjustments to date, this cohort has been monitored and has a cumulative exposure of weekly fluoxetine administration of 7.2 patient-years. No patient has discontinued enteric-coated fluoxetine therapy. No serious adverse events or hospitalisations were reported. There were no new reports of queried events of nausea, headache or sexual dysfunction. There were no new spontaneous reports of nervousness, asthenia, diarrhoea, abnormal thinking or somnolence. Conclusions: In our clinical experience, enteric-coated fluoxetine, administered at higher doses once or twice weekly, was effective and well tolerated for short-term maintenance treatment of major depressive disorder. The simple once-or twice-weekly administration could be a convenient alternative for some patients during long-term treatment of depression.

Six-month depression relapse rates among women treated with acupuncture

Conventional treatments for Major Depression, although reasonably effective, leave many without lasting relief. Alternative approaches would therefore be welcome for both short- and long-term treatment of depression. Thirty-eight women were randomized to one of three treatment conditions in a double-blind randomized controlled trial of acupuncture in depression.1 All participants eventually received eight weeks of acupuncture treatment specifically for depression. From among the 33 women who completed treatment, 26 (79%) were interviewed at six-month follow-up. Relapse rates were comparable to those of established treatments, with four of the 17 women (24%) who achieved full remission at the conclusion of treatment experiencing a relapse six months later. Compared to other empirically validated treatments, acupuncture designed specifically to treat major depression produces results that are comparable in terms of rates of response and of relapse or recurrence. These results suggest a larger trial of acupuncture in the acute- and maintenance-phase treatment of depression is warranted.

Once-Weekly Fluoxetine

Fluoxetine has become a cultural icon. It has been both praised and vilified; however, regardless of viewpoint, it has had an impact on psychiatry and medicine that few other drugs ever will. Therefore, it is remarkable that this compound has been reborn in a new weekly formulation that is absolutely unique and which has the potential to change the way we think about long-term treatment of depression. The development of this agent came from the recognition that the half-life of norfluoxetine, the main metabolite of fluoxetine and a drug that has equal antidepressant activity, ranged from 7 to 15 days. As our focus in psychiatry has shifted from the short-term treatment of depression to the needs of the many patients who require long-term therapy, the advantages of having a drug that could be taken on less than a daily basis became obvious. The data indicate that patients who are maintained on 20mg a day of fluoxetine do equally well when switched to 90 mg/week and, if symptoms do recur, bi-weekly administration is usually effective. Adverse effects are minimal and comparable to those seen with daily administration, with few exceptions. Adherence to the dosage schedule appears to be better with weekly administration. This echoes our clinical experience that patients are enthusiastic about the idea of only needing to take their antidepressant weekly. It can serve as a nice psychological boost to a patient who is doing well to suggest that their progress now allows them to advance to a weekly maintenance dose. The drug should also be a boon for patients in institutional settings where weekly administration may reduce the cost of drug preparation, packaging and delivery. It is perhaps important to emphasize that no other antidepressant has a half-life that would allow administration on a weekly basis. Thus, for patients who are intolerant of fluoxetine and for nonresponders, there are no comparable options. GUEST COMMENTARIES Drugs 2001; 61 (15): 2229-2230 0012-6667/01/0015-2229/$27.50/0

SAT02.02 Optimising long-term treatment of depression

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Antidepressants in long-term therapy: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors.

Although depression has been shown to be a long-term disorder, most research studies have concentrated on its acute treatment. A literature review of the use of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in long-term treatment of depression was performed and recommendations regarding long-term treatment were summarized. Studies conclusively document the need for continuation treatment after initial remission of symptoms to prevent relapse. Studies also suggest that continuation treatment should last a minimum of 3-6 months following acute response. Conclusions from a few maintenance studies clearly show that recurrence rates are lower when patients at risk for recurrence continue their active treatment at its original dose than when they are switched to placebo. Overall, studies conclude that depression is a recurrent, often chronic, lifetime illness requiring long-term treatment. Continuation therapy of 3 to 6 months after acute stabilization should be considered standard for all depressed patients, and maintenance therapy should be considered for many depressed patients. Newer agents, such as the SSRIs, are preferable to the TCAs for long-term treatment based on their superior tolerability and safety. However, because of the limited number of maintenance studies, further studies using a prospective, randomized design are needed to address this issue.

Pharmacokinetics of Reboxetine in Volunteers with Hepatic Impairment

Objective: Reboxetine is a unique selective norepinephrine (noradrenaline) reuptake inhibitor (selective NRI) that is effective and well tolerated at a dosage of 8 to 10 mg/day in the short- and long-term treatment of depression. The objective of the study was to assess reboxetine pharmacokinetics in patients with moderate to severe hepatic impairment.

Sleep changes during long-term treatment of depression with fluvoxamine--a home-based study.

The effects of antidepressants on sleep in depression have been extensively investigated, although to date there have been relatively few studies of newer drug classes such as specific serotonin reuptake inhibitors (SSRIs). All reported studies on SSRIs have been conducted in patients admitted to sleep laboratories and very few longitudinal studies have continued to measure sleep beyond 5 weeks of treatment. The growing trend towards outpatient and community care has highlighted the need for studies of sleep in depression in a more naturalistic setting, and during longer periods of treatment in line with recommended clinical practice. To establish if the changes in sleep architecture and continuity described during early treatment with SSRIs persist after 3 months, to relate these changes to clinical state, and to establish whether home recordings would yield similar results to previous laboratory studies. We have recorded objective sleep parameters in 12 depressed patients before and during 12-week treatment with an SSRI, fluvoxamine. All the sleep recordings were performed in the patients' own homes, using the Oxford Medilog system. At 12 weeks, 7/12 patients had responded (HAM-D decreased by > 50%). REM latency showed the expected increase early in treatment; this change was less obvious at weeks 3 and 12. Amount of REM sleep was decreased at day 2 and week 3, but returned to baseline by week 12. Slow wave sleep was slightly increased at day 2 and decreased at week 12. Of the sleep continuity measures, the only significant change was in sleep onset latency, which was increased at week 3; the other measures showed non-significant worsening at night 2 and week 3, but most were better than baseline by 12 weeks. Subjective sleep (the three sleep items on the HAM-D) showed a progressive improvement over time, especially in the responders. The effects of the SSRI fluvoxamine on objective sleep measures are in the direction predicted by its pharmacological actions and some persist for at least 12 weeks. In addition subjective appraisal of sleep is strongly affected by mood state. All patients found the home recording procedure acceptable and only minimally disruptive.

Reboxetine, the first selective noradrenaline reuptake inhibitor antidepressant: Efficacy and tolerability in 2613 patients

INTRODUCTION: Reboxetine is the first available selective noradrenaline re-uptake inhibitor (selective NRI). This paper gives an overview of its antidepressant efficacy and tolerability in eight randomized double-blind, multicentre clinical trials. The clinical profile of reboxetine is also compared with that of the tricyclic antidepressants (TCAs) desipramine and imipramine and the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. METHODS: Pooled data were analysed from seven short-term (4 - 8 weeks) and one long-term (up to 1 year) trials comparing reboxetine with placebo, imipramine, desipramine or fluoxetine. The tolerability of reboxetine was evaluated in 2613 patients with major depression or dysthymia. Data from 1959 patients with major depressive disorder were included to assess drug efficacy. Efficacy was principally assessed using the Hamilton Depression Rating Scale (HAM-D). RESULTS: Reboxetine was more effective than placebo in three of four short-term trials, and it was as effective as fluoxetine, imipramine and desipramine. In long-term treatment, reboxetine was more effective than placebo in preventing relapse ( S 50% increase in HAM-D) and recurrence (HAM-D total score h 10). In a subset of severely depressed patients, reboxetine was as effective as imipramine and significantly more effective than fluoxetine. Reboxetine was as effective as imipramine in the elderly, but better tolerated. The most common adverse events among the 1503 patients (adults and elderly) who received reboxetine were dry mouth (22%), constipation (15%), sweating (12%) and insomnia (11%). Overall, reboxetine was well tolerated, as well as the SSRI fluoxetine and better than the TCAs imipramine and desipramine. CONCLUSIONS: Reboxetine is effective and well tolerated in the short and long-term treatment of depression. It is as well tolerated as fluoxetine and better than imipramine and desipramine. ( Int J Psych Clin Pract 2000; 4: 201 - 208)

Outcome of different types of long-term antidepressant treatments: a 3-year follow-up study of 14 182 patients

Background: Antidepressant efficacy studies are rare in large populations for prolonged periods. Methods: The efficacy of antidepressants was investigated by using disability pensions due to major affective disorders as the efficacy variable from a large Finnish population ( n=14 182) during a 3-year follow-up. Results: Of all males, 345 (6.0%) were receiving disability pension due to major affective disorder, and of all females, 498 (5.9%). A logistic regression analysis showed a significantly higher risk (age-adjusted ORs, 1.42–4.09) for disability pension in every antidepressant group except the amitriptyline group when compared with fluoxetine group. Those who used a combination of antidepressive agents (age-adjusted OR 4.09) or moclobemide (age-adjusted OR 2.18) had the highest risks. Conclusions: In the study population fluoxetine and amitriptyline were the most efficient antidepressants in the long-term treatment of depression.