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Int J Clin Pract. Apr 2006; 60(4): 482–491.
PMCID: PMC1448696
Tolerability and safety of fluvoxamine and other antidepressants
HGM Westenberg1 and C Sandner2
1Department of Psychiatry, University Medical Centre, Utrecht, The Netherlands
2Clinigoa – Medical Clinic, Lisbon, Portugal
Correspondence to: Dr Cláudio Sandner, Clinigoa – Medical Clinic, Avenida de Goa, 12 Amadora, Lisbon, Portugal Tel.: + 351 934220266 Email: claudio.sandner/at/gmail.com
Received November 2005; Accepted January 2006.
Selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitors (SSRIs) and the 5-HT noradrenaline reuptake inhibitor, venlafaxine, are mainstays in treatment for depression. The highly specific actions of SSRIs of enhancing serotonergic neurotransmission appears to explain their benefit, while lack of direct actions on other neurotransmitter systems is responsible for their superior safety profile compared with tricyclic antidepressants. Although SSRIs (and venlafaxine) have similar adverse effects, certain differences are emerging. Fluvoxamine may have fewer effects on sexual dysfunction and sleep pattern. SSRIs have a cardiovascular safety profile superior to that of tricyclic antidepressants for patients with cardiovascular disease; fluvoxamine is safe in patients with cardiovascular disease and in the elderly. A discontinuation syndrome may develop upon abrupt SSRI cessation. SSRIs are more tolerable than tricyclic antidepressants in overdose, and there is no conclusive evidence to suggest that they are associated with an increased risk of suicide. Although the literature suggests that there are no clinically significant differences in efficacy amongst SSRIs, treatment decisions need to be based on considerations such as patient acceptability, response history and toxicity.
Keywords: Antidepressants, selective serotonin reuptake inhibitors, fluvoxamine, tolerability, safety, review
Over the years, there have been considerable advances in the development of new antidepressants with the emergence of the selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitors (SSRIs) and 5-HT noradrenaline reuptake inhibitors (SNRIs). Since their introduction, it has become apparent that these drugs have certain advantages over the older tricyclic antidepressants and monoamine oxidase inhibitors, notably in the area of safety and tolerability. Most clinicians now consider the SSRIs and some of the other new antidepressants first-line treatment for depression and anxiety disorders. However, the issue of safety and tolerability, and indeed efficacy, becomes more complex when comparing members of the newer generations of antidepressants. Not only are SSRIs chemically different from the tricyclic, tetracyclic and other antidepressant agents, considerable structural differences also exist between the various SSRIs. For example, fluvoxamine is the only monocyclic SSRI and belongs to the 2-aminoethyl oxime ethers of aralkylketones. Therefore, some differential pharmacology between the drugs in the same class may be expected. The aim of this review, which was based on a Medline literature search, is to provide a comprehensive comparative overview of the main clinical features of some antidepressants based on pharmacology, pharmacokinetics, tolerability and safety.
Receptor Binding
Most of the effects of antidepressants, whether therapeutic or adverse, can be directly related to their pharmacology. Although the ultimate mechanism of action of antidepressants remains uncertain, it is reasonable to assume that the effects on monoamine systems in the brain are central to their therapeutic effects. SSRIs attain this effect by blocking the 5-HT transporters (5-HTTs) in the brain. Although this is the primary pharmacological effect of all SSRIs, their spectrum of activity is not confined to the blockade of 5-HTT. Venlafaxine, for instance, is one of the most potent antidepressants at blocking the dopamine transporter, and paroxetine, although the most potent blocker of 5-HTT, also has appreciable affinity for the noradrenaline transporter (NAT) (1). In general, SSRIs are weaker than older antidepressants (especially the tricyclic antidepressants) at blocking receptors for neurotransmitter, but sertraline shows some potency at the α1-adrenoreceptor, paroxetine has anticholinergic properties similar to imipramine, and fluoxetine has significant affinity for the 5-HT2C receptor (26).
In comparison with the other SSRIs, paroxetine has the highest affinity for the muscarinic receptor (Figure 1) (1), which at higher dosages, or at low dosages in slow metabolisers, may lead to anticholinergic side effects such as dry mouth, constipation, dizziness, tachycardia, blurred vision, urinary retention and fatigue (7). Anticholinergic side effects also include memory impairment (7, 8), confusion (7), problems with concentration (7) and sexual dysfunction, but these side effects are less likely to occur at normal dosages of paroxetine (912). Compared with other antidepressants, paroxetine also has an affinity for binding at the NAT (Figure 2) (1).
Figure 1
Figure 1
Relative potency of the antidepressants for binding at muscarinic receptors. Potency of antidepressants for binding at muscarinic receptors based on IC50 values: fluvoxamine, 34,000; venlafaxine, 11,000; citalopram, 5600; fluoxetine, 3100; sertraline, (more ...)
Figure 2
Figure 2
Relative potency of the antidepressants for binding at the noradrenaline transporter. Potency of antidepressants at noradrenaline transporter based on IC50 values: citalopram, 6100; desmethylcitalopram, 740; fluvoxamine, 620; venlafaxine, 620; fluoxetine, (more ...)
Of all the SSRIs, citalopram has the highest affinity at histamine receptors (Figure 3). This property, which may cause somnolence (13), sedation (13, 14), sexual dysfunction (10), weight gain (15, 16), memory impairment (17), attention deficit (17) and psychomotor alterations (18, 19), has no or only minor clinical significance for citalopram at normal dosages.
Figure 3
Figure 3
Relative potency of the antidepressants for binding histaminergic (H1) receptors. Potency of antidepressants for binding H1 receptors based on Ki values: fluvoxamine (1), 29,250; paroxetine (1), 23,770; venlafaxine (5), 11,000; sertraline (1), 6578; fluoxetine (more ...)
Fluvoxamine has virtually no affinity for any of the above receptors, but preclinical evidence suggested that fluvoxamine has a high affinity for the σ1-receptor, which is believed to play a role in psychosis and aggression. As shown in Figure 4, of all the SSRIs, fluvoxamine has the highest affinity at the σ1-receptor in rat brain, followed by sertraline, fluoxetine and citalopram. Paroxetine has the lowest affinity for this binding site (20). All SSRIs are more selective for the σ1-receptor than for the σ2-receptor. Although the clinical significance of binding to this receptor remains uncertain, it might account for the superior efficacy of fluvoxamine in psychotic depression (21, 22).
Figure 4
Figure 4
Relative affinity for σ1-receptors. Affinities of selective serotonin reuptake inhibitors for the subtypes of σ-receptors (Ki ratio σ12) (20)
Half-Life and Active Metabolites
The half-lives of fluvoxamine, paroxetine, sertraline and citalopram are all approximately 1 day. The half-life of fluoxetine is approximately 2 days after a single dose and 6 days after multiple dosing (23). The half-life of venlafaxine is relatively short (about 4 h), and hence this drug requires twice daily (b.i.d.) or three times daily dosing (24); the extended-release formulation (venlafaxine XR) permits once-daily dosing.
Fluoxetine has a pharmacological active metabolite, norfluoxetine, which has a half-life of 7–15 days (2325). Sertraline also has an active metabolite (26), citalopram has three active metabolites (27), and escitalopram has two (28). Of the seven metabolites identified from venlafaxine, at least three of them are pharmacologically active (18).
A long half-life of the parent compound or the presence of active metabolites may cause accumulation, which is associated with an increased risk of late-emergent side effects, may be cardiotoxic (especially in case of overdose) and may have clinically unexpected consequences (29).
The significant longer half-lives of fluoxetine and its metabolite, norfluoxetine, are associated with a significantly slower onset of action in comparison with other SSRIs (29). A double-blind study comparing SSRIs in patients with depression have shown that fluoxetine has a significantly slower onset of therapeutic action compared with fluvoxamine (30). In fact, a slower onset of action with fluoxetine compared with the other SSRIs has been reported in a recent meta-analysis of 20 comparative studies (31). Moreover, the gradual accumulation of norfluoxetine may produce a high ratio of norfluoxetine : fluoxetine plasma concentration, which is associated with a poor clinical response (32, 33). This elevated norfluoxetine : fluoxetine ratio may also explain the loss of therapeutic efficacy sometimes observed in long-term treatment with fluoxetine (34).
With the possible exception of citalopram, SSRIs are relatively safe in cases of overdose (3537). Citalopram's active metabolite, didesmethylcitalopram, has played an important role in several cases of cardiotoxicity (29), because it may cause a QT prolongation (35, 37, 38). After discontinuation, residual amounts of fluoxetine and norfluoxetine in the plasma may increase the potential toxicity of subsequent TCA overdose due to pharmacokinetic drug–drug interactions (39).
It is worth noting that the metabolites of sertraline (desmethylsertraline), fluoxetine (norfluoxetine) and paroxetine all inhibit cytochrome P (CYP)450 isoenzymes, notably CYP 2D6 (23). Although CYP 2D6 makes up only about 2–5% of the total CYP in the human liver, it is a major enzyme catalysing the oxidation of more than 30 drugs (40).
Protein Binding
The plasma protein binding of the SSRIs ranges from about 50% up to 99%. Fluvoxamine and citalopram have the lowest plasma protein binding of all SSRIs, of 77% and 50%, respectively (23). Venlafaxine has the lowest protein binding of all modern antidepressants with a binding of 27% (24). Although this issue is considered of minimal clinical significance, there are reports of important adverse events related to protein-binding displacement interactions (41).
CYP450 2D6 Drug Metabolising Enzymes
The interactions related to CYP liver enzymes may have no effect, lead to intoxication or improve the therapeutic response of a given agent. The different pharmacokinetic profiles of the antidepressants, especially their potential for drug–drug interactions, should always be considered especially when multiple drugs are prescribed (42).
The CYP 2D6 subenzyme metabolises numerous drugs, including many typical and atypical antipsychotics (e.g. risperidone), antiarrhythmics (e.g. flecainide), tricyclic antidepressants (e.g. imipramine and amitryptiline), antihypertensive drugs (e.g. some β-blockers) and codeine (4345). Interindividual variation in the gene that encodes CYP 2D6 plays an important role in the variable drug treatment responses (44). About 5–10% of all Caucasians lack a functional CYP 2D6 enzyme and are phenotypically poor metabolisers (44). Conversely, about 5% are ultra-rapid metabolisers, resulting in rapid biotransformation of antidepressants. In fact, CYP 2D6 polymorphisms may contribute to development of adverse effects or may be a reason for the poor efficacy of antidepressant treatment (46).
Paroxetine and fluoxetine (and norfluoxetine) are very potent inhibitors of CYP 2D6 (42, 4749). Of all SSRIs, fluvoxamine has the lowest potential for drug interactions involving this enzyme (43).
CYP 2D6 may play a minor in the metabolism of citalopram, but one of its main metabolites, N-desmethylcitalopram, is further extensively metabolised by CYP 2D6 to didesmethylcitalopram (45, 50). Indeed, in a recent publication, pharmacokinetic interactions were found for citalopram due to CYP 2D6 (50). The interactions with CYP 2D6 may be clinically significant not only for citalopram but also for escitalopram (51).
CYP 2D6 is the major enzyme involved in the metabolism of venlafaxine (52). Although venlafaxine is considered by some investigators to be a weak inhibitor of CYP 2D6 (43), CYP 2D6 plays an important role in the formation of O-desmethylvenlafaxine that is one of venlafaxine's major metabolites (53). Decreased CYP 2D6 activity has been associated with cardiovascular toxicity observed during treatment with venlafaxine (54).
Fluvoxamine inhibits CYP 1A2, CYP 2C19 and CYP 3A3/4 (5557). Fluoxetine substantially inhibits CYP 2D6, CYP 3A3/4, CYP 2C9 and CYP 2C19 (55, 56, 58); its active metabolite, norfluoxetine, inhibits CYP 3A3/4, CYP 2C19 and CYP 2B6 (59).
As the effect of the SSRIs on hepatic CYP450 enzymes differ markedly and may be clinically important, selection of the antidepressant should be appropriate for the patient (59).
Gastrointestinal Adverse Events
The most common adverse event reported during treatment with SSRIs is nausea, which tends to disappear after some days of treatment (60). The overall incidence of nausea is similar for all SSRIs (61), occurring quite frequently as a consequence of increased availability of 5-HT in the gastrointestinal tract and also probably in central nervous system. Stimulation of 5-HT3 receptors plays a pivotal role in the development of this side effect, as antagonists for this receptor are capable of reducing the effect (62). Nausea is also among the most common adverse reactions for venlafaxine (63, 64).
Recently, sertraline has been shown to cause statistically significantly more diarrhoea than other SSRIs (p < 0.05) (65).
Sexual Dysfunction
Depressed male patients are almost twice as likely to present with erectile dysfunction compared with non-depressed men (66). Furthermore, patients treated with an SSRI may present with sexual dysfunction as an unwanted side effect of therapy. Paroxetine, sertraline and citalopram are reported to cause delayed ejaculation. A double-blind, randomised comparative study in 60 patients with premature ejaculation showed that placebo and fluvoxamine had no effect on the ejaculation time after 6 weeks of treatment, while paroxetine, fluoxetine and sertraline all significantly (p < 0.05) increased ejaculation latency; the greatest effect was seen with paroxetine (67).
The SSRIs are reported to cause sexual dysfunction in the following descending order of frequency: paroxetine, fluoxetine, citalopram, sertraline and fluvoxamine (66). This is confirmed in part in a direct double-blind comparison between fluvoxamine and sertraline in which the incidence of abnormal ejaculation and decreased libido was significantly (p < 0.05) higher with sertraline than with fluvoxamine (68). In addition, in several studies in which patients were specifically interviewed with a sexual dysfunction questionnaire, orgasm/ejaculation delay and impotence were reported significantly more frequently with paroxetine than with other SSRIs (69, 70).
The SNRI, venlafaxine, has been associated with impotence, abnormal ejaculation and orgasm, especially at higher doses, and it is reported to have an incidence of sexual side effects at least as high as that seen with paroxetine and sertraline (71).
Sexual side effects should be taken into consideration before prescribing a drug treatment for depression, because sexual dysfunction may play an important role in compliance with treatment and can act as an additional stress factor for the patient (72).
Central Nervous System Impairment
In contrast to the tricyclic antidepressants, SSRIs at normal clinical doses have little effect on cognitive psychomotor functioning. However, sertraline, paroxetine and fluoxetine have all shown some alerting effects and excitation (73, 74) that may be detrimental in elderly patients. Indeed, fluoxetine has been reported to be associated with an increased incidence of nervousness and insomnia compared with the tricyclic antidepressants (75, 76). Paroxetine has also been shown to impair cognition and vigilance, which may also be particularly problematic in elderly patients (77).
Drug-induced behaviour arousal features in activation, over motivation, pathological anxiety, compromised sexual function and cognitive impairment (78). In contrast to sertraline, paroxetine and fluoxetine, fluvoxamine has been shown to have little or no effect on behavioural arousal (78). Indeed, fluvoxamine has no effect on psychomotor speed, cognitive processing or arousal (73). Similarly, fluvoxamine showed no potentiation of alcohol-related cognitive impairment (79). As fluvoxamine (50 mg and 100 mg) was found not to impair psychomotor performance or cognitive ability in any relevant tests, including choice reaction time, tracking, critical flicker fusion threshold and memory scanning, it may be of value for use in outpatients who wish to carry out the tasks of everyday life.
In a double-blind study comparing dothiepin and venlafaxine in elderly patients, venlafaxine 37.5 mg administered b.i.d. did not have any negative effect on cognitive function and psychomotor performance (80). However, venlafaxine 75 mg/day is not considered to be the usual effective venlafaxine dose for the treatment of major depression.
Sleep Quality
Evidence suggests that fluvoxamine has beneficial effects on sleep in depressed patients. A recent double-blind study comparing fluvoxamine and fluoxetine showed that depressed patients treated with fluvoxamine improved their sleep quality both significantly more and more rapidly than patients on fluoxetine (81). Another direct comparative study involving fluvoxamine and paroxetine (72) showed that paroxetine caused a greater disruption of sleep patterns than fluvoxamine, and the paroxetine-induced sleep disruption persisted into the withdrawal phase (82).
The beneficial effects of fluvoxamine on sleep quality have also been reported in patients with post-traumatic stress disorder (PTSD). Fluvoxamine was effective in reducing all three symptom clusters of PTSD (intrusion, avoidance and hyperardusal), including nightmares and insomnia (83). In addition, patients suffering from other anxiety disorders, such as obsessive-compulsive disorder and panic disorder, have been found to experience a significant reduction of insomnia when treated with fluvoxamine (84). It has been suggested that the beneficial effects of fluvoxamine on sleep may be related to its inhibitory effect on melatonin degradation; this effect has not been observed with other SSRIs (85, 86).
In a double-blind placebo-controlled study, venlafaxine was found to decrease sleep continuity, markedly increase the time to rapid eye movement (REM) sleep and decrease the duration of total REM sleep (87). Other more recent publications confirm that venlafaxine worsens sleep quality (8890).
Bodyweight
Changes in bodyweight are associated with a low acceptance of treatment and an increased risk of non-compliance during long-term treatment by patients (91). Typically, SSRIs mediate a reduction in food intake, particularly in the initial phase of therapy. However, weight is frequently regained after 6 months of treatment and can be followed by additional weight gain during long-term treatment (92).
Paroxetine, fluoxetine, citalopram and sertraline have been shown to significantly increase bodyweight after 6–12 months of administration (93). Weight gain could be related to carbohydrate craving, as reported for citalopram (94). However, an alteration in metabolic rate may be responsible for the weight changes (95). In this regard, fluvoxamine was reported to promote an increase in resting metabolic rate, resulting in less weight gain (95). Of the SSRIs, paroxetine may be responsible for the highest amounts of weight gain (92, 93). However, follow-up over 2 years of patients receiving open-label clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine or sertraline showed that clomipramine was associated with the highest weight increase and fluoxetine and sertraline with the lowest (96).
Weight changes observed with SSRIs appear to involve the interaction of 5-HT with multiple mechanisms, with the extent of weight gain being dependent on small, yet pharmacological important differences in this class of antidepressants (97). Venlafaxine, such as fluoxetine, at least in short term, reduces food intake (98, 99).
Safety in Special Populations
Patients with cardiovascular impairment. The SSRIs are more suitable than the tricyclic antidepressants for the treatment of patients with cardiovascular and cerebrovascular diseases (both of which are associated with a high incidence of depression) due to their superior cardiovascular safety profile. Evidence for the safety of fluoxetine, sertraline and paroxetine has been inferred from cardiac effects in healthy volunteers, while sertraline has also been used safely in patients with recent myocardial infarctions or unstable angina (100). A review of the citalopram database found that the majority of patients with abnormal ECGs had pre-existing cardiac disease or were receiving medication likely to affect the QTc interval (101). Fluvoxamine has been widely studied in patients with cardiovascular impairment, and evidence suggests it has no effect on cardiovascular function in physically healthy patients and is safe in patients with cardiovascular disease (102107).
In contrast, venlafaxine causes increases in heart rate and blood pressure in some patients (108). In a sample of 3744 depressed patients treated with venlafaxine, a dose-dependent elevation of supine diastolic blood pressure was reported that was statistically and clinically significant, especially in doses above 300 mg/day (108). An overall tendency to mildly raised blood pressure may be apparent in 10% of individuals on venlafaxine, regardless of the daily dose (109). Hypertensive crises have also been reported for venlafaxine (110). Regular blood pressure monitoring is advised in patients receiving venlafaxine while discontinuation is recommended in patients with a sustained elevation. Indeed, preliminary evidence suggests that venlafaxine may be an effective treatment in patients with severe orthostatic hypotension (111).
Elderly patients. The good safety profile of the SSRIs in comparison with the tricyclic antidepressants is particularly important when treating elderly patients. Differences in the safety and tolerability profile between the SSRIs suggest that some may be more suitable than others for the treatment of elderly patients. Fluoxetine, for example, is associated with nervousness (112114) and insomnia (114), which suggests that it should be employed with caution in frail, elderly patients. It should also be noted that although considerable interindividual variation exists, higher plasma levels of paroxetine have been observed in elderly patients along with its reduced elimination.
The clearance of citalopram has also been observed to generally decrease with increasing age (115); a dose reduction or close monitoring is therefore advised for the elderly patient taking citalopram.
The excellent safety profile of fluvoxamine in the elderly, without the need of dose adjustments, was confirmed in an analysis of data from 4843 patients (mainly depressed) aged 65–97 years enrolled in world-wide post-marketing studies conducted over periods of up to 1 year (116). Findings from a study in 137 elderly patients aged between 75 and 97 years (mean 81 years), who also had a high incidence of concomitant illnesses and requirement for other medications, have also confirmed the excellent safety of fluvoxamine (117).
Treatment-emergent hypertension may occur in a small percentage of older patients taking venlafaxine in doses above 150 mg/day (118), and thus careful monitoring of these patients is advisable.
Discontinuation Symptoms
Discontinuation symptoms upon abrupt withdrawal have been reported for all SSRIs (119), although it is now evident that they are considerably more common with paroxetine than with the other SSRIs. An evaluation of the UK post-marketing surveillance database of adverse reactions revealed more reports of discontinuation symptoms with paroxetine (0.3 reports per 1000 prescriptions) than sertraline (0.03) or fluvoxamine (0.03), and the least with fluoxetine (0.002) (120).
In a double-blind, placebo-controlled study specifically designed to assess the effects of interruption of fluoxetine, sertraline or paroxetine treatment, placebo substitution for paroxetine was associated with an increase in the number and severity of adverse events following the second missed dose and increases in functional impairment at 5 days (121). Effects were considerably less marked with the other SSRIs. Similar findings were reported in another double-blind, placebo-controlled trial in which treatment with paroxetine, fluoxetine, sertraline or citalopram was suddenly interrupted for 4–7 days (122). Interruption of paroxetine was associated with significantly more cognitive problems and poorer quality of sleep.
Neonatal withdrawal syndrome has also been reported after in utero exposure to paroxetine (123), while high rates of neonatal complications in women exposed to paroxetine during the third trimester of pregnancy have been possibly attributed to the withdrawal syndrome (124).
Of the top 20 medicines in UK with reports of symptoms of withdrawal entered on to the British ADROIT database (125), paroxetine was at the top of the list with 1281 reports. Venlafaxine occupied the second position with 272 reports, while fluoxetine, sertraline and citalopram were fourth, fifth and sixth, respectively. Fluvoxamine was placed 19th (Table 1). It appears that a long drug half-life delays the onset of discontinuation symptoms rather than preventing them. A review of the literature found that the mean length of time for the appearance of discontinuation symptoms was 6.4 days with fluoxetine compared with 2–4 days for sertraline, fluvoxamine and paroxetine (126).
Table 1
Table 1
Antidepressants associated with reports of suspected withdrawal reactions on the UK Adverse Drug Reactions On-line Information Tracking
Suicide Risk
There is controversy about the possibility that SSRI antidepressants might induce suicidality in some patients; the role of antidepressants in suicide prevention has therefore become a major public health question. In a review of randomised controlled trials, meta-analyses of clinical trials and epidemiological studies, an excess of suicidal acts on active treatments compared with placebo made it difficult to sustain the hypothesis that SSRIs do not cause problems in some individuals (127). A more recent systematic review of randomised controlled trials, which included 87,650 patients, also found a significant increase in the odds of suicide attempts for patients receiving SSRIs compared with placebo (128).
Other studies have failed to support either an overall difference in suicide risk between antidepressant- and placebo-treated depressed individuals or a difference between SSRIs and either other types of antidepressants or placebo. Similar suicide rates were seen among those randomly assigned to an SSRI, a standard comparison antidepressant, or placebo in a review of 48,277 depressed patients participating in the Food and Drug Administration (FDA) reports of controlled clinical trials for modern FDA-approved antidepressants (129). Neither was there evidence that the risk of suicide or non-fatal self-harm in adults prescribed SSRIs was higher than in those prescribed tricyclic antidepressants in a UK study of 146,095 individuals with a first prescription of an antidepressant for depression; there was some weak evidence of an increased risk of non-fatal self-harm for current SSRI use among those aged 18 or younger, although none committed suicide (130). Epidemiological studies also have not supported the hypothesis that SSRIs may have a suicide-emergent effect. Over a period of 9 years (1992–2000), treatment of depressed individuals with SSRIs was not associated with an increased risk of suicide in adults, children or adolescents in Sweden (131).
However, there may be an association between the fall in suicide rate and greater use of non-tricyclic antidepressants. This is suggested by data from US where, from 1985 to 1999, there was a decline by 13% in suicide rate and an increase of over fourfold in antidepressant prescription rates, with the increase mostly due to SSRIs (132). Data from all US individuals who committed suicide between 1996 and 1998 showed that prescriptions for SSRIs and other new-generation non-SSRI antidepressants were associated with lower suicide rates and that higher suicide rates in rural areas were associated with fewer antidepressant prescriptions (133). This, along with evidence to suggest that most of those who commit suicide and who have major depressive disorder at the time of death are either untreated or receiving subtherapeutic doses of antidepressants (134), implies that improved treatment delivery of antidepressants may potentially reduce suicide rates.
Safety in Overdose
The SSRIs are considerably safer than tricyclic antidepressants if taken in overdose. However, citalopram may be a possible exception to the overall good safety profile of the SSRIs in overdose.
In a review of 393 cases admitted to hospital for antidepressant overdose (no co-medication) from 1987 to 2003, 5-HT syndrome was relatively common (14% of cases). Despite this, all the SSRI were demonstrated to be relatively safe in overdose and only citalopram was significantly associated with QTc prolongation. The overall incidence of seizures was 1.9% and coma was 2.4% (35). In contrast, in a retrospective review of 225 patients, citalopram was associated with a significantly longer QT interval on ECG recording, but mean QTc durations were not significantly different between all drugs studied. Only venlafaxine and citalopram caused seizures and were associated with admission to intensive care units (38). In another study in 538 patients hospitalised due to antidepressant overdose, SSRIs were shown to be less likely to cause coma, to require admission to an intensive care unit and prolong the QRS, but were more likely to cause 5-HT toxicity than venlafaxine. Venlafaxine was comparable with the tricyclics in terms of the risk of seizures and suicide (126).
The SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram), and also the SNRI venlafaxine, have become a mainstay and first-line treatment for depression. The highly specific actions of the SSRIs involving enhancement of predominantly serotonergic neurotransmission explain their beneficial effects in depressed patients and patients with anxiety disorders, while the lack of direct actions on other neurotransmitter systems is responsible for their superior safety profile as compared with that of tricyclic antidepressants.
As a class, the SSRIs possess the following mild to moderate adverse effects that do not require dose reductions or discontinuation: erectile and ejaculatory dysfunction, decreased libido, jitteriness, sweating, tachycardia, tremors, anorexia, anxiety, diarrhoea, headache, insomnia and nausea. Although a comparison of the adverse effects of SSRIs (and venlafaxine) reveals little distinction among the agents, certain differences are emerging. For example, the impact of SSRIs on sexual function is perhaps the most deleterious side effect from the point of view of the patient's quality of life. In contrast to several other SSRIs and also venlafaxine, evidence suggests that fluvoxamine has beneficial effects on sleep in depressed patients and a lower impact on bodyweight. In terms of cardiotoxicity, it is established that the SSRIs are more suitable than the tricyclic antidepressants for the treatment of patients with cardiovascular disease due to a superior cardiovascular safety profile. Fluvoxamine has been widely studied in this regard, and evidence suggests it has no effect on cardiovascular function in physically healthy patients and is safe in patients with cardiovascular disease. Fluvoxamine also has an excellent safety profile in frail elderly patients. A discontinuation syndrome (involving disequilibrium, nausea, vomiting, fatigue, sleep disturbances, lethargy, irritability and agitation) may develop upon abrupt cessation of an SSRI. This syndrome is more common with the SSRIs with shorter half-lives and inactive metabolites. Finally, the SSRIs are considerably more tolerable than tricyclic antidepressants in overdose, and there is no conclusive evidence to suggest that they are associated with an increased risk of suicide.
This review therefore suggests that while clinically significant differences in efficacy amongst SSRIs do not exist, treatment decisions need to be based on considerations such as patient acceptability, patient history of prior response, toxicity and cost. It is noteworthy in this respect that fluvoxamine has a comparatively good profile in terms of adverse events. It has a particularly low impact on sexual function (this may therefore reduce patient non-compliance) and an excellent safety profile in the elderly.
1. Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol. 1999;19:467–89. [PubMed]
2. Hyttel J. Comparative pharmacology of selective serotonin reuptake inhibitors (SSRIs) Nord J Psychiatry. 1993;47(Suppl. 30):5–12.
3. Leonard B. Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. Drugs. 1992;43(Suppl. 2):3–10. [PubMed]
4. Dechant K, Clissold S. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs. 1991;41:225–53. [PubMed]
5. Wong D, Threlkeld P, Robertson D. Affinities of fluoxetine, its enantiomers, and other inhibitors of serotonin uptake for subtypes of serotonin receptors. Neuropsychopharmacology. 1991;5:43–7. [PubMed]
6. Hyttel J, Arnt J, Sánchez C. The pharmacology of citalopram. Rev Contemp Pharmacother. 1995;6:271–85.
7. The Pharmacological Basic of Therapeutics. 9 1996. Goodman and Gilman.
8. Stein RA, Strickland TL. A review of the neuropsychological effects of commonly used prescription medications. Arch Clin Neuropsychol. 1998;13:259–84. [PubMed]
9. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19:67–85. [PubMed]
10. Smith PJ, Talbert RL. Sexual dysfunction with antihypertensive and antipsychotic agents. Clin Pharm. 1986;5:373–84. [PubMed]
11. Gross MD. Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J Psychiatry. 1982;139:1193–4. [PubMed]
12. Keltner NL, McAfee KM, Taylor CL. Mechanisms and treatment of SSRI-induced sexual dysfunction. Perspect Psychiatr Care. 2002;38:111–6. [PubMed]
13. Fawcett J, Barking RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect Disord. 1998;5:267–85. [PubMed]
14. Blokland A, Scholtissen B, Vermeeren A, Ramaekers J. Dissociable effects of histamine H1 antagonist of reaction-time performance in rats. Pharmacol Biochem Behav. 2001;70:427–36. [PubMed]
15. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-Fluoretine. Biol Psychiatry. 2001;50:345–50. [PubMed]
16. Richelson E. The pharmacology of antidepressants at the synapse: focus on newer compounds. J Clin Psychiatry. 1994;55(Suppl. A):34–9. [PubMed]
17. Kay GG. The effects of antihistamines on cognition and performance. J Allergy Clin Immunol. 2000;105(6 II):622–7. [PubMed]
18. Muth EA, Moyer JA, Haskins T, et al. Biochemical, neurophysiological and behavioural effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine. Drug Dev Res. 1991;23:191–9.
19. Rombaut NEI, Hindmarch I. Psychometric aspects of anti-histamines: a review. Hum Psychopharmacol. 1994;9:157–69.
20. Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptor in rat brain. Eur J Pharmacol. 1996;307:117–9. [PubMed]
21. Stahl S. Antidepressant treatment of psychotic depression: potential role of the sigma receptor. (Submitted) [PubMed]
22. Zanardi R, Franchini L, Serretti A, et al. Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry. 2000;61:26–9. [PubMed]
23. van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1993;24(Suppl. 1):203–9. 1–9. [PubMed]
24. Ereshefsky L, Dugan D. Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: focus on venlafaxine. Depress Anxiety. 2000;12(Suppl. 1):30–44. [PubMed]
25. Lemberger L, Bergstrom RF, Wolen RL, et al. Fluoxetine: clinical pharmacology disposition. J Clin Psychiatry. 1985;46:14–9. [PubMed]
26. Doogan GD, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry. 1988;49(Suppl. 8):46–51. [PubMed]
27. Milne RJ, Goa L. Citalopram: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in depressive illness. Drugs. 1991;41:450–77. [PubMed]
28. Moltke LL. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation; inhibitory effects and comparison to R-citalopram. Drug Metab Dispos. 2001;29:1102–9. [PubMed]
29. Goodnick PJ, Goldstein BJ. Selective serotonin reuptake inhibitors in affective disorders – I. Basic pharmacology. J Psychopharmacol. 1998;12(Suppl. B):S5–S20. [PubMed]
30. Dalery J, Honig A. Fluvoxamine versus fluoxetine in major depressive episode: a double-blind randomized comparison. Hum Psychopharmacol. 2003;18:379–84. [PubMed]
31. Messiha F. Fluoxetine: adverse effects and drug-drug interactions. J Toxicol Clin Toxicol. 1993;31:603–30. [PubMed]
32. Montgomery SA, Baldwin D, Shah A, et al. Plasma-level response relationships with fluoxetine and zimelidine. Clin Neuropharmacol. 1990;13(Suppl. 1):S71–5. [PubMed]
33. Tyrer SP, Marshall EF, Griffiths HW. The relationship between response to fluoxetine, plasma drug levels, imipramine binding to platelet membranes and whole-blood 5-HT. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14:797–805. [PubMed]
34. Fava M, Rappe SM, Pava JA, et al. Relapse in patients on long-term fluoxetine treatment: response to increased fluoxetine dose. J Clin Psychiatry. 1995;56:52–5. [PubMed]
35. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277–85. [PubMed]
36. Hamplova-Peichlova J, Krusek J, Paclt I, et al. Citalopram inhibits L-type calcium channel current in rat cardiomyocytes in culture. Physiol Res. 2002;51:317–21. [PubMed]
37. Engebretsen KM, Harris CR, Wood JE. Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25:163–6. [PubMed]
38. Kelly CA, Dhaun N, Laing WJ, et al. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol. 2004;42:67–71. [PubMed]
39. Jarvis MR. Clinical pharmacokinetics of tricyclic antidepressant overdose. Psychopharmacol Bull. 1991;27:541–50. [PubMed]
40. Broesen K. Differences in interactions of SSRIs. Int Clin Psychopharmacol. 1998;13(Suppl. 5):S45–S47. [PubMed]
41. DeVane CL. Clinical significance of drug binding, protein binding, and binding displacement drug interactions. Psychopharmacol Bull. 2002;36:5–21. [PubMed]
42. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85:11–28. [PubMed]
43. Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6. Clin Pharmacokinet. 1995;29(Suppl. 1):10–8. (discussion 18–9) [PubMed]
44. Roberts R, Joyce P, Kennedy MA. Rapid and comprehensive determination of cytochrome P450 poor metabolizer genotypes by multiplex polymerase chain reaction. Hum Mutat. 2000;16:77–85. [PubMed]
45. Brosen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction with citalopram. Eur Neuropychopharmacol. 2001;11:275–83. [PubMed]
46. Charlier C, Broly F, Lhermitte M, et al. Polymorphisms in the CYP2D6 gene: association with plasmatic concentrations of fluoxetine and paroxetine. Ther Drug Monit. 2003;25:738–42. [PubMed]
47. Brosen K. Differences in interactions of SSRIs. Int Clin Psychopharmacol. 1998;13(Suppl. 5):S45–7. [PubMed]
48. Alfaro CL, Lam YW, Simpson J, Ereshefsky L. CYP2D6 status of extensive metabolizers after-multiple dose of fluoxetine, fluvoxamine, paroxetine, or sertraline. J Clin Psychopharmacol. 1999;19:155–63. [PubMed]
49. Brosen K. Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie. 2004;59:5–12. [PubMed]
50. Holmgren P, Carlsson B, Zackrisson AL, et al. Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYP2D6 and CYP2C19. J Anal Toxicol. 2004;28:94–104. [PubMed]
51. Caccia S. Metabolism of the newest antidepressants: comparisons with predecessors. Drugs. 2004;7:143–50. [PubMed]
52. Lessard E, Yessine MA, Hamelin BA, et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol. 2001;21:175–84. [PubMed]
53. Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology. 1999;20:480–90. [PubMed]
54. Lessard E, Yessine MA, Hamelin BA, et al. Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics. 1999;9:435–43. [PubMed]
55. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors – an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(Suppl. 1):1–21. [PubMed]
56. Hemeriyck A, Bepaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3:13–37. [PubMed]
57. Schmider J, Greenblatt DJ, von Moltke LL, et al. Inhibition of CYP2C9 by SSRIs in vitro: studies of phenytoin p-hydroxilation. Br J Clin Pharmacol. 1997;280:927–33.
58. Sproule BA, Naranjo CA, Brenmer KE, Hassan PC. SSRLs and CNS drug interactions. Clin Pharmacokinet. 1997;33:454–71. [PubMed]
59. Hesse LM, Venkatakrishnan K, Court MH, et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos. 2000;28:1176–83. [PubMed]
60. Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl. 2000;403:17–25. [PubMed]
61. Trindade E, Menon D, Topfer LA, Coloma C. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ. 1998;159:1245–52. [PMC free article] [PubMed]
62. Leonard BE. The comparative pharmacology of new antidepressants. J Clin Psychiatry. 1993;54(Suppl.):3–15. (discussion 16–7). [PubMed]
63. Ballus C, Quiros G, De Flores T, et al. The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia. Int Clin Psychopharmacol. 2000;15:43–8. [PubMed]
64. de Montigny C, Silverstone PH, Debonnel G, et al. Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial. J Clin Psychopharmacol. 1999;19:401–6. [PubMed]
65. Meijer WE, Heerdink ER, van Eijk JT, Leufkens HG. Adverse events in users of sertraline: results from an observational study in psychiatric practice in The Netherlands. Pharmacoepidemiol Drug Saf. 2002;11:655–62. [PubMed]
66. Labbate LA. Sex and serotonin reuptake inhibitor antidepressants. Psychiatr Ann. 1999;29:571–9.
67. Waldinger M, Hengeveld M, Zwinderman A, Olivier B. The effect of SSRIs on ejaculation: a double-blind, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. J Clin Psychopharmacol. 1998;18:274–81. [PubMed]
68. Nemeroff CB, Ninan PT, Ballenger J, et al. Double-blind multicenter comparison of fluvoxamine versus sertraline in the treatment of depressed outpatients. Depression. 1995;3:163–9.
69. Montejo A, Llorca G, Izquierdo J, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176–94. [PubMed]
70. Montejo A, Llorca G, Izquierdo J, et al. Sexual dysfunction secondary to SSRIs. A comparative analysis of 308 patients. Actas Luso Esp Neurol Psiquiatr Cienc Afines. 1996;24:311–21. [PubMed]
71. Montejo A, Llorca G, Izquierdo J, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry. 2001;62(Suppl. 3):10–21. [PubMed]
72. Keltner NL, McAfee KM, Taylor CL. Mechanism and treatment of SSRis-induced sexual dysfunction. Perspect Psychiatr Care. 2002;38:111–6. [PubMed]
73. Hindmarch I. The behavioural toxicity of the selective serotonin reuptake inhibitors. Int Clin Psychopharmacol. 1995;9(Suppl. 4):13–7. [PubMed]
74. Sherwood N. Comparative behavioural toxicity of the selective serotonin reuptake inhibitors. Hum Psychopharmacol. 1995;10
75. Wernicke JF. The side effect profile and safety of fluoxetine. J Clin Psychiatry. 1985;46:59–67. [PubMed]
76. Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs. 1986;32:481–508. [PubMed]
77. Schmitt J, Kruizinga M, Riedel W. Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors. J Psychopharmacol. 2001;15:173–9. [PubMed]
78. Hindmarch I. The behavioural toxicity of antidepressants: effects on cognition and sexual function. Int Clin Psychopharmacol. 1998;13(Suppl. 6):S5–S8. [PubMed]
79. van Harten J. Fluvoxamine does not interact with alcohol or potentiate alcohol-related impairment of cognitive function. Clin Pharmacol Ther. 1992;52:427–35. [PubMed]
80. Trick L, Stanley N, Rigney U, Hindmarch I. A double-blind, randomized, 26-week study comparing the cognitive and psychomotor effects and efficacy of 75 mg (37.5 mg b.i.d.) venlafaxine and 75 mg (25 mg mane, 50 mg nocte) dothiepin in elderly patients with moderate major depression being treated in general practice. J Psychopharmacol. 2004;18:205–14. [PubMed]
81. Dalery J, Honig A. Fluvoxamine versus fluoxetine in major depressive episode: a double-blind randomised comparison. Hum Psychopharmacol. 2003;18:379–84. [PubMed]
82. Silvestri R, Pace-Schott E, Gersh T, et al. Effects of fluvoxamine and paroxetine on sleep structure in normal subjects: a home-based Nightcap evaluation during drug administration and withdrawal. J Clin Psychiatry. 2001;62:642–52. [PubMed]
83. Neylan TC, Metzler TJ, Schoenfeld FB, et al. Fluvoxamine and sleep disturbances in posttraumatic stress disorder. J Trauma Stress. 2001;14:461–7. [PubMed]
84. Dewulf L, Hendrickx B, Lesaffre E. Epidemiological data of patients treated with fluvoxamine: results from a 12 week non-comparative multicentre study. Int Clin Psychopharmacol. 1995;9(Suppl. 4):67–72. [PubMed]
85. von Bahr C, Ursing C, Yasui N, et al. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects – an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol. 2000;56:123–7. [PubMed]
86. Härtter S, Wang X, Weigmann H, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol. 2001;21:167–74. [PubMed]
87. Luthringer R, Toussaint M, Schaltenbrand N, et al. A double-blind, placebo-controlled evaluation of the effect of orally administered venlafaxine on sleep in in-patients with major depression. Psychopharmacol Bull. 1996;32:637–46. [PubMed]
88. Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R. Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers. J Clin Psychiatry. 1997;58:348–50. [PubMed]
89. Salin-Pascual RJ, Moro-Lopez ML. Effects of venlafaxine in the sleep architecture of rats. Psychopharmacology (Berl) 1997;129:295–6. [PubMed]
90. Guelfi JD, Ansseau M, Timmerman L, Korsgaard S., Mirtazapine-Venlafaxine Study Group Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic features. J Clin Psychopharmacol. 2001;21:425–31. [PubMed]
91. Sussman N, Ginsberg D. Weight gain associated with SSRIs. Primary Psychiatry. 1998;1:36–41.
92. Fergunson JM. SSRI antidepressant medications: adverse effects and tolerability. Primary Care Companion. J Clin Pschiatry. 2001;3:22–7. [PubMed]
93. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61(Suppl.):37–41. [PubMed]
94. Bower CD, Harvey BH. Phasic craving for carbohydrate observed with citalopram. Int Clin Psychopharmacol. 1996;11:273–8. [PubMed]
95. Fernstrom MH. Depression, antidepressants and body weight change. Ann NY Acad Sci. 1998;575:31–9. [PubMed]
96. Maina G, Albert U, Salvi V, Bogetto F. Weight gain during long-term treatment of obsessive compulsive disorder: a prospective comparison between serotonin reuptake inhibitors. J Clin Psychiatry. 2004;65:1365–71. [PubMed]
97. Harvey BH, Bower CD. Neuropharmacology of paradoxic weight gain with selective serotonin reuptake inhibitors. Clin Neuropharmacol. 2000;23:90–7. [PubMed]
98. Malhotra S, King KH, Welge JA, et al. Venlafaxine treatment of binge-eating disorder associated with obesity: a series of 35 patients. J Clin Psychiatry. 2002;63:802–6. [PubMed]
99. Jackson HC, Needham AM, Hutchins LJ, et al. Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. Br J Pharmacol. 1997;121:1758–62. [PubMed]
100. Hale A. New antidepressants: use in high-risk patients. J Clin Psychiatry. 1993;54(Suppl.):61–70. [PubMed]
101. Baldwin D, Johnson F. Tolerability and safety of citalopram. Rev Contemp Pharmacother. 1995;6:315–25.
102. Laird L, Lydiard R, Morton W, et al. Cardiovascular effects of imipramine, fluvoxamine and placebo in depressed outpatients. J Clin Psychiatry. 1993;54:224–8. [PubMed]
103. Hewer W, Rost W, Gattaz W. Cardiovascular effects of fluvoxamine and maprotiline in depressed patients. Eur Arch Psychiatry Clin Neurosci. 1995;246:1–6. [PubMed]
104. Hochberg H, Kanter D, Houser V. Electrocardiographic findings during extended clinical trials of fluvoxamine in depression: one years experience. Pharmacopsychiatry. 1995;28:253–6. [PubMed]
105. Strik J, Honig A, Lousberg R, et al. Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients. Int Clin Psychopharmacol. 1998;13:263–7. [PubMed]
106. Präger G, Stollmaier W, Parger R, et al. Safety and tolerance of fluvoxamine in cardiac patients. TW Neurologie Psychiatrie. 1991;5:548–62.
107. Präger G, Cimander K, Wagner W, et al. The cardiotrophic effect of antidepressants: a comparison with fluvoxamine. Adv Pharmacother. 1986;2:133–50.
108. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of a data from 3744 depressed patients. J Clin Psychiatry. 1998;59:502–8. [PubMed]
109. Harrison CL, Ferrier N, Young AH. Tolerability of high-dose venlafaxine in depressed patients. J Psychopharmacol. 2004;18:200–4. [PubMed]
110. Khurana RN, Baudendistel TE. Hypertensive crisis associated with venlafaxine. Am J Med. 2003;115:676–7. [PubMed]
111. Grubb B, Kosinski D. Preliminary observations on the effects of venlafaxine hydrochloride in the treatment of severe refractory orthostatic hypotension. J Seroton Res. 1996;3:85–9.
112. Salchner P, Singewald N. Neuroanatomical substrates involved in the anxiogenic-like effect of acute fluoxetine treatment. Neuropharmacology. 2002;43:1238–48. [PubMed]
113. Chouinard G, Saxena B, Belanger MC, et al. A Canadian multicenter double-blind study of paroxetine and fluorxetine in major depressive disorder. J Affect Disord. 1999;54:39–48. [PubMed]
114. Zajecka J, Amsterdam JD, Quitkin FM, et al. Changes in adverse events reported by patients during 6 months of fluoxetine therapy. Psychiatry. 1999;60:389–94. [PubMed]
115. Fredericson Overo K, Toft B, Christophersen L, Gylding-Sabroe JP. Kinetics of citalopram in elderly patients. Psychopharmacology (Berl) 1985;86:253–7. [PubMed]
116. Wagner W, Hauser V, Wong L. The safety profile of fluvoxamine in elderly patients. Hum Psychopharmacol. 1996;11:267–72.
117. Jaquenoud E, Kat M. The safety of fluvoxamine in very elderly patients with depression and somatic symptoms. Prim Care Psychiatry. 1997;3:175–81.
118. Staab JP, Evans DL. Efficacy of venlafaxine in geriatric depression. Depress Anxiety. 2000;12(Suppl. 1):63–8. [PubMed]
119. Coupland N, Bell CJ, Potokar J. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol. 1996;16:356–62. [PubMed]
120. Schatzberg AF, Rosenbaum JF, Haddad P, et al. Antidepressant discontinuation syndrome: an update on serotonin uptake inhibitors. J Clin Psychiatry. 1997;58(Suppl.):3–4. [PubMed]
121. Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo controlled trial. Br J Psychiatry. 2000;176:363–8. [PubMed]
122. Hindmarch I, Kimber S, Cockle S. Abrupt and brief discontinuation of antidepressant treatment: effects on cognitive function and psychomotor performance. Int Clin Psychopharmacol. 2000;15:305–18. [PubMed]
123. Nordeng H, Lindemann R, Perminov K, et al. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr. 2001;90:288–91. [PubMed]
124. Costei A, Kozer E, Ho T, et al. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med. 2002;156:1129–32. [PubMed]
125. Medicines Control Agency. UK. ADROIT - Adverse Drug Reactions On-line Information Tracking. SSRI withdrawal reactions reported until July, 2002. 2002. [16 March 2005]. http://www.socialaudit.ofg.uk/43800046.htm.
126. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM. 2003;96:369–74. [PubMed]
127. Healy D, Whitaker C. Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci. 2003;28:331–7. [PMC free article] [PubMed]
128. Fergusson D, Doucette S, Cranley Glass K, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ. 2005;330:396. [PMC free article] [PubMed]
129. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry. 2003;160:790–2111. [PubMed]
130. Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ. 2005;330:389. [PMC free article] [PubMed]
131. Isacsson G, Holmgren P, Ahlner J. Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14 857 suicides. Acta Psychiatr Scand. 2005;111:286. [PubMed]
132. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States, 1985–1999. J Clin Psychiatry. 2004;65:1456–62. [PubMed]
133. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry. 2005;62:165–72. [PubMed]
134. Isacsson G, Holmgren P, Druid H, Bergman U. Psychotropics and suicide prevention. Implications from toxicological screening of 5281 suicides in Sweden 1992–1994. Br J Psychiatry. 1999;174:259–65. [PubMed]
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