Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability

Background: A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against tricyclic antidepressants (TCAs) in depressed patients was carried out. Methods: Efficacy data from 102 randomised controlled trials (10706 patients) were pooled to provide a summary variance-weighted effect size. Tolerability data from 95 studies (10553 patients) were combined to give variance-weighted relative risk of drop out for all reasons and for adverse effects from each study. The effect of age, treatment setting, severity and TCA dose were examined as well as the performance of individual SSRIs and TCAs where there were sufficient studies. Results: There is no overall difference in efficacy between SSRIs and TCAs (effect size -0.03, 95% confidence interval -0.09 to 0.03). TCAs do appear more effective in in-patients (-0.23, -0.40 to -0.05) and amitriptyline is more effective than SSRI comparators (-0.14, -0.25 to -0.03) but publication bias cannot be excluded. The SSRIs are better tolerated, with significantly lower rates of treatment discontinuations overall (relative risk 0.88, 0.83 to 0.93; number needed to treat 26) and due to side effects (0.73, 0.67 to 0.80; number needed to treat 33). Individual SSRIs show a similar advantage except for fluvoxamine which does not differ from the TCAs. Individual TCAs show a similar disadvantage in tolerability compared to SSRIs except for dothiepin against which SSRI treatment results in more side-effect related drop outs (2.64, 1.50 to 4.63; number needed to harm 12). Limitations: The evidence is from short-term studies and subgroup analyses may result in chance results. Conclusions: Overall efficacy between the two classes is comparable but SSRIs are not proven to be as effective as TCAs in in-patients and against amitriptyline. SSRIs have a modest advantage in terms of tolerability against most TCAs.     

Recommendations for treatment of neuropathic pain

Tricyclic antidepressants (TCAs), selective serotonin and norepinephrine reuptake inibitors (SSNRIs), calcium channel alpha2-delta ligands and topical lidocaine are recommended as a first-line treatment for patients with neuropathic pain. In patients who have failed to respond to these first-line medications alone or in combination, opioid analgetics or tramadol can be used as a second-line treatment alone or in combination with one of the first-line medications. In some specific situations, opioid analgetics or tramadol can also be considered for first-line use.     

The pharmacogenetics of the selective serotonin reuptake inhibitors

Summary Citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs), which are thought to act as antidepressants through their ability to inhibit presynaptic serotonin reuptake in the brain. The elimination of the SSRIs proceeds predominantly via oxidation catalyzed by cytochrome P450 in the liver. Paroxetine and fluoxetine are potent inhibitors of cytochrome P4502D6 and hence may cause serious interactions with drugs metabolized by this isozyme, notably tricyclic antidepressants, some neuroleptics, and some antiarrhythmics. Citalopram, fluvoxamine and sertraline do not share this property. Fluvoxamine is the only SSRI that is a potent inhibitor of cytochrome P4501A2 and hence causes serious pharmacokinetic interactions with amitriptyline, clomipramine, imipramine, theophylline, and presumably caffeine and other drugs which are metabolized by the isozyme. Citalopram and fluoxetine are administered as racemates, but practically nothing is known about the stereoselective metabolism of the two drugs. Citalopram is partially metabolized via the mephenytoin oxidation polymorphism, and paroxetine is partially metabolized via the sparteine/debrisoquine oxidation polymorphism. The pharmacogenetic differences in the oxidation of the SSRIs themselves are probably of no clinical relevance.Abbreviations CYP cytochrome P450 - EM extensive metabolizer - PM poor metabolizer - SSRI selective serotonin reuptake inhibitor     

Cerebral metabolic effects of fluoxetine, fluvoxamine, paroxetine and sertraline in the conscious rat

The selective serotonin reuptake inhibitors (SSRI) exert a wide range of neurochemical and therapeutic activities. To investigate the neural effectors of SSRIs, we measured the regional cerebral metabolic rates for glucose (rCMRglc) in 56 brain regions of Fischer-344 rats 30 min after intraperitoneal injection of 0.4, 4 or 40 mg/kg of fluoxetine or fluvoxamine or after 4 mg/kg of paroxetine or sertraline. Both shared and drug-specific effects were detected. While all four SSRIs similarly reduced rCMRglc in a network of subcortical brain regions including the amygdala, locus coeruleus, basal ganglia and hypothalamic paraventricular nuclei, fluvoxamine, paroxetine and sertraline reduced rCMRglc also in the hippocampus and sertraline in the lateral habenula. The topography and the relation to dose of rCMRglc reductions by SSRIs differ from those of other classes of antidepressants, thus suggesting that SSRIs may specifically modulate brain areas involved in the physiological responses to stress.     

Treatment options in the management of adolescent depression

Treatment for depression in children and adolescents often requires pharmacotherapy with tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), followed by psychotherapy. Most studies have not found the TCAs to be more effective than placebo in the treatment of depression in children and adolescents. Initial reports, however, have found the SSRIs to be more effective and better tolerated. In the small proportion of children who have treatment-resistant depression, TCAs plus lithium, monoamine oxidase inhibitors (MAOIs) or electroconvulsive therapy (ECT) may be useful. More studies on the treatment of depression in children and adolescents are needed, as adult data cannot simply be extrapolated.     

Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion.

Tricyclic antidepressants have multiple sites of pharmacological actions which are responsible for their tolerability and toxicological problems as well as their efficacy. That fact has prompted the search for antidepressants with fewer sites of action. That search resulted in the serotonin selective reuptake inhibitors (SSRIs), with presumably only one site of action. Although the SSRIs are safer and better tolerated than the TCAs, a significant percentage of patients do not benefit from SSRIs. A group of "atypical antidepressants" including bupropion, nefazodone, and venlafaxine are known to have multiple sites of antidepressant action but do not interact at sites associated with side effects or tolerance. Thus this group of antidepressants present an important alternative to the SSRIs in the pharmacological therapy of depression. The basic pharmacological properties of bupropion, nefazodone, and venlafaxine are presented along with clinical profiles and the role of these three antidepressants in the pharmacotherapy of depression is discussed.     

Analgesic effect of intrathecally γ-aminobutyric acid transporter-1 inhibitor NO-711 administrating on neuropathic pain in rats

To investigate the analgesic effect of intrathecally administered γ-aminobutyric acid (GABA) transporter-1 inhibitor NO-711 on the sciatic nerve chronic constriction injury (CCI) rats. 5 days after intrathecal catheter placement, neuropathic pain model was established by CCI of sciatic nerve on rats. Withdrawal thresholds for mechanical allodynia and latency for thermal hyperalgesia were measured in all animals. All rats operated upon for CCI displayed decreased withdrawal thresholds for mechanical allodynia and latency for thermal hyperalgesia, which has significant difference compared with sham groups. After intrathecal NO-711 administration, withdrawal thresholds and latency were significantly increased on CCI rats compared with control group after 1 day. The results show that GABA transporter-1 inhibitor could effectively develop analgesic effect in sciatic nerve CCI rats’ model.     

Fatal toxicity associated with antidepressant use in primary care.

BACKGROUND: New selective serotonin reuptake inhibitors (SSRIs) are perceived to be much safer in use than older tricyclic antidepressants (TCAs). However, previous assessments of association with fatal toxicity were made too soon after the introduction of the new drugs to permit accurate estimation. AIM: To determine the level of association of antidepressant drugs with fatal poisoning in the treatment of depression. METHOD: National data for England and Wales for three years (1993 to 1995) for fatal poisonings associated with antidepressants were obtained and, together with national primary care data on prescribing, were used to calculate fatality association by antidepressant drug. RESULTS: There were substantial variations between drugs in the level of association with fatal poisoning. Assuming an average treatment episode lasted three months, one fatality is associated with 11,800 treatment episodes of antidepressant use (95% CI = 11,120 to 12,580) when only single substance fatalities are considered. For SSRIs as a group the association was one in 411,800 (95% CI = 243,300 to 1.34 million) and for TCAs one in 8130 (95% CI = 7650 to 8670). However, for one of the newer TCAs, lofepramine, the single substance fatality rate associated with its use was one in 233,700 (95% CI = 124,500 to 1.89 million), which is not statistically significantly different from the SSRIs (P = 0.35). CONCLUSIONS: Estimated death rates associated with specific antidepressants should be compared with caution because drugs may be used selectively in patients with differing severity of depression. The proportion of these fatalities that could be prevented by switching to safer antidepressants is unclear when so few deaths are recorded as accidental; when there is intent to do self-harm the potential for switching to other means is unknown. However, this approach to relative toxicity may remain the best available since it is unlikely that a randomised trial will ever be conducted with a large enough sample size to obtain experimental data. Fatalities from antidepressant poisoning are very rare but if safety is paramount then lofepramine or an SSRI are justifiable treatment choices.     

Intrathecal S-nitroso-N-acetylpenicillamine and L-cysteine attenuate nerve injury-induced allodynia through noradrenergic activation in rats

Spinal norepinephrine release and activation of spinal alpha(2)-adrenergic receptors represent important components of descending control of nociception. Recent studies have shown that nitric oxide is capable of stimulating neuronal norepinephrine release in the presence of thiol-containing compounds such as L-cysteine. In the present study, we tested a hypothesis in a rodent model of neuropathic pain that intrathecal injection of the nitric oxide donor S-nitroso-N-acetylpenicillamine and L-cysteine produces an antiallodynic action mediated by the spinal alpha(2)-adrenergic receptors. Allodynia was induced in rats by ligation of the left lumbar L5/L6 spinal nerves. Mechanical allodynia was quantified by application of von Frey filaments to the left hindpaw. Intrathecal injection of 20-100microg of S-nitroso-N-acetylpenicillamine in the presence of 200microg of L-cysteine, but not D-cysteine, dose-dependently attenuated the allodynia. Intrathecal injection of a combination of 100microg of S-nitroso-N-acetylpenicillamine and 50-200microg of L-cysteine also inhibited the allodynia in a dose-dependent manner. Pretreatment with a nitric oxide scavenger, carboxy-PTIO, or depletion of norepinephrine with a specific neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, prevented the antiallodynic action of intrathecal S-nitroso-N-acetylpenicillamine and L-cysteine. Furthermore, the antiallodynic effect produced by intrathecal injection of a combination of S-nitroso-N-acetylpenicillamine and L-cysteine was abolished by pretreatment with intrathecal injection of a non-specific alpha-adrenergic receptor antagonist, phentolamine, or an alpha(2) receptor antagonist, idazoxan.This study provides the first functional evidence that spinal nitric oxide interacts with the thiol-containing compounds to produce an antiallodynic effect in neuropathic pain. We propose that such an action is mediated by endogenous norepinephrine and spinal alpha(2)-adrenergic receptors.     

Selective serotonin reuptake inhibitors and tricyclic antidepressants in the acute treatment of chronic depression and dysthymia: A systematic review and meta-analysis

IntroductionChronic depression represents a substantial portion of depressive disorders and is associated with severe consequences. This review examined the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in the treatment of chronic depression. Additionally, the comparative effectiveness of the two types of antidepressants has been examined.MethodsA systematic search was conducted in the following databases: CENTRAL, MEDLINE, EMBASE, ISI Web of Science, BIOSIS, PsycINFO, and CINAHL. Primary efficacy outcome was a response to treatment; primary acceptance outcome was dropping out of the study. Only randomized controlled trials were considered.ResultsWe identified 20 studies with 22 relevant comparisons. 19 studies focused on samples with a majority of dysthymic patients. Both SSRIs and TCAs are efficacious in terms of response rates when compared to placebo (Benefit Ratio [BR]=1.49; p<0.001 for SSRIs and BR=1.74; p<0.001 for TCAs) and no statistically significant differences between the active drugs and placebo in terms of dropout rates could be found. No differences in effectiveness were found between SSRIs and TCAs in terms of response rates (BR=1.01; p=0.91), yet, SSRIs showed statistically better acceptability in terms of dropout rates than TCAs (Odds Ratio [OR]=0.41; p=0.02).LimitationsThe methodological quality of the primary studies was evaluated as unclear in many cases and more evidence is needed to assess the efficacy of SSRIs and TCAs in patients suffering from chronic forms of depression other than dysthymia.ConclusionsThis systematic review provides evidence for the efficacy of both SSRIs and TCAs in the treatment of chronic depression and showed a better acceptability of SSRIs.     

Efficacy of fluvoxamine in treatment-refractory depression

The efficacy of the potent and selective unicyclic serotonin reuptake inhibitor, fluvoxamine, was evaluated in 38 consecutively admitted depressed patients judged refractory to standard antidepressants using operationalized criteria. Twenty-eight patients completed a single-blind protocol involving greater than or equal to 2 weeks of placebo and 4-6 weeks of active fluvoxamine. Eight (29%) were judged responders to fluvoxamine alone, eight (29%) responded to lithium augmentation of fluvoxamine and two (7%) responded to fluvoxamine, lithium and perphenazine. These data suggest that selective and potent serotonin reuptake inhibitors may be effective in patients refractory to generally available antidepressant medications.     

Intrathecally administered Sema3A protein attenuates neuropathic pain behavior in rats with chronic constriction injury of the sciatic nerve

Semaphorins, one of the repulsive axonal guidance factors during development, are produced under pathological conditions in adult animals. In the neuropathic pain state associated with peripheral nerve injury, synaptic reorganization occurs in spinal cord dorsal horn. In the present study, we investigated the roles of intrathecal administration of Sema3A, a secreted semaphorin, in the spinal cord of chronic constriction injury (CCI) model rat. Neuropilin 1 (NPR1) and Plexin A (PlexA), co-receptors of Sema3A, were expressed in the dorsal horn of na?ve rats. NPR1, and not PlexA, protein expression increased in the dorsal spinal cord of CCI rats. Recombinant Sema3A protein attenuated mechanical allodynia and heat hyperalgesia in CCI rats, whereas heat-inactivated Sema3A had no effect. Immunohistochemistry revealed that Sema3A partially restored the decrease of isolectin B4-positive unmyelinated nerve terminals in lamina II of the ipsilateral dorsal horn of CCI rats. Contrary to our expectations, Sema3A did not change the distribution of myelinated fibers in lamina II at 7 days after CCI. Those results suggested that the suppressive role for Sema3A in the development of neuropathic pain associated with peripheral nerve injury in adult rats, which seemed to be independent from prevention of the myelinated fiber sprouting into lamina II.     

Cerebral metabolic effects of fluoxetine,fluvoxamine, paroxetine and sertraline in the conscious rat

The selective serotonin reuptake inhibitors (SSRI) exert a wide range of neurochemical and therapeutic activities. To investigate the neural effectors of SSRIs, we measured the regional cerebral metabolic rates for glucose (rCMRglc) in 56 brain regions of Fischer-344 rats 30 min after intraperitoneal injection of 0.4, 4 or 40 mg/kg of fluoxetine or fluvoxamine or after 4 mg/kg of paroxetine or sertraline. Both shared and drug-specific effects were detected. While all four SSRIs similarly reduced rCMRglc in a network of subcortical brain regions including the amygdala, locus coeruleus, basal ganglia and hypothalamic paraventricular nuclei, fluvoxamine, paroxetine and sertraline reduced rCMRglc also in the hippocampus and sertraline in the lateral habenula. The topography and the relation to dose of rCMRglc reductions by SSRIs differ from those of other classes of antidepressants, thus suggesting that SSRIs may specifically modulate brain areas involved in the physiological responses to stress.     

High-performance liquid chromatographic method to screen and quantitate seven selective serotonin reuptake inhibitors in human serum

A high-performance liquid chromatographic screening method (HPLC) is described for the determination of seven selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, milnacipran, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine) and for three pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram and norfluoxetine). A tricyclic antidepressant, clomipramine, was used as an internal standard. The method consists of liquid extraction of serum after alcalinisation at pH 9.50, followed by chromatography on a Beckman C18 reversed-phase column. Compounds were detected at 200.4 nm. The standard curves were linear over a working range of 50-1,000 ng/ml for fluvoxamine, 15-1,000 ng/ml for fluoxetine, 25-500 ng/ml for norfluoxetine, 50-500 ng/ml for sertraline, 20-500 ng/ml for paroxetine, 25-550 ng/ml for citalopram, 25-750 ng/ml for desmethylcitalopram, 25-800 ng/ml for didesmethylcitalopram, 25-650 ng/ml for milnacipran, and 25-500 ng/ml for venlafaxine. The quantitation limits of the method were 15 ng/ml for fluoxetine, 20 ng/ml for paroxetine, 25 ng/ml for venlafaxine, norfluoxetine and citalopram, and its metabolites, 40 ng/ml for sertraline and 50 ng/ml for fluvoxamine. No interferences were noted with this sensitive and specific method which can be used for therapeutic drug monitoring.     

Electroacupuncture potentiates the antiallodynic effect of intrathecal neostigmine in a rat model of neuropathic pain

This study was performed to examine whether electroacupuncture potentiates the neostigmine-induced antiallodynia in neuropathic pain rats. Although intrathecal neostigmine (0.05, 0.1, and 0.3 microg) dose-dependently relieved cold allodynia, 0.3 microg neostigmine caused side effects. The coapplication of 0.1 microg neostigmine and electroacupuncture, however, produced potent antiallodynia, which was parallel to the effect of 0.3 microg neostigmine, without side effects. These results indicate that electroacupuncture can enhance the antiallodynic action of intrathecal neostigmine.