Combination Of Selective Serotonin Reuptake Inhibitors Research Articles

Interaction Between Selective Serotonin Reuptake Inhibitors and Nonsteroidal Antiinflammatory Drugs: Review of the Literature

To evaluate the evidence of an interaction between selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) producing an increased risk for gastrointestinal adverse outcomes such as bleeding. We searched MEDLINE for English-language literature published between 1966 and August 2005. All studies examining gastrointestinal adverse effects from an SSRI-NSAID combination were included. Four retrospective studies examined gastrointestinal adverse outcomes from the combination of SSRIs and NSAIDs. The risk ratio for an upper gastrointestinal bleed from this drug combination (compared with not receiving either agent) ranged from 3.3-15.6, and the risk ratio for gastrointestinal adverse effects was 12.4. Two studies found that the risk for an upper gastrointestinal bleed from the drug combination exceeded the additive risk of the agents alone. The risk ratio for an upper gastrointestinal bleed from an SSRI-aspirin interaction was 1.9-7.2. In addition, the number needed to harm in terms of an upper gastrointestinal bleed from an SSRI-NSAID combination ranged from 62-75 patient-years, and the number needed to harm for gastrointestinal adverse effects was 2 patient-years. Concurrent use of an SSRI and NSAID increases the risk of gastrointestinal adverse outcomes such as bleeding. Clinicians must take care to avoid these negative outcomes by altering NSAID or SSRI therapy, or by providing ulcer-protective drugs.

Antidepressant-like activity of selective serotonin reuptake inhibitors combined with a NK1 receptor antagonist in the mouse forced swimming test

Substance P antagonists of the neurokinin-1 receptor type (NK1) have growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurons. In line with this assumption, previous intracerebral in vivo microdialysis experiments provided evidence that the NK1 receptor antagonists did not change basal cortical 5-HT levels. However, we found that increases in cortical 5-HT overflow caused by systemic injection of the selective serotonin reuptake inhibitor (SSRI), paroxetine was higher in freely moving (C57BL/6x129sv) NK1−/− mutants than in wild-type NK1+/+ mice [17]. More recently, a pharmacological study has led to a similar conclusion since GR205171, a NK1 receptor antagonist, potentiated paroxetine-induced increases in cortical 5-HT dialysate following its acute systemic or intra-raphe administration to wild-type mice [25]. In the present study, we tested whether an acute combination of SSRI and NK1 receptor antagonist could display antidepressant-like activity using the forced swimming test in Swiss mice. We found that a single systemic dose of GR205171 (10 and 30 mg/kg, i.p.) had no effect by itself. However, it selectively potentiated the antidepressant-like activity of subactive doses of two serotonergic antidepressant drugs, citalopram and paroxetine (without psychomotor stimulant activity), but not that of noradrenaline reuptake inhibitor, desipramine. In agreement with neurochemical data, the present study confirms that co-administration of a NK1 receptor antagonist with an antidepressant drug such as a SSRI may have a therapeutic potential to improve the treatment of major depressive episodes in human compared to SSRI alone.

5-Hydroxytryptophan plus SSRIs for interferon-induced depression: Synergistic mechanisms for normalizing synaptic serotonin

Interferon-alpha (IFN) is widely used in the treatment of certain cancers and viral infections, including hepatitis C (HCV). Unfortunately, depression is a common side effect of IFN therapy, affecting approximately a third of HCV patients receiving IFN therapy. Studies have shown that selective serotonin reuptake inhibitors (SSRIs) can effectively treat IFN-induced depression in only 63-75% of cases. For the remaining percentage, depression often necessitates dose reduction of or discontinuation from IFN therapy. Emerging evidence indicates that IFN may cause depression by affecting brain serotonin. IFN has been shown to increase serotonin reuptake and to decrease serotonin synthesis. We hypothesize that SSRIs are not fully effective because they affect only serotonin reuptake, not serotonin synthesis, and that effective treatment must address both uptake and synthesis. 5-Hydroxytryptophan (5-HTP) effectively increases central nervous system synthesis of serotonin. It is the immediate precursor of serotonin and is widely available as a dietary supplement, which is well absorbed after an oral dose. Several double-blind studies have shown 5-HTP to be effective in the treatment of nondrug-induced depression. We hypothesize that patients who become depressed on IFN will respond to the synergistic combination of SSRIs plus 5-HTP.

Acceleration of onset of action in schedule-induced polydipsia: combinations of SSRI and 5-HT 1A and 5-HT 1B receptor antagonists

Onset of action is a key unmet need in the treatment of depression. However, very few preclinical models in which the effects of antidepressants can be shown are suitable for screening for onset. In this context, previous literature suggests that a slow onset of action of selective serotonin reuptake inhibitors (SSRIs) is observed in schedule-induced polydipsia (SIP). The current investigation was performed to determine the latency to reduce SIP of the SSRI, fluoxetine, and of two treatments known to facilitate 5-HT neurotransmission to a greater extent than an SSRI alone. These treatments included interaction studies for fluoxetine+the 5-HT 1A antagonist, WAY 100635, and for fluoxetine+the 5-HT 1B partial agonist, GR 127935. Food-restricted rats were trained on a fixed interval schedule with drinking water freely available. Once water intake was stable, rats were randomly assigned to vehicle of treatment groups. Daily treatment was continued for 3 (interaction studies) or 18 days (fluoxetine alone study). Fluoxetine significantly reduced SIP after 5–6 days of treatment, with the maximal effect evidenced after 8 days. WAY 100635 and GR 127935 accelerated the onset of action of fluoxetine, with significant effects observed on treatment day 1. These data suggest that SIP may be useful to assess the onset of action of serotonin enhancers.

Selective serotonin reuptake inhibitors in the treatment of panic disorder and agoraphobia

This review article summarizes comparator-controlled, short-term studies with currently available selective serotonin reuptake inhibitors (SSRIs) in the treatment of panic disorder and agoraphobia. Fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram have all been proven to be superior to pill-placebo in the treatment of panic disorder, agoraphobia and associated symptoms such as depression. Direct comparisons with other antidepressants, benzodiazepines, cognitive-behavioural therapies or combinations of SSRIs with psychotherapeutic interventions are scarce. The majority of studies have reported on fluvoxamine whereas, to date, sertraline and citalopram have been compared only with placebo. Meta-analyses have suggested that combining an antidepressant with exposure in vivo produces the greatest treatment gains. Since this procedure is already commonly used in everyday clinical practice, it is recommended that future research in the treatment of panic disorder be directed towards the investigation of a combination of SSRIs with exposure therapy.

Venlafaxine and Bupropion Combination Therapy in a Case of Treatment-Resistant Depression

To report the therapeutic efficacy of venlafaxine and bupropion in a patient with treatment-refractory major depression. A 21-year-old white woman with chronic and recurrent major depression presented with lack of response to several antidepressants. On examination, the patient exhibited neurovegetative signs of depression, guilt feelings, and suicidal ideation. The patient was administered venlafaxine 75 mg three times daily. The dose was titrated to 150 mg three times daily over the next month. Later bupropion was instituted up to 100 mg three times daily over a four-month period. The patient responded favorably to combination therapy and has remained free of depression for approximately 23 months. Venlafaxine and bupropion are antidepressant agents with unique pharmacologic profiles, each effective in the treatment of depression. Recent data indicate that combinations of selective serotonin-reuptake inhibitors and bupropion can convert partial response to full response in patients with treatment-resistant depression. We considered whether a combination of venlafaxine and bupropion would reduce the depressive symptoms of a patient who was unresponsive to various classes of psychotropic agents. Gradual administration of venlafaxine and bupropion acted synergistically to significantly reduce depressive symptoms (p < 0.002) and significantly increase social function (p < 0.002) over a period of eight months. To our knowledge this is the first report of successful combination therapy with venlafaxine and bupropion in treatment of chronic recurrent and refractory major depression.

Selective Serotonin Reuptake Inhibitors and Tricyclic Antidepressants in Combination

The selective serotonin reuptake inhibitors (SSRIs) are now widely used in the treatment of depressive illness. Interest has grown in the use of SSRIs as alternatives to tricyclic antidepressants (TCAs) and in the therapeutic use of combinations of SSRIs and TCAs in refractory depression. MEDLINE and PSYCLit literature searches were conducted. Reference sections from papers retrieved were scrutinised for other relevant reports. Of 41 relevant articles identified, 35 were selected for review. Fluoxetine, fluvoxamine, paroxetine and sertraline may substantially increase TCA plasma levels when given concurrently. Such interactions may give rise to adverse effects. The effect of sertraline may be less profound than that of fluoxetine, fluvoxamine and paroxetine. Limited data suggest that citalopram may not affect TCA serum levels. There is scant literature evidence to support the use of SSRIs in combination with TCAs as a treatment for refractory depression.