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Possible monoamine oxidase inhibitor-serotonin uptake inhibitor interaction: fluoxetine clinical data and preclinical findings.

The primary objective of this article is to review information pertinent to and emphasize the seriousness of a potential adverse monoamine oxidase inhibitor (MAOI)-serotonin uptake inhibitor interaction by considering, within the context of preclinical data, clinical cases in which an MAOI and fluoxetine hydrochloride, a specific serotonin uptake inhibitor, were administered in close temporal proximity. Clinical cases were identified by a review of spontaneous adverse event reports submitted voluntarily to Eli Lilly and Company through its drug surveillance program and by a review of reports of MAOI interactions published in the scientific literature. A discussion of eight selected clinical cases of acute adverse reactions (seven with fatal outcomes; one with a favorable response after cyproheptadine therapy) reported to Eli Lilly and Company in which an MAOI was initiated concurrently or shortly after the discontinuation of fluoxetine and a review of preclinical data suggest a possible role of serotonin and/or serotonin-dopamine interactions in the hypermetabolic state that may occur when a serotonin uptake inhibitor and an MAOI are coadministered, although alternative etiologic processes are possible as well. Data reviewed reinforce the idea that the administration of an MAOI in close temporal proximity to fluoxetine is contraindicated.

Adult↗

Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects.

Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive-compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.

Autoreceptors↗

Neurally mediated syncope and serotonin reuptake inhibitors.

Serotonin (5-hydroxytryptamine or 5HT) is a neurotransmitter which appears to play a prominent role in central regulation of heart rate and blood pressure. Recent evidence suggests that the activation of cerebral serotonin receptors results in a depressor effect principally through sympatho-inhibition. Several common clinical disorders resulting in hypotension leading to syncope are neurally mediated syncope, carotid sinus hypersensitivity and orthostatic hypotension, each of which may involve a serotonergic component. This brief review provides a summary of serotonergic blood pressure regulation, as well as the initial experience with the clinical effects of the serotonin reuptake inhibitors in the therapy of the aforementioned disorders.

Animals↗

5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors.

Serotonin (5-HT), a well-known neurotransmitter of the central nervous system, has been implicated in diverse aspects of immune regulation. Here we show that 5-HT can efficiently drive programmed cell death in established Burkitt lymphoma (BL) lines that remain faithful to the original biopsy phenotype (group 1). Group 1 BL cells cultured in the presence of 5-HT exhibited marked suppression of DNA synthesis that was accompanied by extensive apoptosis-serotonin-driven apoptosis was complete within 24 hours, was preceded by early caspase activation, and was accompanied by a decline in mitochondrial membrane potential. BL cells that had drifted to a lymphoblastic group 3 phenotype were relatively resistant to these actions of serotonin, and the forced ectopic expression of either bcl-2 or bcl-x(L) provided substantial protection from 5-HT-induced apoptosis. 5-HT receptor antagonists (SDZ205-557, granisetron, methysergide) failed to inhibit serotonin-induced apoptosis, whereas the selective serotonin reuptake inhibitors (SSRI)-fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa)-substantially blocked the monoamine actions. Western blot analysis showed that BL cells expressed protein for the 5-HT transporter, and transport assays confirmed active uptake of serotonin by the cells. Unlike what was suggested for neuronal cells, there was no evidence that intracellular oxidative metabolites were responsible for the 5-HT-induced programmed death of BL cells. These data indicate that serotonin drives apoptosis in biopsylike BL cells after its entry through an active transport mechanism, and they suggest a novel therapeutic modality for Burkitt lymphoma.

Apoptosis↗

Autoreceptors remain functional after prolonged treatment with a serotonin reuptake inhibitor.

Serotonin (5-hydroxytryptamine, 5-HT) autoreceptors may desensitize during prolonged administration of antidepressant drugs. If autoreceptors desensitize, their inhibitory influence on extracellular 5-HT should be attenuated. To test this hypothesis, the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg kg(-1), s.c., b.i.d.) or saline was administered for 14 days to rats. After a 24-h washout period, rats were anesthetized, and implanted with dialysis probes for determination of 5-HT in the frontal cortex (FCx) and dorsal hippocampus (DH). In response to citalopram (5 mg kg(-1), s.c.) challenge, there were moderate increases in 5-HT in the FCx and DH of both the chronic citalopram and saline pretreatment groups. After subsequent administration of the 5-HT(1A/1B) autoreceptor antagonist, (-)-penbutolol, there were further increases in 5-HT in the FCx and DH of the saline pretreatment group. Moreover, contrary to the expected effect if autoreceptors were desensitized, the potentiation produced by (-)-penbutolol was greater in the FCx and DH of the chronic citalopram group as compared to rats pretreated with saline. These results suggest that autoreceptors still restrain the increase in 5-HT produced by an SSRI after prolonged administration.

Adrenergic beta-Antagonists↗

Induction of mania with serotonin reuptake inhibitors.

Serotonin reuptake inhibitors (SRIs) are now considered the first-line treatment for depression, but they have not been well studied in bipolar disorder. Recently, some authors have recommended that patients at risk for antidepressant-induced mania be treated with SRIs rather than tricyclic antidepressants (TCAs). Clinical information about 11 patients who developed mania during treatment with SRIs is described. These patients were found to have personal or family histories of hypomania or mania, but these disorders were not usually recognized at the time of the patients' initial treatment for depression. The SRI-induced manic episodes were also quite severe, having psychotic features or requiring patients to be secluded for extreme agitation, but patients responded completely to antimanic treatment. The risk of treatment-emergent mania with SRIs is not trivial, especially among patients at risk for bipolar disorder. Additional research is needed to compare the actual rate of drug-induced mania with SRIs and TCAs in patients with different bipolar subtypes, while controlling for concurrent antimanic drug use.

Adult↗

Monoamine oxidase inhibitors and serotonin uptake inhibitors: differential effects on [3H]serotonin binding sites in rat brain.

Rats were administered either monoamine oxidase inhibitors or serotonin uptake inhibitors for either 1, 4 or 16 days. The binding of [3H]serotonin to brain homogenates and the concentration of serotonin in brain was measured at these times. Treatment with inhibitors of serotonin uptake did not change the specific binding of [3H]serotonin in either cerebral cortex or hippocampus, nor did it produce any consistent alterations in the concentration of serotonin in the cerebral cortex. In contrast, monoamine oxidase inhibitors capable of inhibiting A-type monoamine oxidase significantly decreased [3H]serotonin binding after both 4 and 16 days of treatment; serotonin concentrations were significantly elevated at all time intervals. Inhibitors of B-type monoamine oxidase had no effect on either [3H]serotonin binding or serotonin concentrations in cerebral cortex. The reduction in labeled serotonin binding caused by monoamine oxidase inhibitors is due to a decrease in the maximum number of specific binding sites with no change in the affinity of the binding sites for labeled serotonin.

Amitriptyline↗

Effects of systemic injections of vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats.

We examined the effect of Vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1A (5-HT(1A)) receptor agonist [Bartoszyk, G.D., Hegenbart, R., Ziegler, H., 1997. EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. Eur. J. Pharmacol. 322, 147-153.], on change in affect following predator stress. Vilazodone and vehicle injection (intraperitoneal) occurred either 10 min after predator stress (prophylactic testing), or 90 min prior to behavioral testing for the effects of predator stress (therapeutic testing). Predator stress involved unprotected exposure of rats to a domestic cat. Behavioral effects of stress were evaluated with hole board, plus-maze, and acoustic startle tests 1 week after stress. Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle. In prophylactic testing, Vilazodone affected stress potentiation of startle at doses above 5 mg/kg. Vilazodone increased stress elevation of startle at 10 mg/kg. Higher doses of Vilazodone (20 and 40 mg/kg) blocked stress potentiation of startle. In contrast, Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. In therapeutic testing, Vilazodone increased stress elevation of startle at all doses. In contrast, therapeutic Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. Taken together, the data suggest a prophylactic potential for Vilazodone in the treatment of changes in hypervigilance following severe stress.

Animals↗

Failure of serotonin inhibitor to effect nocturnal GH and prolactin secretion in patients with Duchenne muscular dystrophy.

Growth hormone (GH) and prolactin (PRL) secretion was evaluated in seven patients with Duchenne muscular dystrophy. GH and PRL levels following sleep and 24 h mean serum GH and PRL concentrations were normal in these subjects. Overnight GH and PRL concentrations were evaluated in four of these patients before and following administration of the serotonin inhibitor, parachlorophenylalanine (PCPA). Although PCPA produced a significant decrease in urinary 5HIAA concentrations, the treatment had no significant effect on GH and PRL levels. These findings raise the possibility that serotonin may not be involved in nocturnal GH and PRL secretion in these patients.

Child↗

Lack of effects by tricyclic antidepressant and serotonin inhibitors on anorexia in MCG 101 tumor-bearing mice with eicosanoid-related cachexia.

OBJECTIVES: Anorexia is a major clinical problem in large number of patients with advanced cancer disease. Serotonergic mechanisms are assumed to play a role in the process of feeding behavior during normal and pathologic circumstances, which may also involve cancer anorexia according to previous experimental and clinical studies. METHODS: In the present study, we evaluated the effect of the tricyclic antidepressants desipramine (7.5 mg x kg(-1) x d(-1), intraperitoneal) and imipramine (2 to 5 mg. kg(-1) x d(-1), intraperitoneal) the serotonin synthesis inhibitor para-chlorophenylalanine (300 mg x kg(-1) x d(-1), intraperitoneal), the serotonin receptor 5-HT(2C) antagonist cyproheptadine (5 mg x kg(-1) x d(-1), intraperitoneal) and the selective serotonin reuptake inhibitor citalopram (20 mg x kg(-1) x d(-1), intraperitoneal) on anorexia in MCG-101 tumor-bearing mice, a model with significant anorexia and cachexia sensitive to cyclooxygenase inhibition. Also, MCG 101-bearing mice develop well-recognized alterations in brain tryptophan/serotonin metabolism as increased Trp, 5-HPT, and 5-HIAA during tumor progression. RESULTS: Daily provision of desipramine, imipramine, para-chloropheylalanine, cyproheptadine, and citalopram at doses that cause behavioral and metabolic alterations in normal mice did not alter food intake or body weight in tumor-bearing and healthy control mice. Also, the treatments did not decrease elevated plasma concentrations of interleukin-6 and prostaglandin E(2) in the tumor-bearing mice. CONCLUSIONS: Thus, our results do not support previous observations that serotonin metabolism itself is a major factor behind anorexia in tumor-bearing animals in general. Rather, other mechanisms, such as eicosanoid and nitric oxide-dependent pathways, seem to be more important for induction of anorexia along tumor progression in the present model.

Animals↗

Measuring the serotonin uptake site using [3H]paroxetine--a new serotonin uptake inhibitor.

Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand.

Animals↗