Serotonin discontinuation effects

Venlafaxine (Effexor, Effexor XR). Venlafaxine works by blocking the reuptake of both serotonin and norepinephrine. Because of this dual action, some believe that venlafaxine may be more effective than the SSRIs when treating severe depression. Its side effects and toxicity are similar to the SSRIs with abdominal discomfort, sexual dysfunction, and anxiety being commonly reported. At higher doses, it may mildly elevate blood pressure therefore, blood pressure should be checked periodically. When stopping venlafaxine, serotonin discontinuation symptoms may be especially problematic. Therefore, gradually tapering of the dose every 2-4 weeks is recommended. 

Recently, several groups have clinically evaluated compounds designed to increase or decrease synaptic levels of multiple neurotransmitters concurrently, such as norepinephrine plus dopamine or norepinephrine plus serotonin. The intent is to effectively treat a broader population with similar symptoms. Conversely, Merck and Pfizer s discontinuance of clinical trials of peptide Y antagonists for depression does not disprove the validation of that target until the results are better understood and can answer such questions as Was efficacy inadequate for a potent and selective compound Was selectivity of the compound for the target inadequate Does the molecular target not relate directly to the disease or have too many disconnects in the pathway to the disease ... 

Paroxetine. Paroxetine, also a serotonin reuptake inhibitor, has been the subject of a case report in two subjects. Ringold [1994] reported the effective treatment of two individuals who had not responded to prior therapy with fluoxetine and sertraline. Both individuals had comorbid psychiatric problems. Subject A demonstrated both social phobia and dysthymia. Although her symptoms of dysthymia were clinically responsive to fluoxetine therapy, her social phobia symptoms were resistant. Subject B had body dysmorphic disorder, obsessive-compulsive disorder, and social phobia. His obsessive-compulsive disorder symptoms benefited from fluoxetine therapy, but his social anxiety was resistant. Sertraline therapy was attempted in both subjects. Subject A required discontinuation because of adverse effects. Subject B experienced a worsening of both obsessive-compulsive disorder and social phobia symptoms. Both subjects demonstrated a positive response in their symptoms when switched to paroxetine [20 mg/day]. 

Anderson DN, Wilkinson AM, Abou-Saleh MT, et al Recovery from depression after electroconvulsive therapy is accompanied by evidence of increased tetra-hydrobiopterin-dependent hydroxylation. Acta Psychiatr Scand 90 10-13, 1994 Anderson IM, Cowen PJ Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers. Psychopharmacology 106 428-432, 1992 Anderson IM, Tomenson BM Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants a meta-analysis. BMJ 310 1433-1438, 1995... 

Thus, virtually all side effects of the SSRIs can be understood as undesirable actions of serotonin in undesirable pathways at undesirable receptor subtypes. This appears to be the cost of doing business, as it is not possible for a systemically administered SSRI to act only at the desirable receptors in the desirable places it must act everywhere it is distributed, which means all over the brain and all over the body. Fortunately, SSRI side effects are more of a nuisance than a danger, and they generally attenuate over time, although they can cause an important subset of patients to discontinue an SSRI prematurely. 

The discovery of the antidepressant effect of medications was coincidental to their use for other disorders. Initial work published in 1952 reported that iproniazid (originally used for the treatment of tuberculosis) could elevate mood. Although the use of iproniazid was discontinued due to toxicity, many other additional medications have been tested and approved for the treatment of depression. These include monoamine oxidase inhibitors, tricyclics, selective serotonin reuptake inhibitors, and a heterogeneous class of atypical drugs. 

Methysergide (Sansert ) is believed to alter the ability of serotonin to cause inflammation, platelet aggregation (blood clotting), and dilation of blood vessels. However, methysergide has some undesirable side effects, such as motor incoordination and dizziness and can cause heart problems. Usually, the drug is intentionally discontinued for 4-6 weeks twice a year because of these problems. Thus, methysergide is used only in special cases. 

SSRIs PROCARBAZINE T risk of serotonin syndrome and CNS toxicity Additive toxicity Monitor BP closely and also CNS side-effects. Because of the long half-life of fluoxetine and its active metabolites, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of therapy with an MAOI... 

Goethe JW, Woolley SB, Cardoni AA, et al. Selective serotonin reuptake inhibitor discontinuation side effects and other factors that influence medication adherence. J Clin Psychopharmacol 2007 27(5) 451-8. 

To avoid drug toxicity and prevent the precipitation of serotonin syndrome, duration cf effect should be considered when switching between antidepressants (e.g., a MAO inhibitor should not be started for 5 weeks after discontinuing fluoxetine 2-3 weeks should elapse between stopping a nonselective MAO inhibitor and initiating therapy with a tricyclic antidepressant). 

Psychiatric evaluation of a patient after 6 weeks of treatment with a monoamine oxidase inhibitor (MAOI) shows no improvement. The psychiatrist now writes a prescription for fluoxetine which the patient starts two days after her final dose of the MAOI. Since the MAOIs used as antidepressants continue to exert effects for 2 or more weeks after discontinuance, the most likely result of the administration of fluoxetine now will be to cause (A) A rapid amelioration of her depressive symptoms Electrocardiographic abnormalities Extrapyramidal dysfunction The serotonin syndrome Weight gain... 

C. Serotonin syndrome (see p 21) is characterized by confusion, hypomania, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, incoordination, and hyperthermia. This reaction may be seen when a patient taking an MAO inhibitor (p 269) ingests a serotonin uptake blocker. Because of the long duration of effects of MAO inhibitors and most of the serotonin uptake blookers, this reaotion can occur up to several days to weeks after either treatment regimen has been discontinued. The syndrome has also been described in patients taking an overdose of an SSRI or combinations of various SSRIs without concomitant MAO inhibitor use. 

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