选择性5-羟色胺再摄取抑制剂撤药综合征42例的临床分析

目的:探讨选择性5-羟色胺再摄取抑制剂(SSRI)撤药综合征的临床特点、诱发因素及预防。方法:回顾性调查42例SSRI撤综合征的临床症状,诱发因素及处理。结果:42例撤药综合征以头晕、恶心、呕吐、头痛、感觉异常、心情低落、失眠、焦虑、激越等症状为主。撤药症状发生于停药后的1～5d,持续1～7d。42例中应用帕罗西汀27例,舍曲林6例,西酞普兰6例,氟西汀3例。诱发因素:自行突然停药30例,漏服6例,减药4例,换药2例。结论:骤停SSRI可引起撤药综合征,以帕罗西汀较易发生,应引起临床上重视。缓慢减量或使用半衰期较长的SSRI可预防撤药综合征的发生。     

An assessment of selective serotonin reuptake inhibitor discontinuation symptoms with citalopram

The selective serotonin reuptake inhibitors (SSRIs) have recently been associated with a variety of somatic and psychiatric symptoms upon abrupt drug discontinuation. These symptoms have been variously termed SSRI withdrawal, or SSRI discontinuation syndrome. Although all of the available SSRIs have been reported to cause discontinuation symptoms, some appear to have a greater propensity to cause these adverse events than others. Data from a previously completed placebo-controlled, double-blind study designed to assess citalopram in depression relapse prevention were analysed to assess patients for the emergence of discontinuation effects following randomization to placebo after 8 weeks of active drug treatment. Side-effects that occurred during the first 2 weeks following randomization to active drug (n = 150) or placebo (n = 72) were measured using the UKU unwanted side-effect list. The proportion of patients that experienced one or more events over the 2-week period following randomization was similar in the two groups, and there was no association between citalopram dose prior to randomization and the reporting of symptoms. Most of the events that did occur were mild in intensity and none resulted in discontinuation from the study. Events occurring at a higher frequency in the placebo group were most associated with the central nervous system (CNS). These events may reflect a re-emergence of depressive symptoms, since only 14.8% of patients randomized to placebo who did not relapse experienced CNS events, a low symptom incidence that was non-significant (P = 0.562) compared to patients continuing treatment (10.9%). Therefore, this assessment suggests that any symptoms associated with rapid discontinuation of citalopram are mild and transient, and emphasizes the significant role re-emerging depression and / or anxiety may play in the assessment and identification of SSRI discontinuation symptoms.     

Selective serotonin reuptake inhibitors and withdrawal symptoms: a review of the literature

There are accumulating reports of withdrawal symptoms emerging following the discontinuation of selective serotonin reuptake inhibitor antidepressants. This report summarizes published reports, characterizes the withdrawal syndrome, discusses potential mechanisms of withdrawal, and makes recommendations for prevention and management. A computerized search was conducted using MEDLINE (1985–1996) to retrieve all case reports and pertinent studies of antidepressant withdrawal. A total of 46 case reports and two drug discontinuation studies were retrieved. All of the selective serotonin reuptake inhibitors were implicated in withdrawal reactions with paroxetine most often cited in case reports. Withdrawal reactions were characterized most commonly by dizziness, fatigue/weakness, nausea, headache, myalgias and paresthesias. The occurrence of withdrawal did not appear to be related to dose or treatment duration. Symptoms generally appeared 1–4 days after drug discontinuation, and persisted for up to 25 days. Time of onset and duration of symptoms differed little among the agents. The pathophysiology/pharmacology of withdrawal is unclear but may involve multiple neurotransmitter systems. It is concluded that all of the SSRIs can produce withdrawal symptoms and if discontinued, they should be tapered over 1–2 weeks to minimize this possibility. Some patients may require a more extended tapering period. No specific treatment for severe withdrawal symptoms is recommended beyond reinstitution of the antidepressant with subsequent gradual tapering as tolerated. © 1997 John Wiley & Sons, Ltd.     

Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia

The aim of this investigation was to explore the prevalence and features of discontinuation syndromes ensuing with gradual tapering of selective serotonin reuptake inhibitors (SSRIs), in optimal clinical conditions in patients with panic disorder and agoraphobia. Twenty-six consecutive outpatients met the DSM-IV criteria for panic disorder and agoraphobia while taking SSRIs. Twenty remitted upon behavioural treatment. Antidepressant drugs were then tapered at the slowest possible pace and with appropriate patient education. Patients were assessed with the Discontinuation-Emergent Signs and Symptoms (DESS) checklist 2 wk, 1 month and 1 yr after discontinuation. Nine of the 20 patients (45%) experienced a discontinuation syndrome, which subsided within a month in all but three patients who had been taking paroxetine for a long time. Discontinuation syndromes appeared to be fairly common even when performed with slow tapering and during clinical remission. In some cases disturbances persisted for months after discontinuation.     

N-methyl-citalopram: A quaternary selective serotonin reuptake inhibitor

We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [³H]citalopram and uptake studies with [³H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10⁻⁷ M as well as [³H]ketanserin binding to rat brain membranes at 10⁻⁵ M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.     

Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine

Recent findings demonstrated the dysregulation of imidazoline receptor binding sites in major depression and their normalization by chronic treatment with antidepressants including selective serotonin reuptake inhibitors (SSRIs). Present study investigated the role of agmatine and imidazoline receptors in antidepressant like effect of SSRIs and imipramine in mouse forced swimming test (FST) paradigm. The antidepressant like effect of fluoxetine or paroxetine was potentiated by imidazoline I₁/I₂ receptor agonist agmatine (5-10 mg/kg, ip), imidazoline I₁ receptor agonists, moxonidine (0.25-0.5 mg/kg, ip) and clonidine (0.015-0.03 mg/kg, ip), imidazoline I₂ receptor agonist, 2-(2-benzofuranyl)-2-imidazoline (5-10 mg/kg, ip) as well as by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine, an agmatine biosynthetic precursor (40 μg/mouse, icv), ornithine decarboxylase inhibitor, difluoromethyl ornithine (12.5 μg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 μg/mouse, icv) and agmatinase inhibitor, arcaine (50 μg/mouse, icv). Conversely, prior administration of I₁ receptor antagonist, efaroxan (1 mg/kg, ip), I₂ receptor antagonist, idazoxan (0.25 mg/kg, ip) and arginine decarboxylase inhibitor, d-arginine (100 mg/kg, ip) blocked the antidepressant like effect of paroxetine (10 mg/kg, ip) and fluoxetine (20 mg/kg, ip). On the other hand, antidepressant like effect of imipramine was neither augmented nor attenuated by any of the above drugs. Mice pretreated with SSRIs but not imipramine and exposed to FST showed higher concentration of agmatine in brain as compared to saline control. This effect of SSRIs on agmatine levels was completely blocked by arginine decarboxylase inhibitor d-arginine but not by imidazoline receptor antagonists, efaroxan or idazoxan. These results demonstrate that modulation of imidazoline receptors by agmatine are implicated in the antidepressant like effect of SSRIs and may be projected as a potential therapeutic target for the treatment of depressive disorders.     

Safety of selective serotonin reuptake inhibitors in pregnancy

Psychiatric treatment with selective serotonin reuptake inhibitors (SSRIs) may be desirable or necessary during pregnancy; however, the benefit of these treatments must balance the benefits to the mother with any risk to the developing foetus. At the present time, the role of serotonin in normal central nervous system development, as well as the effects of altering serotonin transmission at critical periods of embryo development, remains to be further clarified. Depression has a high prevalence in pregnant women (around 10%) and approximately one-half of the pregnancies are unplanned, making necessary that physicians have to know the risks associated with the decision to use this kind of antidepressants during pregnancy. The effects of antidepressants in pregnancy could be classified in several main categories: the teratogenic possible effects; the effects on the normal development of the brain and neuropsychological functions; the effects on birth weight and/or early delivery; the risk of increased bleeding on the mother during delivery; the neuropsychological behaviour and adaptation after delivery, including not only neonatal withdrawal syndromes but also pain reactivity and increased parasympathetic cardiac modulation during recovery after an acute noxious event and in a wide range of neurobehavioural outcomes; and medium- to long-term effects in neurocognitive functions in those children. These areas are reviewed according to the most recent published cohort-controlled studies and prospective surveys regarding SSRIs use in pregnancy. The review tries to clarify the blurred aspects of the use of SSRI during pregnancy and to give sensible and up-to-dated guidelines for the treatment of psychiatric disorders with SSRI during pregnancy.     

Treatment of selective mutism: focus on selective serotonin reuptake inhibitors

Abstract Selective mutism is a pediatric psychiatric disorder that occurs when a child consistently fails to speak in specific situations in which speaking is expected, such as at school and social gatherings, but speaks appropriately in other settings. Selective mutism often is diagnosed when a child starts school and does not talk to teachers or peers, but talks to family members at home; the condition is frequently accompanied by anxiety and shyness. Although the underlying etiology of the condition remains unclear, psychotherapy is the preferred initial treatment, with the support of parents and teachers. If the child does not respond to psychotherapy, addition of pharmacologic treatment should be considered, depending on the severity of symptoms and presence of other illnesses. Although data are limited to case reports and trials with small patient populations and short follow-up periods, some patients with selective mutism respond to therapy with selective serotonin reuptake inhibitors (SSRIs). Fluoxetine is the most studied SSRI as treatment for the condition, although further investigation is required to determine the optimal dosage and duration of therapy.     

Effects of chronic selective serotonin reuptake inhibitors on 8-OH-DPAT-induced facilitation of ejaculation in rats: comparison of fluvoxamine and paroxetine

Rationale Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) can delay ejaculation in humans, but the extent of this effect differs between SSRIs. The involvement of 5-HT_1A receptors is likely, since 5-HT_1A receptor agonists accelerate ejaculation and chronic SSRI treatment is thought to desensitize 5-HT_1A receptors.Objectives This study was conducted to examine the effects of chronic pretreatment with the SSRIs fluvoxamine and paroxetine on the facilitation of ejaculation induced by the 5-HT_1A receptor agonist 8-OH-DPAT.Methods Sexually experienced Wistar rats with normal ejaculatory behavior were treated for 22 days with vehicle, fluvoxamine (30 mg/kg/day), or paroxetine (10 or 20 mg/kg/day, p.o.). On day 22, rats received a challenge with saline or 8-OH-DPAT (0.4 mg/kg, s.c.). Sexual behavior was tested on days 1, 8, 15, and 22 of the SSRI-treatment.Results Treatment with both doses of paroxetine, but not fluvoxamine, delayed ejaculation. 8-OH-DPAT strongly accelerated ejaculation under vehicle conditions. Pretreatment with paroxetine reduced the effects of 8-OH-DPAT on ejaculation in a dose-dependent manner and more strongly than fluvoxamine.Conclusions SSRIs affect 5-HT_1A receptors involved in ejaculation. The degree to which this occurs, with paroxetine exerting a stronger effect than fluvoxamine, might determine the extent of SSRI-induced delayed ejaculation.     

Acute anxiogenic-like effects of selective serotonin reuptake inhibitors are attenuated by the benzodiazepine diazepam in BALB/c mice

Selective serotonin re-uptake inhibitors (SSRIs), which are used commonly to treat anxiety disorders, have characteristic anxiogenic effects following acute administration. Treatment with anxiolytic benzodiazepines (BZs) may reduce these effects, although little is known about potential drug interactions. Our study evaluated acute anxiogenic-like effects of SSRIs, alone and combined with a BZ. Adult male BALB/c mice received fluoxetine (3.0-30.0 mg/kg, i.p.) or citalopram (3.0-30.0 mg/kg, i.p.) alone or in combination with diazepam (0.3-10.0 mg/kg, i.p.), after which they were evaluated with the light/dark and open-field tests for anxiogenesis/anxiolysis. In addition, release of the stress hormone corticosterone was assessed following combined SSRI/BZ administration. In the light/dark and open-field tests, acute SSRIs produced a behavioral profile consistent with anxiogenesis, while diazepam produced an anxiolytic-like profile. Pre-treatment with diazepam (0.3-10 mg/kg) reversed the effects of an anxiogenic-like dose of an SSRI (18 mg/kg fluoxetine, 30 mg/kg citalopram) in both light/dark and open-field tests. Diazepam, fluoxetine or citalopram, and their combination all significantly increased plasma corticosterone levels to the same degree. These findings suggest that a BZ-type drug can attenuate acute anxiogenic-like effects of an SSRI via a mechanism independent of corticosterone regulation.     

Utility of selective serotonin reuptake inhibitors in premature ejaculation

The introduction of selective serotonin reuptake inhibitors (SSRIs) has revolutionized our understanding of the treatment of premature ejaculation. Lifelong premature ejaculation may be a neurobiological phenomenon, namely part of a biological variability of the intravaginal ejaculation latency time in men. Animal studies support this view, and an animal model for premature and delayed ejaculation has recently been developed. It is proposed that drug treatment of premature ejaculation should consist of 5-hydroxytryptamine (5-HT)2c receptor stimulation and/or 5-HT1A receptor inhibition. A meta-analysis of 35 daily treatment studies with selective serotonin reuptake inhibitors (SSRIs) and clomipramine demonstrated comparable efficacy of clomipramine with the SSRIs sertraline and fluoxetine in delaying ejaculation, whereas the efficacy of the SSRI paroxetine was greater than all other SSRIs and clomipramine. It is postulated that acute treatment with SSRIs, including those with short half-lives, will not produce an ejaculation delay equivalent to that induced by daily treatment of SSRIs.     

Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors

Psychotropic drugs have been shown to have antimicrobial activity against several groups of microorganisms. Some of these drugs, such as the new antidepressant agents sertraline, fluoxetine and paroxetine are known to act as efflux pump inhibitors in human cells. Their activity has been studied, alone and combined with antibiotics, against bacterial species, mainly in multiply resistant strains. These agents have surprising activity, mainly against Gram positive microorganisms. They also show synergistic activity when combined with some antibiotics against several bacteria, shown by a decrease in MICs, that converts strains previously resistant to the category of sensitive, and modify physiological aspects related with pathogenicity.     

Running wheel activity is sensitive to acute treatment with selective inhibitors for either serotonin or norepinephrine reuptake

Rationale  Most antidepressants (AD) directly or indirectly enhance the serotonergic tone in the CNS. Since the serotonin system is involved in both, the modulation of mood and motor behavior, it was reasoned that these drugs might also interfere with running wheel activity (RWA), a form of positively motivated motor behavior, which might be linked to pathological states like obsessive–compulsive disorder (OCD). Objectives  We used RWA to characterize ADs from all major classes. Effects on RWA were compared to effects on general locomotor activity (LOC) to control for unspecific effects on general locomotion. Methods  Two hours before lights-off, mice were treated with either vehicle or one of the following AD: the selective serotonin reuptake inhibitors (SSRIs) citalopram (3–10 mg/kg), paroxetine (1–10 mg/kg) and fluoxetine (2–6.6 mg/kg), the selective norepinephrine reuptake inhibitor (SNRI) reboxetine (1–10 mg/kg), the monoamine oxidase (MAO) inhibitors tranylcypromine (1–3 mg/kg) and moclobemide (3–10 mg/kg), and the tricyclic ADs desipramine and imipramine (10–30 mg/kg, each). LOC and RWA were measured after lights-off. Results  At the highest dose tested, all ADs, with the exception of the MAO inhibitors, significantly reduced RWA. Both tricyclics inhibited RWA only at doses that similarly affected LOC. In contrast, all SSRI and reboxetine inhibited RWA at doses that left LOC unaffected. Conclusions  SSRI and the SNRI reboxetine inhibit RWA at doses not suppressing LOC. RWA may represent a simple behavioral readout of positively motivated behavior that merits further attention for psychopharmacology.     

Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes

Objective: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Methods: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)-warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers. Results: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (K_m) of 133 μM and a mean apparent maximal velocity (V_max) of 248 pmol · min⁻¹ · mg⁻¹; formation of 7-hydroxywarfarin yielded a mean K_m of 3.7 μM and a mean V_max of 10.5 pmol · min⁻¹ ·  mg⁻¹. Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (K_i) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4–17.3) μM and 13.0 (8.4–18.7) μM, respectively. The average K_i value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0–125) μM. Conclusion: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism. Received: 20 July 1998 / Accepted in revised form: 6 October 1998     

Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression

Objective The aim of the investigation was to study the effects of withdrawing selective serotonin reuptake inhibitor (SSRI) drugs in nursing home patients, who had no documented diagnosis or symptoms of depression.Setting The setting of the study was in 11 nursing homes in the county of Stockholm, Sweden.Participants Participants were patients without dementia or history of depression who had received treatment with SSRI drugs for more than 6 months and who had no indications of anxiety disorder or major depressionDesign The included patients (n=70) were randomized to either the intervention group (withdrawal of SSRI) or the control group (no change in treatment), 35 patients to each group.Main outcome measures The patients were subjected to assessment using the following instruments: Montgomery-Åsberg depression rating scale, global assessment for functioning, health index and a symptom assessment form. Assessment was made at the start of the study and at the 3-month and 6-month follow-ups.Results We found no significant difference between the intervention and control groups in any outcome measure.Conclusion Treatment with SSRI drugs in patients without clinical major depression or anxiety disorder is often unjustified and should be discontinued.