Doses Of Selective Serotonin Reuptake Inhibitors Research Articles

Dose-response relationship of recent antidepressants in the short-term treatment of depression

Antidepressant drugs are widely recommended for the treatment of depressive disorders, and finding the "right dose for the right patient" is an important issue. Whatever antidepressant is prescribed, a proportion of adult patients with major depression fail to respond satisfactorily to adequate first-line treatment. A frequent strategy for patients with insufficient response to an initial antidepressant dose is to increase the dose. This review is about this strategy, ie, the possible benefits of prescribing higher doses of recent antidepressants. The results show that a flat dose-response curve is a class phenomenon for selective serotonin reuptake inhibitors (SSRIs), according to randomized, controlled, fixed-dose clinical trials. For the serotonin and noradrenaline reuptake inhibitors (SNRIs), the strategy of dose increase may be relevant for venlafaxine, in order to increase the number of responders. Thus, the subgroup of patients for whom high doses of SSRIs could be useful remains to be defined.

Interferon for Hepatitis C Patients With Psychiatric Disorders

Back to table of contents Previous article Next article Letter to the EditorFull AccessInterferon for Hepatitis C Patients With Psychiatric DisordersGREGORY M. ASNIS, M.D., RICHARD De La GARZA, Ph.D., SIMON A. REGO, Psy.D., MARGARET A. HENDERSON, M.D., and JOHN F. REINUS, M.D., GREGORY M. ASNISSearch for more papers by this author, M.D., RICHARD De La GARZASearch for more papers by this author, Ph.D., SIMON A. REGOSearch for more papers by this author, Psy.D., MARGARET A. HENDERSONSearch for more papers by this author, M.D., and JOHN F. REINUSSearch for more papers by this author, M.D., The Bronx, N.Y.Published Online:1 Dec 2004https://doi.org/10.1176/appi.ajp.161.12.2332AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We read with interest the report by Dr. Onyike et al. involving a patient who developed mania while being treated with pegylated IFN-α and ribavirin. This is important since pegylated IFN-α is used in the treatment of chronic hepatitis C and other viral illnesses and has been associated with a significantly lower incidence of depression in comparison to unmodified IFN-α (1). While pegylated IFN-α may also be associated with a reduced incidence of mania, it is important for clinicians to be aware of this potential side effect. Neuropsychiatric disturbances usually occur after repeated IFN-α exposure (days or months) or upon treatment discontinuation. The latter may have been an important factor in the reported case since the patient missed many doses of IFN-α before starting the new course of pegylated IFN-α. Since preclinical studies have shown that IFN-α decreases dopamine in the brain (2), a sudden withdrawal from IFN-α may have induced a surge of this neurotransmitter, which has been hypothesized to be important in mania.The authors minimized the likelihood that the selective serotonin reuptake inhibitor (SSRI) fluoxetine may have been implicated in the switching process since it was initiated years earlier and the dose was doubled over 4 months before this mood alteration. We take the opposite view, suggesting that fluoxetine may have contributed to the switching process. This opinion is partially based upon recent work by Ramasubbu (3), who described two depressed patients—one with unipolar depression and the other with dysthymia. In both instances, the patient became hypomanic when the SSRI (sertraline and paroxetine, respectively) dose was significantly increased, and the hypomania resolved with subsequent dose reduction. In these cases, the switching occurred approximately 1 month after the dose increase, similar to the case by Dr. Onyike et al., in which mania developed 4 months after the SSRI dose increase.In addition to less serious side effects (e.g., gastrointestinal symptoms), antidepressants, including SSRIs, are capable of inducing hypomanic/manic episodes (4). This is a particular concern in patients with a history of bipolar disorder but has also been described in nonbipolar depressives (3), including the patient presented by Dr. Onyike et al. Patients with a previous history of IFN-α-induced depression may also prove to be especially vulnerable.Gastroenterologists frequently treat patients with chronic hepatitis C with a history of bipolar or major depressive disorder. These physicians should consider consultation with a psychiatrist since many of these patients are already taking antidepressants and/or necessitate prescriptions of antidepressants to prevent and/or treat IFN-α-induced depression. A psychiatrist would more effectively be able to monitor and/or intervene if a hypomanic/manic episode occurred.

Binding of [123I]beta-CIT to brain serotonin and dopamine transporters (SERT & DAT) after multiple dose administration of sertraline

Previous work suggests that virtual saturation of brain SERT occurs after administration of therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). This study determined [123I]β-CIT binding in the brain after multiple dose (8 days) administration of sertraline 25mg and 50mg (randomized, double-blinded, placebo controlled) and 150mg (open-label, preceded by 50mg QD × 3 days and 100mg QD × 3 days) with a 7–day washout after the first 2 periods. Six healthy subjects had baseline brain single photon emission computed tomography scans with [123I]β-CIT, a high affinity SERT and DAT radiotracer. Follow-up scans occurred 1h after the day 8 sertraline dose for each period (20-24h after [123I]β-CIT infusion). Mean±SD [123I]β-CIT binding in the brainstem (baseline 1.65±0.39, follow-up 0.77±0.3) and the striatum (baseline 9.79±3.48, follow-up 8.17±2.66) was used to estimate percent displacement by sertraline 150mg at SERT (53%) and DAT (17%), respectively. Results from the double-blind portion of the study are pending. Brainstem displacement was comparable to historical citalopram (40mg/day) data (51%) and appears to represent SERT saturation. However, striatal [123I]β-CIT binding usually increases with SSRIs via an unknown mechanism. The decrease observed indicates that sertraline also binds to DAT. These results reinforce prior findings that therapeutic doses of SSRIs saturate SERT and suggest that sertraline 150mg is the only SSRI with minimal DAT occupancy. Clinical Pharmacology & Therapeutics (2004) 75, P20–P20; doi: 10.1016/j.clpt.2003.11.077

A systematic chart review of the nature of psychiatric adverse events in children and adolescents treated with selective serotonin reuptake inhibitors.

Despite a rapidly growing literature on the efficacy of the selective serotonin reuptake inhibitors (SSRI) in the treatment of juvenile psychiatric disorders, relatively little is described about emotional, behavioral, and cognitive adverse effects associated with their use. To this end we completed a retrospective analysis of medical charts to determine the incidence, nature, and clinical correlates of treatment emergent adverse effects in the behavioral, cognitive, and emotional domains. We systematically evaluated the medical charts of children treated with SSRI for depressive or obsessive-compulsive disorders for a mean (+/- SD) of 26.9 + 20.8 months to determine the incidence, nature, and clinical correlates of treatment emergent psychiatric adverse events (PAE). Charts were reviewed for diagnoses, type and dose of SSRI and adjunct medication, specific type of PAE, and time to onset and offset of PAE. In total, 82 charts of children and adolescents (mean age 12.2 +/- 3.2 years) were examined. PAE occurred in 22% of children and were most commonly related to disturbances in mood. PAE were not associated with psychiatric diagnosis(es), age, sex, concurrent medications, doses or specific serotonin reuptake inhibitors. The onset of PAE was observed typically 3 months after SSRI exposure (median = 91 days). Although PAE diminished with SSRI discontinuation, those that emerged early in treatment diminished significantly more rapidly than those that emerged later (median offset was 10 and 49 days, respectively). Re-exposure to an SSRI resulted in another PAE in 44% (n = 18) of the group. Based on the retrospective review of medical charts, youth receiving SSRI appear to be at risk for treatment emergent PAE and recurrence with re-exposure to an SSRI. Prospective longer term studies evaluating the course and prognosis of youths manifesting PAE to SSRI are necessary.

Selective serotonin reuptake inhibitor discontinuation syndrome in children: Six case reports

Background: Antidepressant discontinuation syndrome refers to a cluster of symptoms that occur after abrupt dose reduction or discontinuation of antidepressant medication. Selective serotonin reuptake inhibitors (SSRIs) are increasingly being used for the treatment of depression and other psychiatric disorders in children and adolescents, but published data on SSRI discontinuation syndrome in children are limited. Objective: This paper presents 6 case reports of SSRI discontinuation syndrome in children. Results: SSRI discontinuation syndrome was diagnosed in 6 patients (4 boys, 2 girls; mean age, 11.33 ± 1.75 years) according to established criteria. Three patients had been taking paroxetine, 2 fluvoxamine, and 1 sertraline for an average of 4.00 ± 1.67 months (range, 3–6 months) before abrupt discontinuation or dose reduction. Dizziness/lightheadedness/drowsiness, poor concentration, nausea, headache, and fatigue were the most frequent symptoms. As in previous studies in adults, the 6 patients experienced SSRI discontinuation symptoms 1 to 5 days (mean 2.92 ± 1.63 days) after SSRI discontinuation or dose reduction. In all patients, symptoms resolved on reinitiation of treatment with the same SSRI or a different one. Conclusions: The case reports presented in this article suggest that SSRI discontinuation syndrome can and does occur in children when treatment is stopped or the SSRI dose is reduced abruptly, and is quite similar to that reported in adults. Placebo-controlled prospective studies are needed in children to further assess the prevalence and clinical presentation of SSRI discontinuation syndrome and to develop management strategies for this condition.

Disinhibition of libido: an adverse effect of SSRI?

Background: The article focuses on adverse drug reactions (ADR) to selective serotonin reuptake inhibitors (SSRI) concerning libido and sexual behaviour: cases of disinhibition of libido observed at the Psychiatric Hospital of Kilchberg near Zurich are described. Method: Within the scope of a drug safety program, the physicians of the hospital are regularly asked about severe and unexpected events under drug treatment. Results: During remission of depression, five outpatients noticed an increase of libido experienced as strange to them, i.e. preoccupation with sexual thoughts, first appearance of promiscuity, of unsafe sexual intercourse, and of excessive pursuit of pornography, respectively, during administration, change in dose or discontinuation of SSRI. Discussion: The case studies suggest that SSRI treatment might be associated with increase and disinhibition of libido. The phenomena are discussed as a ‘selective switch’ into partly manic symptomatology or an induction of mixed states with prevailing sexual symptoms.

Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients.

This study was initiated in order to describe and evaluate the effects of a therapeutic drug monitoring (TDM) routine of selective serotonin reuptake inhibitors (SSRIs) on treatment strategies and drug costs in depressed elderly patients. Blood samples were drawn from elderly depressed patients and analysed for steady-state trough serum concentrations of citalopram (n = 48), paroxetine (n = 48) or sertraline (n = 39). A global efficacy evaluation was made at baseline and after 6-9 months. Antidepressant drug costs before and after TDM were estimated. Eight samples were excluded due to technical problems or noncompliance. In 65 of the 127 (51.2%) remaining cases, the treatment strategy was changed according to the TDM outcome, in most a reduction of the prescribed dose. Bioanalytical TDM costs included the antidepressant drug costs after TDM were reduced by 10.2%. The results support the utility of TDM in the search for the individual minimum effective SSRI dose in the elderly.

Is premenstrual dysphoric disorder a distinct clinical entity?

Does the evidence now available support the concept of premenstrual dysphoric disorder (PMDD) as a distinct clinical disorder such that the relative safety and efficacy of potential treatment can be evaluated? In a roundtable discussion of this question, a wealth of information was reviewed by a panel of experts. The key characteristics of PMDD, with clear onset and offset of symptoms closely linked to the menstrual cycle and the prominence of symptoms of anger, irritability, and internal tension, were contrasted with those of known mood and anxiety disorders. PMDD displays a distinct clinical picture that, in the absence of treatment, is remarkably stable from cycle to cycle and over time. Effective treatment of PMDD can be accomplished with serotinergic agents. At least 60% of patients respond to selective serotonin reuptake inhibitors (SSRIs). In comparison with other disorders, PMDD symptoms respond to low doses of SSRIs and to intermittent dosing. Normal functioning of the hypothalamic-pituitary-adrenal (HPA) axis, biologic characteristics generally related to the serotonin system, and a genetic component unrelated to major depression are further features of PMDD that separate it from other affective (mood) disorders. Based on this evidence, the consensus of the group was that PMDD is a distinct clinical entity. Potential treatments for this disorder can now be evaluated on this basis to meet the clear need for effective therapy.

Management of SSRI-induced sexual dysfunction.

To describe the occurrence and management of sexual dysfunction induced by selective serotonin-reuptake inhibitors (SSRIs), to provide an overview of sexual dysfunction, reports of SSRI-induced sexual dysfunction, and management strategies. Information was retrieved from a MEDLINE English-literature search from January 1986 to July 1998 and by review of references. Indexing terms included sexual dysfunction, antidepressants, selective serotonergic reuptake inhibitors, fluoxetine, sertraline, paroxetine, fluvoxamine, clomipramine, buspirone, nefazodone, bupropion, cyproheptadine, amantadine, yohimbine, and central nervous system stimulants. There are no controlled studies describing SSRI-induced sexual dysfunction or its management. Twenty-one studies are presented, including 2 open-label studies, 12 case series, and 7 case reports. SSRI-induced sexual dysfunction is described with fluoxetine, paroxetine, sertraline, and fluvoxamine for 3-24 weeks of therapy. Data were organized according to the pharmacologic agent used in the management of SSRI dysfunction, target population, SSRI implicated, type of sexual dysfunction, experimental design, and treatment response. Data were extracted from methodology and results sections of reports. Methodologic flaws included failure to account for gender differences, omission of SSRI dose and duration, and use of concomitant drugs. The frequency of reports suggests that SSRI-induced dysfunction is a common adverse effect; controlled studies are necessary to determine prevalence. Most reports have occurred with fluoxetine, but this phenomenon may be related to its widespread use. Further study is needed to evaluate baseline sexual function, to define target populations, and to compare SSRIs in inducing sexual dysfunction. Serotonin antagonists and dopamine agonists have been used most often to treat SSRI-induced dysfunction and have generally been effective, but controlled studies are also needed.

Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test.

Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to investigate further the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg(-1), i.p.) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg(-1), i.p.; P < 0.01), paroxetine (4 mg kg(-1), i.p.; P < 0.01), citalopram (4 mg kg(-1), i.p.; P < 0.01) and sertraline (2 mg kg(-1), i.p.; P < 0.01) in the forced swimming test. However, pretreatment with buspirone did not induce antidepressant-like effects when tested in combination with fluoxetine (4 mg kg(-1), i.p.). Each antidepressant tested reduced immobility time in the forced swimming test [citalopram (16 mg kg(-1), i.p.; P < 0.01), fluoxetine (32 mg kg(-1), i.p.; P < 0.01), fluvoxamine (32 mg kg(-1), i.p.; P < 0.01), paroxetine (16 mg kg(-1), i.p.; P < 0.01) and sertraline (16 mg kg(-1), i.p.; P < 0.01)]. Pretreatment with buspirone (0.5 mg kg(-1), i.p.), or its major metabolite 1-PP (0.5 mg kg(-1), i.p.), attenuated all SSRI-induced anti-immobility effects (P < 0.01). Concomitant studies of locomotor activity ruled out any stimulant or sedative effects of the interactions. The results of the present study suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-HT1A receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (1-PP) acting at alpha2-adrenoreceptors.

Changing patterns of antidepressant use and costs in a health maintenance organisation.

This study examined changes in the utilisation and costs of different antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs), and changes in the use of mental health services in a US health maintenance organisation (HMO) over the 8-year period following the introduction of SSRIs. It was hypothesised that SSRIs would be used increasingly in this setting, and that SSRI users would show a pattern of mental health service utilisation that was indicative of more severe psychiatric illnesses or prior treatment failures. Both hypotheses were accepted. The use of antidepressants nearly tripled over the 8-year period, with SSRIs showing the largest increase; per capita antidepressant costs increased more than 10-fold, largely because of the high cost per unit of SSRIs. Estimated daily doses of SSRIs were largely within the recommended ranges, although the duration of use was short if their primary purpose was the treatment of depression. Incident (first-time) users of SSRIs, and patients who switched to SSRIs from other antidepressants, used more inpatient and outpatient mental health services than users of other antidepressants. Use of the psychiatric hospital among antidepressant users increased, then decreased back to its first year level, psychiatric hospital days appeared to decrease over time, and outpatient mental health visits increased. The inverse relationship between use of SSRIs and use of inpatient mental health services suggests the need for a cost-effectiveness analysis in this setting.

Effects of serotonin reuptake inhibitors on hemostasis.

To examine the hematologic safety profile of the selective serotonin reuptake inhibitors (SSRIs), with particular emphasis on the effects of these drugs on platelet aggregation. Platelet aggregation studies were undertaken at baseline, and repeated 2 and 4 weeks after the initiation of treatment with an SSRI. Other investigations undertaken included analysis of serum electrolyte and liver enzyme concentrations, complete blood count, and coagulation studies. Patients were also assessed for clinical signs of bleeding. Eight patients (7 treated with fluoxetine, 1 with paroxetine) completed the study protocol. Repeated ANOVA revealed no abnormalities in platelet aggregation, hematopoiesis, or coagulation profile. No patient developed clinical signs of abnormal hemostasis during the study period. A statistically significant elevation in the mean serum bilirubin concentration was detected, but this was not of clinical significance. Although the SSRIs may cause abnormal hemostasis, this effect is probably rare. Another possibility is that abnormal hemostasis is more likely to occur when high doses of SSRIs are administered.