Antidepressant Withdrawal Research Articles

SSRI and SNRI withdrawal symptoms reported on an internet forum.

Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants.

AJP Board Member Responds to NYT Story On Antidepressant Withdrawal

<i>AJP</i> Board Member Responds to <i>NYT</i> Story On Antidepressant Withdrawal

Looking for bipolarity in antidepressant discontinuation manic states: Update and diagnostic considerations of the phenomenon

BackgroundAntidepressant withdrawal manic states are intriguing and under-recognized phenomena. The associated patho-physiological pathways are ill defined and the inclusion of the phenomena in the bipolar spectrum disorders is questionable. This study aims to update a review on antidepressant discontinuation manic states published in 2008 and to look for hints alluding to bipolar disorder in the affected published cases and in the literature. It also reviews the different hypotheses proposed to explain discontinuation mania. MethodsWe searched Pubmed using the key words: ‘antidepressant withdrawal’ or ‘antidepressant discontinuation’ plus ‘mania’ or ‘hypomania’ from January 2008 until January 2018. ResultsFive new eligible reports were identified since the last review in 2008, involving the antidepressants Amitriptyline, Fluoxetine, Escitalopram and Mirtazapine. Hypotheses involve the implication of Catecholamines, Acetylcholine and Serotonin in the pathophysiology of this paradoxical phenomenon. Careful analysis of the total 29 cases revealed psychiatric histories in favor of a bipolar spectrum disorder in 12 individuals while five were already known to have bipolar disorder. LimitationsThis review is based on case reports with associated recall bias, and lack of in-depth description at times. ConclusionsAntidepressant discontinuation manic or hypomanic states do not occur randomly. An individual susceptibility to bipolar disorder must be considered.

Transience of antidepressant‐induced Gαs signaling potentiation revealed by high‐throughput real‐time cAMP accumulation

Gαs is found at high concentrations in cholesterol rich membrane microdomains known as lipid rafts. These domains suppress coupling between Gαs and effectors such as adenylyl cyclase (AC), leading to decreased cAMP. Antidepressant drugs with diverse mechanisms of action have reliably shown the ability to promote the translocation of Gαs out of lipid rafts in cellular and animal models, leading to increased cAMP, pCREB and BDNF. In cells from depressed subjects Gαs is found at higher concentrations in lipid rafts. Importantly, this difference is eliminated in individuals who respond positively to antidepressant drug treatment, while in non‐responders the increased raft localization of Gαs is maintained. This differential localization may allow Gαs translocation out of lipid rafts to serve as a novel biomarker to screen for effective antidepressants.Although antidepressant drugs have been shown to gradually accumulate in lipid rafts, the relevant binding site, or sites, remain unknown. Notably, the S‐stereoisomer of the selective serotonin reuptake inhibitor citalopram binds to these raft regions, even in cells lacking the serotonin transporter, while the non‐antidepressant R‐stereoisomer does not. This suggests a novel, stereospecific protein target for antidepressant drugs may exist within lipid rafts. Little is known about the reversibility of this process, or whether antidepressant drug withdrawal itself produces unique signaling effects.In this study we use a combination of techniques including live cell cAMP accumulation analysis, fluorescence recovery after photobleaching (FRAP) of GFP tagged Gαs, and detection of antidepressant drug concentration via mass spectrometry. This allows determination of both the effects of extended antidepressant treatment on Gαs localization and signaling, as well as the effect of antidepressant withdrawal. Agents that increase cAMP concentrations, such as forskolin, produce greater effects following antidepressant treatment due to Gαs translocation out of lipid rafts and into closer association with AC. Gαs mobility within the membrane is also inhibited following antidepressant treatment due to formation of this Gαs/AC complex, and this reduction in mobility is observed as an increased FRAP half‐time with GFP tagged Gαs. The localization of the antidepressant drugs themselves are also quantified via mass spectrometry following separation of raft vs. non‐raft membrane regions.Analyzing these effects both during antidepressant treatment and following removal of the drug provides insight not only into the ways these drugs regulate cellular processes, but also how the cell responds to their withdrawal. It appears that antidepressant drug removal not only reverses the effects seen with extended treatment, but can also produce a lasting suppression of these processes. This work provides the next steps towards determining a binding site for antidepressants within lipid rafts, and will lead to the development of a more realistic screen for antidepressant drug development.Support or Funding InformationFunding: NIH R01AT009169; VA BX001149This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

NICE guidelines on antidepressant withdrawal in ‘urgent need of correction’, say researchers

NICE guidelines on antidepressant withdrawal in ‘urgent need of correction’, say researchers

Stopping Antidepressants and Anxiolytics as Major Concerns Reported in Online Health Communities: A Text Mining Approach.

BackgroundInternet is a particularly dynamic way to quickly capture the perceptions of a population in real time. Complementary to traditional face-to-face communication, online social networks help patients to improve self-esteem and self-help.ObjectiveThe aim of this study was to use text mining on material from an online forum exploring patients’ concerns about treatment (antidepressants and anxiolytics).MethodsConcerns about treatment were collected from discussion titles in patients’ online community related to antidepressants and anxiolytics. To examine the content of these titles automatically, we used text mining methods, such as word frequency in a document-term matrix and co-occurrence of words using a network analysis. It was thus possible to identify topics discussed on the forum.ResultsThe forum included 2415 discussions on antidepressants and anxiolytics over a period of 3 years. After a preprocessing step, the text mining algorithm identified the 99 most frequently occurring words in titles, among which were escitalopram, withdrawal, antidepressant, venlafaxine, paroxetine, and effect. Patients’ concerns were related to antidepressant withdrawal, the need to share experience about symptoms, effects, and questions on weight gain with some drugs.ConclusionsPatients’ expression on the Internet is a potential additional resource in addressing patients’ concerns about treatment. Patient profiles are close to that of patients treated in psychiatry.

Measurement, Education and Tracking in Integrated Care (METRIC): use of a culturally adapted education tool versus standard education to increase engagement in depression treatment among Hispanic patients: study protocol for a randomized control trial

BackgroundSignificant mental health disparities exist for Hispanic populations, especially with regard to depression treatment. Stigma and poor communication between patients and their providers result in low use of antidepressant medications and early treatment withdrawal. Cultural factors which influence treatment decisions among Hispanics include fears about the addictive and harmful properties of antidepressants, worries about taking too many pills, and the stigma attached to taking medications. Primary care settings often are the gateway to identifying undiagnosed or untreated mental health disorders, particularly for people with co-morbid physical health conditions. Hispanics, in particular, are more likely to receive mental healthcare in primary care settings. Recent recommendations from the U.S. Preventive Services Task Force are that primary care providers screen adult patients for depression only if systems are in place to ensure adequate treatment and follow-up.MethodsWe are conducting a randomized controlled trial among 150 depressed adult Hispanics in a primary care safety net setting, testing the effectiveness of a culturally appropriate depression education intervention to reduce stigma and increase uptake in depression treatment among Hispanics, and implement a Measurement-Based Integrated Care (MBIC) model with collaborative, multidisciplinary treatment and culturally tailored care management strategies.DiscussionThis study protocol represents the first randomized control trial of the culturally adapted depression education fotonovela, Secret Feelings, among Hispanics in a primary care setting. The education intervention will be implemented after diagnosis using an innovative screening technology and enrolled in measurement-based integrated care for the treatment of depression, which will help build the evidence around cultural adaptations in treatment to reduce mental health disparities.Trial registrationClinicalTrials.gov, NCT02702596. Registered on 20 March 2016.

Antidepressant withdrawal mania: Two case reports

IntroductionAlthough rarely reported, antidepressant discontinuation may induce hypomania or mania even in the absence of bipolar disorder [1,2].ObjectivesWe report two cases of antidepressant withdrawal induced mania.MethodsClinical process consultation and PubMed search were performed in November 2016 using the search keywords antidepressant, mania and discontinuation.ResultsCase report 1: a dysthymic 60 years old woman with 20 years of psychiatric following had been treated with venlafaxine 150 mg/daily the past year. She abruptly stopped taking this drug, developing heightened mood, irritability and racing thoughts five days later. She was admitted at our hospital, initiating then valproate and antipsychotics. Two weeks later, the hypomania clinical state remitted completely.Case report 2: a 64 years old woman, with a 12-year-old diagnosis of unipolar depression was brought to our emergency service with complaints of disorganized behavior, paranoid delusional ideas, excessive speech, irritable mood and reduced need for sleep, 1 week after abrupt trazodone 150 mg/daily discontinuation. Valproic acid 1000 mg/daily and olanzapine 20 mg/daily were introduced, with gradual improvement of symptoms. Two weeks later she was completely asymptomatic.ConclusionPsychiatrists should be aware of the risk of antidepressant withdrawal induced mania. More studies should be conducted about this subject, aiming for the clarification of risk factors and the establishment of clinical criteria for this phenomenon.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Predicting relapse after antidepressant withdrawal - a systematic review.

A substantial proportion of the burden of depression arises from its recurrent nature. The risk of relapse after antidepressant medication (ADM) discontinuation is high but not uniform. Predictors of individual relapse risk after antidepressant discontinuation could help to guide treatment and mitigate the long-term course of depression. We conducted a systematic literature search in PubMed to identify relapse predictors using the search terms '(depress* OR MDD*) AND (relapse* OR recurren*) AND (predict* OR risk) AND (discontinu* OR withdraw* OR maintenance OR maintain or continu*) AND (antidepress* OR medication OR drug)' for published studies until November 2014. Studies investigating predictors of relapse in patients aged between 18 and 65 years with a main diagnosis of major depressive disorder (MDD), who remitted from a depressive episode while treated with ADM and were followed up for at least 6 months to assess relapse after part of the sample discontinued their ADM, were included in the review. Although relevant information is present in many studies, only 13 studies based on nine separate samples investigated predictors for relapse after ADM discontinuation. There are multiple promising predictors, including markers of true treatment response and the number of prior episodes. However, the existing evidence is weak and there are no established, validated markers of individual relapse risk after antidepressant cessation. There is little evidence to guide discontinuation decisions in an individualized manner beyond overall recurrence risk. Thus, there is a pressing need to investigate neurobiological markers of individual relapse risk, focusing on treatment discontinuation.

A review of the management of antidepressant discontinuation symptoms

Strong evidence supports the existence of a discontinuation syndrome following the withdrawal of antidepressant medication, particularly second-generation antidepressants. The syndrome is a common phenomenon and guidance as to best avoid the symptoms is essential for both practitioners and patients. The current study reviewed the available literature on the best methods of discontinuation for antidepressants in order to avoid or prevent the occurrence of any unpleasant side effects associated with antidepressant withdrawal. Accordingly, an electronic search of the PubMed/MedLine database and Google Scholar was conducted to find relevant literature published within the last 10 years. From this, 18 related articles were identified; five clinical studies, one case series, one consensus panel's recommendations and 11 literature reviews. Of the articles reviewed there is a general consensus as to tapering the drug slowly over a period of weeks or months. Also, in those patients who experience severe symptoms the drug should be reinstated and discontinued more gradually. The discontinuation syndrome does not occur as frequently or severely with longer-acting agents such as fluoxetine and therefore it is recommended that switching to this drug prior to withdrawal may be advisable. The articles reviewed also emphasize the need for patient education and reassurance throughout the discontinuation process. One in particular adds that cognitive behavioural therapy may be a useful tool in easing the patients' distress. However, this review highlights the lack of controlled data to support the available guidelines. Furthermore, the guidance which is available is somewhat conflicting. Research approaches should address this issue as well as develop appropriate methods of withdrawal for specific drugs.

Memantine prevents “bipolar-like” behavior induced by chronic treatment with imipramine in rats

A great deal of evidence suggests that virtually all antidepressant treatments induce a dopaminergic behavioral supersensitivity. We have suggested that this effect may play a key role not only in the antidepressant effect of these treatments, but also in their ability to induce a switch from depression to mania. In 2003-4 we found that the sensitization of dopamine receptors induced by imipramine is followed, after imipramine withdrawal, by a desensitization of these receptors associated with a depressive-like behavior assessed in the forced swimming test. The dopamine receptor sensitization can be prevented by MK-801, an NMDA receptor antagonist, but not by currently used mood stabilizers (lithium, carbamazepine, valproate). These observations led us to suggest – and later confirm - with preliminary clinical observations that memantine may have an acute antimanic and a long-lasting mood-stabilizing effect in treatment-resistant bipolar disorder patients. Here we present data showing that memantine prevents not only the dopamine receptor sensitization induced by imipramine, as observed with MK-801, but also the ensuing desensitization and the associated depressive-like behaviorq observed after antidepressant withdrawal.

The utility of polysomnography for the diagnosis of NREM parasomnias: an observational study over 4 years of clinical practice.

Polysomnography (PSG) is considered the gold standard for diagnosis of non-rapid eye movement (NREM) parasomnias, however its diagnostic yield has been rarely reported. We aimed to assess the diagnostic value of polysomnography in different categories of patients with suspected NREM parasomnia and define variables that can affect the outcome. 124 adults referred for polysomnography for suspected NREM parasomnia were retrospectively identified and divided into clinical categories based on their history. Each polysomnography was analysed for features of NREM parasomnia or different sleep disorders and for presence of potential precipitants. The impact on the outcome of number of recording nights and concomitant consumption of benzodiazepines and antidepressants was assessed. Overall, PSG confirmed NREM parasomnias in 60.5 % patients and showed a different sleep disorder in another 16 %. Precipitants were found in 21 % of the 124 patients. However, PSG showed limited value when the NREM parasomnia was clinically uncomplicated, since it rarely revealed a different diagnosis or unsuspected precipitants (5 % respectively), but became essential for people with unusual features in the history where different or overlapping diagnoses (18 %) or unsuspected precipitants (24 %) were commonly identified. Taking benzodiazepines or antidepressants during the PSG reduced the diagnostic yield. PSG has a high diagnostic yield in patients with suspected NREM parasomnia, and can reveal a different diagnosis or precipitants in over 40 % of people with complicated or atypical presentation or those with a history of epilepsy. We suggest that PSG should be performed for one night in the first instance, with leg electrodes and respiratory measurements and after benzodiazepine and antidepressant withdrawal.

Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats

Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10–20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children’s developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers’ anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10mg/kg/day p.o.) to examine its effects on offspring’s emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams’ pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim Test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7–21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.

Delayed multifocal recurrent stress-induced cardiomyopathy after antidepressants withdrawal

Stress-induced cardiomyopathy is an acute disease characterized by a large left ventricular apical dyskinesia (“apical ballooning”), triggered by intense emotional or physical stress, acute illnesses or, rarely, by alcohol or opiates withdrawal. Connection to stress and apical asynergy suggest a catecholamine-mediated pathogenesis.We recently observed a typical apical stress-induced cardiomyopathy, arising two weeks after a long-lasting antidepressant treatment withdrawal and recurring, a week later, with evidence of inferior wall akinesia.The reported case has several unusual features: 1) both episodes were not preceded by relevant triggering event (except antidepressant discontinuation); 2) early heterozonal relapse was observed; 3) the latency between antidepressant discontinuation and stress-induced cardiomyopathy onset is unusually long.The lack of relevant triggering stress and the evidence of multifocal asynergies could support the hypothesis of a non-catecholaminergic pathogenesis. Moreover, the long latency after antidepressant withdrawal may suggest that prolonged antidepressant treatments may have delayed pathological consequences, possibly related to their known neuroplastic effects.

Mania/hypomania associated with withdrawal of antidepressants

Although paradoxical mania/hypomania due to antidepressant withdrawal is rarely reported in the literature as case report, it is possible that it may be observed more commonly in the clinical settings. Paradoxical mania/hypomania is reported to be associated with tricyclic antidepressants as well as selective serotonin reuptake inhibitors and other antidepressants. Although paradoxical mania/hypomania due to sertraline and paroxetine withdrawal are reported individually, we will discuss a patient with paradoxical mania/hypomania due to withdrawal of both antidepressants administered at two different time periods, since this is the only case reported so far.

Mania during antidepressant withdrawal in late‐onset depression

Mania during antidepressant withdrawal in late‐onset depression

1764 – Case report: antidepressant withdrawal mania

Introduction Antidepressant withdrawal mania is a rare paradoxical event. It was initially reported in unipolar patients but it can also occur in bipolar patients, despite adequate mood-stabilizing treatment. It has been described with all antidepressant classes and may be self-limited or require medical hospitalization. Tapered withdrawal doesn’t seem to prevent the condition, though most reported cases developed after abrupt antidepressant discontinuation. Chronic antidepressant therapy enhances dopaminergic neurotransmission in the mesolimbic system. Noradrenergic hyperactivity and cholinergic overdrive secondary to antidepressant cessation are the most accepted theoretical mechanisms proposed. Objectives Case report, discussion and literature review. Aims We report a case of fluoxetine withdrawal mania and discuss its implications on clinical practice. Methods Case report and non systematic literature review. Results We present a case of a divorced 59-year-old woman who developed a manic episode shortly after antidepressant discontinuation. She was under antidepressant therapy since 2001, due to an unipolar chronic depressive disorder. She was put on fluoxetine 20 mg q.d. since 2005. On May 2012, she discontinued the antidepressant therapy upon misunderstanding medical advice. Few weeks later, she was involuntarily admitted to our inpatient unit presenting a manic episode with psychotic features. She started valproic acid 1000 mg q.d. and risperidone 4 mg q.d. and a complete remission was quickly obtained. Conclusions This case illustrates the potential for mania related to antidepressant discontinuation. Differential diagnosis includes spontaneous mania, antidepressant withdrawal syndrome and antidepressant induced mania. Finally, the authors discuss the adequacy of categorizing this entity in bipolar spectrum disorders.

Studies of Long-Term Use of Antidepressants

Depression is a recurrent illness in which afflicted individuals have an increased risk for recurrence as a function of a greater number of previous episodes. Consequently, prevention of future episodes is central to improving the prognosis. The current recommendation is to use antidepressants over prolonged periods of time to prevent further episodes of depression. However, the database for this practice is limited and can be interpreted in multiple ways. Review of the relevant literature was performed. MEDLINE and PubMed databases were searched from inception to 5 September 2011 for randomized, placebo-controlled trials of at least 18 months duration. After treatment of an acute depressive episode, antidepressants clearly prevent relapse back into the same depressive episode. This is demonstrated by an adequate number of randomized, blinded, placebo-controlled, 1-year continuation trials. The ability of antidepressants to prevent recurrence of future episodes is less clear. Randomized, blinded, placebo-controlled trials of 18 months or longer are infrequent - 18 studies were identified. While nearly all show that antidepressant continuation is superior to placebo in preventing resurgence of depressive symptoms, nearly all of the difference occurs in the first 6 months after randomization. This pattern strongly suggests that the apparent superiority of antidepressants may be due to (i) their ability to prevent recurrence, (ii) antidepressant withdrawal (characterized by depressive symptoms) in patients switched to placebo or (iii) a combination of these phenomena.

Avoidance learning during antidepressant withdrawal in mice

Shuttle-box avoidance acquisition, locomotor activity and density of adrenoreceptors in the cerebral cortex have been evaluated, in CD-1 mice, during withdrawal from repeated treatment with desipramine or mianserin (5 or 14 daily injections of antidepressant drug, 10 mg kg-1). Withdrawal from mianserin did not produce any behavioural or neurochemical change. Mice withdrawn from desipramine exhibited avoidance facilitation, when training started 24 h (but not 72 or 120 h) after the last injection. Locomotor activity was not affected and no change was found in the density of beta-adrenoreceptors. An up-regulation of alpha 2- and, to a lesser extent, of alpha 1-adrenoreceptors, occurred 72 h following desipramine withdrawal. However, the assessment of the role played by these neurochemical changes in the avoidance facilitation observed during withdrawal from the antidepressant treatment requires further study.

Neonatal Exposure to Citalopram Selectively Alters the Expression of the Serotonin Transporter in the Hippocampus: Dose‐Dependent Effects

Infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) late in pregnancy have been reported to exhibit signs of antidepressant withdrawal. Such evidence suggests that these drugs access the fetal brain in utero at biologically significant levels. Recent studies in rodents have revealed that early exposure to antidepressants can lead to long lasting abnormalities in adult behaviors, and result in robust decreases in the expression of a major serotonin synthetic enzyme (tryptophan hydroxylase) along the raphe midline. In the present investigation, we injected rat pups with citalopram (CTM: 5 mg/kg, 10 mg/kg, and 20 mg/kg) from postnatal Days 8-21, and examined serotonin transporter (SERT) labeling in the hippocampus, ventrobasal thalamic complex, and caudate-putamen when the subjects reached adulthood. Our data support the idea, that forebrain targets in receipt of innervation from the raphe midline are particularly vulnerable to the effects of CTM. SERT-immunoreactive fiber density was preferentially decreased throughout all sectors of the hippocampal formation, whereas the subcortical structures, each supplied by more lateral and rostral aspects of the raphe complex, respectively, were not significantly affected. Reductions in SERT staining were also found to be dose-dependent. These findings suggest that SSRIs may not only interfere with the establishment of chemically balanced circuits in the neonate but also impose selective impairment on higher cortical function and cognitive processes via more circumscribed (i.e., regionally specific) deficits in 5-HT action.