Long-term Antidepressant Effects Research Articles

IMPACT OF PROLONGED USE OF ANTIDEPRESSANTS ON NEUROPLASTICITY

Antidepressants are widely used in the treatment of depressive and anxiety disorders and are essential for the management of these conditions. However, the impact of prolonged use of these drugs on neuroplasticity - the brain’s ability to reorganize itself, forming new neural connections - has been a topic of growing interest and debate in the scientific community. This abstract addresses the effects of prolonged use of antidepressants on neuroplasticity, considering their implications for long-term mental health. The aim of this paper is to examine and synthesize the scientific evidence on the impact of long-term use of antidepressants on neuroplasticity, with a focus on how these changes can influence the effectiveness of treatment and the long-term prognosis of patients. This study conducts a literature review on the long-term effects of antidepressants on neuroplasticity, investigating both the therapeutic potentials and the associated risks. The review focuses on how neuroplasticity can influence treatment outcomes, tolerance to antidepressants, and the impacts on specific populations, such as the elderly and individuals with hormonal variations. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs), have been shown to influence neuroplasticity in several ways. Pre-clinical and clinical studies suggest that prolonged use of these drugs can promote neurogenesis, particularly in the hippocampus, an area of the brain crucial for memory and learning. This neurogenic effect is associated with an improvement in depressive symptoms and the brain’s ability to adapt to new challenges. In addition, antidepressants appear to increase the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which plays a vital role in the survival and growth of neurons. The increase in BDNF levels may contribute to the restoration of synaptic connectivity, which is often compromised in patients with depression. However, there is controversy about the long-term effects of continuous use of these drugs on neuroplasticity. Some studies suggest that, despite the initial benefits, prolonged use can lead to a “rigidity” in brain plasticity, making it difficult to adapt to new treatments or therapeutic strategies. In addition, the impact on other areas of the brain, such as the prefrontal cortex, which is involved in decision-making and emotional control, is still poorly understood and requires further research. These findings raise questions about the optimal duration of treatment with antidepressants and the need for continuous monitoring of patients’ long-term mental health. Neuroplasticity may be a crucial factor in individual response to treatment and the possibility of relapse or development of resistance to treatment. Therefore, the prolonged use of antidepressants has a significant impact on neuroplasticity, initially promoting neurogenic effects and an increase in synaptic connectivity, which can improve depressive symptoms. However, the long-term effects still need to be better understood, especially with regard to the possible “rigidity” in brain plasticity and the implications for ongoing treatment. To maximize the benefits and minimize the risks, it is essential that treatment with antidepressants is carefully monitored, with attention to changes in neuroplasticity over time. More research is needed to elucidate the underlying mechanisms and guide clinical practice towards more effective and safer strategies for the management of depression and other related disorders.

Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression.

Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis

QuestionTricyclic antidepressants are used to treat depression worldwide, but the adverse effects have not been systematically assessed. Our objective was to assess the beneficial and harmful effects of all tricyclic...

Electroacupuncture Ameliorates Depression-Like Behaviors Comorbid to Chronic Neuropathic Pain via Tet1-Mediated Restoration of Adult Neurogenesis.

Although electroacupuncture (EA) stimulation is a widely used therapy for chronic pain and comorbid psychiatric disorders, its long-term effects on chronic neuropathic pain-induced depression and the underlying mechanisms remain elusive. In the present study, we found that EA stimulation was able to restore adult neurogenesis in the ventral dentate gyrus (DG), by both increasing neuronal differentiation and restoring the normal morphology of newborn dendrites, in mice with spared nerve injury surgery. By ablating the Nestin+ neural stem cells (NSCs) via diphtheria toxin fragment A expression, we further proved that neurogenesis in the ventral DG was crucial to the long-term, but not the immediate antidepressant effect of EA, nor was it associated with nociception. Furthermore, we found that the restoration of neurogenesis was dependent on Tet1-mediated epigenetic modification upon EA treatment. Tet1 could bind to the promoter of the Prox1 gene, thus catalyzing its demethylation and facilitating its expression, which finally contributed to the restoration of neurogenesis and amelioration of depression-like behaviors induced by chronic neuropathic pain. Thus, we conclude that EA stimulation restores inhibited Tet1 expression in hippocampal NSCs of mice with chronic neuropathic pain, and increased Tet1 expression ameliorates hypermethylation of Prox1 and restores normal adult neurogenesis in the ventral DG, which contributes to the long-term antidepressant effect of EA.

Anti-Inflammatory Action of Antidepressants: Investigating the Longitudinal Effect of Antidepressants on White Blood Cell Count

Introduction: Antidepressants have documented anti-inflammatory effects on pro-inflammatory biomarkers. However, the long-term effects of antidepressants on inflammatory markers and the effects of different antidepressant classes on pro-inflammatory biomarkers are largely unexplored. Here, we evaluate the short- and long-term effects of all antidepressant classes on a clinical immune marker, white blood cell count (WBC). Methods: Using a retrospective study design, we extracted WBC count and prescription medications from electronic health records at Vanderbilt University Medical Center. We created a longitudinal model to evaluate the short- and long-term effects of these medications on WBC count. We validated our longitudinal model using two known anti-inflammatory medications, biologic immunosuppressants, and chemotherapy, and one medication class without known immunomodulatory properties, contraceptives. We used the longitudinal model to determine the effects of antidepressant use on WBC count stratified by drug class. Results: Biologic immunosuppressant and chemotherapy use was associated with decreased WBC count, but contraceptive use did not associate with changes in WBC count, validating our longitudinal modeling approach. All antidepressant classes were associated with decreased WBC count in the long-term cohorts. SSRI and atypical use also associated with decreased WBC count in the short-term cohort. Conclusions: Using electronic health record data, we show all antidepressant classes exhibit anti-inflammatory effects on a clinical immune marker, WBC count. Additionally, our results indicate that in some cases the anti-inflammatory effects of antidepressants persist over at least a 1-year time frame. Our work contributes to the immunomodulatory knowledge of antidepressants and motivates future studies investigating alternative therapeutic routes for antidepressants.

A combination of neuroimaging and plasma metabolomic analysis suggests inflammation is associated with white matter structural connectivity in major depressive disorder

BackgroundMajor depressive disorder (MDD) is a common mental disorder with unknown pathophysiology. The abnormality of white matter structural connectivity and dysregulation of metabolome in MDD had been widely reported previously. Exploration of the relationship between white matter structural connectivity and plasma metabolites would be helpful for explanation of molecular mechanism for the findings from neuroimaging researches in MDD. MethodsThe diffusion spectrum imaging data were collected for identification of difference of white matter structural connectivity between MDD (n = 49) and HC (n = 68). The plasma metabolite profiles were acquired by liquid chromatography-mass spectrometry analysis and clustered as co-expression modules. The correlation analysis was performed to identify structural connectivity associated metabolite. ResultsWe identified two structural connectivity related metabolite modules. One module was correlated with fractional anisotropy (FA) value between left middle temporal gyrus and left inferior temporal gyrus, which were enriched in tryptophan metabolism pathway; another module was correlated with fiber numbers (FN) between right fusiform gyrus and right inferior temporal gyrus, which was enriched in lysophosphatidylcholine (LPC), lysophosphatidylinositol (LPI) and lysophosphatidylglycerol (LPG) lipid sets. l-Kynurenine in tryptophan metabolism pathway was negatively correlated with FN between right fusiform gyrus and right inferior temporal gyrus, and LPC was positively correlated with FA value between left middle temporal gyrus and left inferior temporal gyrus in MDD. LimitationsFirst, the sample size was relatively small. Second, the long-term effects of antidepressants were not excluded. ConclusionThe results suggested inflammation-related mechanism was associated with white matter structural connectivity in MDD.

The cognitive effects of esketamine: what do we know so far?

IntroductionEsketamine is an S-enantiomer of ketamine approved by the EMA for treatment-resistant depression (TRD). As an NMDA receptor antagonist, its administration results in increase of glutamate release and AMPA receptor activation, supporting both rapid-onset and long-term antidepressant effects. Short-term tolerability seems acceptable but major concerns remain regarding long-term safety, specifically regarding potential neurocognitive toxicity.ObjectivesTo clarify the potential short and long-term cognitive beneficial-effects and side-effects of esketamine.MethodsResearch was made using the Medline database, through the Pubmed search engine, using the keywords: “esketamine”, “cognition”. Only randomized-controlled trials were considered.ResultsOne study focused on the effects of intranasal esketamine (INE) on cognitive functioning in 24 healthy individuals, who were evaluated pre- and postdose (40 min, 2h, 4h and 6h). The results showed a decline in cognitive performance at 40 min postdose, returning to comparable levels as placebo by 2h postdose. Another study, with a follow-up of 1 year, involving 802 TRD patients, accessed the long-term safety of INE. In patients aged <65 years-old, performance on all cognitive tests remained stable or slightly improved from baseline during long-term treatment. In patients ≥ 65 years-old, the mean performance on all tests improved or remained stable, while the simple and choice reaction time began slowing at week 20.ConclusionsEsketamine has proven to be a promising new option for the treatment of TRD and available studies have shown promising results regarding patients’ cognitive function. Larger clinical trials are needed to further evaluate its short-term and long-term cognitive effects.DisclosureNo significant relationships.

Cannabinoids and Psychedelics for Neuropsychiatric Symptoms of Alzheimer's: Addressing Disparities Through Clinical Trials

AD and other forms of dementia are commonly associated with neuropsychiatric symptoms, including anxiety, agitation, and depression, all of which can lead to more rapid cognitive decline and a poor quality of life for both caregivers and patients.There are currently no FDA approved medications to treat neuropsychiatric symptoms associated with dementia. Instead, current treatment options include off-label use of psychotropic medications that are associated with well-established risks. Alternative therapeutic options include cannabinoids and psychedelics. This session will focus on discussing the safety and efficacy of cannabinoids in treating anxiety and agitation associated with Alzheimer's dementia, as well as the safety and efficacy of psychedelics in treating depression in older adults with dementia.The history of medicinal cannabis use dates back as far as 4000BC. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, activates cannabinoid receptors (mainly CB1 and CB2 receptors), producing anxiolytic and antidepressant effects while also reducing reduce brain inflammation. Cannabidiol (CBD), the major non-intoxicating component of cannabis, possesses low affinity to CB1 and CB2 receptors. CBD modulates systems outside of the endocannabinoid system, producing antioxidant and antipsychotic effects. Both THC and CBD have shown evidence of therapeutic effects on anxiety and pain. We will discuss three studies evaluating the use of cannabinoids as potential forms of treatment for agitation and anxiety in dementia.Psychedelics are also being introduced as potential mental health treatments. Past research has shown psychedelics can produce long-term anxiolytic and antidepressant effects after a single administration. A pilot trial at Johns Hopkins is examining the safety and efficacy of psilocybin treatment for participants with mild cognitive impairment (MCI) and depressive symptoms. The study hypothesizes that the psilocybin treatment will be associated with a significant reduction in depressive symptoms.Overall, these trials collectively guide research towards furthering our understanding of the pathology of Alzheimer's dementia and other forms of dementia and improving the quality of life for older adults and their caregivers.

Repeated Yueju, But Not Fluoxetine, Induced Sustained Antidepressant Activity in a Mouse Model of Chronic Learned Helplessness: Involvement of CaMKII Signaling in the Hippocampus.

Objective Depression is characterized with long disease length, whereas one major disadvantage of current mainstream treatment of depression is a high rate of relapse and recurrence. A sustained antidepressant activity is proposed to facilitate the prevention of relapse/recurrence. Here we compared the long-term antidepressant effect of Yueju, a traditional Chinese medicine formula, and a conventional antidepressant, fluoxetine, as well as revealing the underlying mechanism of long-term antidepressant effect of Yueju. Methods Clinical long-term depression condition was modelled by using chronic learned helplessness (cLH) protocol in ICR strain mice. The short-term and long-term antidepressant effects of drugs were assessed with learned helplessness (LH), tail suspension test (TST), forced swim test (FST), and novelty-suppressed feeding (NSF) test. The expression of PKA, CaMKII signaling, and NR1, the NMDA receptor subunit, in hippocampus was determined. A CaMKII inhibitor (KN-62) was used to assess the role of CaMKII signaling in antidepressant effects of Yueju or fluoxetine. Results In the mice exposed to chronic learned helplessness (cLH) procedure, administration of Yueju or fluoxetine for 3 weeks elicited comparable antidepressant effects, indicated by learned helplessness test, as well as TST and NSF. However, 5 days after termination of the 3-week-long drug administration, only mice previously treated with Yueju still showed the alleviation of depressive-like behaviors. At this time, the downregulation of PKA and p-CaMKII/CaMKII and upregulation of NMDA receptor subunit NR1 in the hippocampus were normalized in animals previously treated with Yueju. In contrast, none of the expressions of these proteins were changed in mice previously treated with fluoxetine. Interestingly, an administration of KN-62 blunted the antidepressant effect of Yueju. Conclusion These findings showed the sustained antidepressant efficacy of chronic treatment with routine dose of Yueju and the CaMKII signaling activation may play a critical role in the sustained antidepressant response.

Optogenetic stimulation of ventral tegmental area dopaminergic neurons in a female rodent model of depression: The effect of different stimulation patterns.

Major depressive disorder is one of the most common mental disorders, and more than 300million of people suffer from depression worldwide. Recent clinical trials indicate that deep brain stimulation of the superolateral medial forebrain bundle (mfb) can have rapid and long-term antidepressant effects in patients with treatment-resistant depression. However, the mechanisms of action are elusive. In this study, using female rats, we demonstrate the antidepressant effects of selective optogenetic stimulation of the ventral tegmental area's dopaminergic (DA) neurons passing through the mfb and compare different stimulation patterns. Chronic mild unpredictable stress (CMUS) induced depressive-like, but not anxiety-like phenotype. Short-term and long-term stimulation demonstrated antidepressant effect (OSST) and improved anxiolytic effect (EPM), while long-term stimulation during CMUS induction prevented depressive-like behavior (OSST and USV) and improved anxiolytic effect (EPM). The results highlight that long-term accumulative stimulation on DA pathways is required for antidepressant and anxiolytic effect.

Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review.

Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.

No antidepressant effects of low intensity transcranial pulsed electromagnetic fields for treatment resistant depression

BackgroundNoninvasive neurostimulation with transcranial Pulsed Electromagnetic Fields (tPEMF) may be a promising method for treatment resistant depression (TRD). Studies shown substantial improvement of depressive symptoms in patients with TRD, but there is no information on long-term antidepressant effects. The aim of this study was to investigate the short- and long-term efficacy of tPEMF in participants with TRD. MethodsEligible participants with TRD in this sham-controlled double-blind multicenter trial were randomly assigned to five weeks either daily active or sham tPEMF. Severity of depression and anxiety was assessed pre- and directly post-treatment and five and fifteen weeks post-treatment. Primary outcome was change on the 17-item Hamilton depression rating scale directly post-treatment. Secondary outcome was change on the Hamilton-17 during follow-up and change on the Inventory of Depressive Symptomatology Self-Report and the Beck Anxiety Index. ResultsOf the 55 included participants, 50 completed the treatment protocol. Depressive symptoms improved over time in both groups. The improvement continued until the last follow-up measure. There was no difference in outcome between the active and the sham group on change in depression post-treatment or on any secondary measure. ConclusionTreatment with this type of active tPEMF was not superior to sham in patients with TRD. This is in contrast to a previous study using a similar design and power calculation, but a higher magnetic field strength, that reported improvement of depression after treatment with tPEMF compared to sham. An important limitation of our study was the fact that no different dosing regimens were tried.

Predicting Antidepressant Citalopram Treatment Response via Changes in Brain Functional Connectivity After Acute Intravenous Challenge.

Introduction: The early and therapy-specific prediction of treatment success in major depressive disorder is of paramount importance due to high lifetime prevalence, and heterogeneity of response to standard medication and symptom expression. Hence, this study assessed the predictability of long-term antidepressant effects of escitalopram based on the short-term influence of citalopram on functional connectivity.Methods: Twenty nine subjects suffering from major depression were scanned twice with resting-state functional magnetic resonance imaging under the influence of intravenous citalopram and placebo in a randomized, double-blinded cross-over fashion. Symptom factors were identified for the Hamilton depression rating scale (HAM-D) and Beck's depression inventory (BDI) taken before and after a median of seven weeks of escitalopram therapy. Predictors were calculated from whole-brain functional connectivity, fed into robust regression models, and cross-validated.Results: Significant predictive power could be demonstrated for one HAM-D factor describing insomnia and the total score (r = 0.45–0.55). Remission and response could furthermore be predicted with an area under the receiver operating characteristic curve of 0.73 and 0.68, respectively. Functional regions with high influence on the predictor were located especially in the ventral attention, fronto-parietal, and default mode networks.Conclusion: It was shown that medication-specific antidepressant symptom improvements can be predicted using functional connectivity measured during acute pharmacological challenge as an easily assessable imaging marker. The regions with high influence have previously been related to major depression as well as the response to selective serotonin reuptake inhibitors, corroborating the advantages of the current approach of focusing on treatment-specific symptom improvements.

An initial exploration of hair cortisol responses to antidepressants in unmedicated patients with depression.

ObjectiveMajor depressive disorder is associated with abnormal functioning of the hypothalamic–pituitary–adrenal (HPA) axis. Studies using hair cortisol to measure the effect of antidepressants on the HPA axis are lacking. The aim of this study was to explore the long-term effects of antidepressants on hair cortisol concentration (HCC).MethodsParticipants were 42 patients and 36 healthy individuals. The patients took antidepressants for 4 weeks. Patient HCC was measured pre-treatment and post-treatment. The HCC of healthy controls was also measured.ResultsPatient post-treatment HCC (mean ± standard deviation: 34.40 ± 32.57 pmol/mg) was significantly higher than patient pre-treatment HCC (17.42 ± 12.40 pmol/mg) and healthy control HCC (10.22 ± 7.99 pmol/mg). No significant correlation was found between Hamilton Depression Rating Scale scores and HCC at pre-treatment or post-treatment.ConclusionsHair cortisol concentration analysis could be used to monitor the dynamics of the effects of antidepressants on the HPA axis.

New evidence for refinement of anesthetic choice in procedures preceding the forced swimming test and the elevated plus-maze

Previous studies indicated that some general anesthetics induce long-term antidepressant and/or anxiolytic-like effects. This raises the concern about the use of anesthesia in surgeries that precede psychopharmacological tests, since it may be a potential bias on results depending on the experimental design used. Thus, we evaluated whether general anesthetics used in surgeries preceding psychopharmacological tests would affect rats behavior in tests predictive of antidepressant or anxiolytic-like effects. We tested if a single exposure to sub-anesthetic or anesthetic doses of tribromoethanol, chloral hydrate, thiopental or isoflurane would change rats behavior in the forced swimming test (FST) or in the elevated plus-maze (EPM) test, at 2 h or 7 days after their administration. We also evaluated whether prior anesthesia would interfere in the detection of the antidepressant-like effect of imipramine or the anxiolytic-like effect of diazepam. Previous anesthesia with the aforementioned anesthetics did not change rats behaviors in FST per se nor it changed the antidepressant-like effect induced by imipramine treatment. Rats previously anesthetized with tribromoethanol or chloral hydrate exhibited, respectively, anxiogenic-like and anxiolytic-like behaviors in the EPM. Prior anesthesia with thiopental or isoflurane did not produce any per se effect in rats behaviors in the EPM nor disturbed the anxiolytic-like effect of diazepam. Our results suggest that, in our experimental conditions, tribromoethanol and chloral hydrate are improper anesthetics for surgeries that precede behavioral analysis in the EPM. Isoflurane or thiopental may be suitable for anesthesia before evaluation in the EPM or in the FST.

Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial

Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/− 4) at baseline to 12.9 (SD +/− 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.

Is Ketamine the Future Clozapine for Depression? A Case Series and Literature Review on Maintenance Ketamine in Treatment-resistant Depression With Suicidal Behavior

Ketamine has shown effectiveness as a rapid-acting antidepressant with antisuicidal effects in terms of reduction of suicidal ideation in the short term. However, the evidence for long-term maintenance ketamine therapy for treatment-resistant depression (TRD) and suicidal behavior is limited. This case series (N=13) highlights the role of adjunctive serial maintenance ketamine infusions in restoring functionality in treatment-resistant unipolar and bipolar (mixed) depression with significant suicide risk and multiple comorbidities, including alcohol dependence. Two cases of TRD achieved functional remission with long-term maintenance ketamine treatment. The first case illustrates the potential synergistic interaction between ketamine and lamotrigine to achieve a sustained antidepressant response in the patient for 7 months. The second case may possibly be the longest reported case of maintenance ketamine therapy, with treatment continuing for 5 years to date. Ketamine treatment showed acute effectiveness in another 7 cases, especially in terms of reduction of suicidal ideation, albeit without significant long-term antidepressant effect. Factors that may contribute to lack of effectiveness of serial ketamine include inadequate mood stabilization in TRD in bipolar spectrum diagnoses, concomitant benzodiazepine use, complex comorbidities, and adverse effects such as significant hypertension and severe dissociation. Future systematic controlled studies are warranted to establish the efficacy and safety profile of long-term ketamine as maintenance therapy for TRD with suicidal behavior.

Long-term treatment effect of trauma-affected refugees with flexible cognitive behavioural therapy and antidepressants

Few studies exist on the long-term effect of treatment of trauma-affected refugees. The purpose of this study was to estimate the long-term treatment effects of cognitive behavioural therapy and antidepressants (sertraline and mianserin) in trauma-affected refugees. Follow-ups were conducted 6 and 18 months after a randomised controlled clinical trial. The included patients were refugees with war-related traumatic experiences, PTSD and without psychotic disorders. We found a small improvement over time in PTSD, depression and anxiety symptoms and level of functioning, but the improvement was not associated with any specific treatment. Personality change after catastrophic experiences and life events influenced the symptom level at all follow-ups while depression at completion of treatment was associated with a steeper decline in symptom load at the follow-ups. In spite of the limited decline in symptom scores and treatment effects immediately after treatment, the condition of the treated trauma-affected refugees was significantly improved 6 and 18 months after treatment although the improvement was small.

Long-Term Acute-Phase Treatment With Antidepressants, 8 Weeks and Beyond: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials.

In clinical practice, acute antidepressant treatment is often applied for several months until remission is achieved. However, data on treatment outcomes beyond 8 weeks are sparse and no systematic review exists to date. This study aims at assessing efficacy and tolerability of antidepressants compared to placebo in acute treatment at and beyond 8 weeks. MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 using generic terms for depressive and affective disorders combined with generic terms for individual drugs and placebo. Double-blind, randomized, placebo-controlled studies of 8 weeks or more comparing antidepressant monotherapy to placebo in adult patients with acute depressive disorder. Data extraction and synthesis followed guidelines of the Cochrane Collaboration. All data were extracted independently by 2 reviewers. Primary outcome was standardized mean difference (SMD) between antidepressant and placebo; secondary outcomes were response, remission, and dropouts. Of 6,043 articles screened, we selected 104 studies that met criteria and included 35,052 patients. Active treatment was statistically significantly superior to placebo, with consistent effect sizes (SMD [95% CL]) after 8, 12, 16, 20, and 24 weeks: 0.27 (0.24, 0.30), 0.34 (0.25, 0.43), 0.24 (0.09, 0.40), 0.31 (0.12, 0.51), and 0.34 (0.18, 0.50), respectively. Results remained stable across secondary outcomes and subgroup and sensitivity analyses. Effect sizes of antidepressant monotherapy compared to placebo seem to be stable over 6 months. These results challenge the assumption that long-term antidepressant effects are due to the natural course of the disorder rather than to a pharmacologic effect.

AGOMELATINE IN THE TREATMENT OF ANXIETY AND DEPRESSIVE DISORDERS IN PATIENTS WITH ISCHEMIC HEART DISEASE

According to the World Health Organization, anxiety and depressive disorders will be the second leading cause of disability by 2020. The review is devoted to the modern concepts of the pathophysiology of depression in patients with ischemic heart disease (IHD) and to the possibilities of antidepressant therapy. The paper presents analysis of international and domestic researches devoted to efficiency and safety of agomelatine in patients both with chronic IHD and with unstable angina and acute myocardial infarction. The review also discusses different points of view, indicating the need for further studies to evaluate the short and long term effects of antidepressants in patients with IHD in combination with anxiety and depressive disorders.