Long-term Antidepressant Treatment Research Articles

The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression.

Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed.

Prediction of long-term treatment response to selective serotonin reuptake inhibitors (SSRIs) using scalp and source loudness dependence of auditory evoked potentials (LDAEP) analysis in patients with major depressive disorder.

Background: Animal and clinical studies have demonstrated that the loudness dependence of auditory evoked potentials (LDAEP) is inversely related to central serotonergic activity, with a high LDAEP reflecting weak serotonergic neurotransmission and vice versa, though the findings in humans have been less consistent. In addition, a high pretreatment LDAEP appears to predict a favorable response to antidepressant treatments that augment the actions of serotonin. The aim of this study was to test whether the baseline LDAEP is correlated with response to long-term maintenance treatment in patients with major depressive disorder (MDD). Methods: Scalp N1, P2 and N1/P2 LDAEP and standardized low resolution brain electromagnetic tomography-localized N1, P2, and N1/P2 LDAEP were evaluated in 41 MDD patients before and after they received antidepressant treatment (escitalopram (n = 32, 10.0 ± 4.0 mg/day), sertraline (n = 7, 78.6 ± 26.7 mg/day), and paroxetine controlled-release formulation (n = 2, 18.8 ± 8.8 mg/day)) for more than 12 weeks. A treatment response was defined as a reduction in the Beck Depression Inventory (BDI) score of >50% between baseline and follow-up. Results: The responders had higher baseline scalp P2 and N1/P2 LDAEP than nonresponders (p = 0.017; p = 0.036). In addition, changes in total BDI score between baseline and follow-up were larger in subjects with a high baseline N1/P2 LDAEP than those with a low baseline N1/P2 LDAEP (p = 0.009). There were significantly more responders in the high-LDAEP group than in the low-LDAEP group (p = 0.041). Conclusions: The findings of this study reveal that a high baseline LDAEP is associated with a clinical response to long-term antidepressant treatment.

P.2.e.001 Emotional blunting following long-term antidepressant treatment

P.2.e.001 Emotional blunting following long-term antidepressant treatment

Road to nowhere

Road to nowhere

Long-Term Antidepressant Treatment Inhibits Neuropathic Pain-Induced CREB and PLCγ-1 Phosphorylation in the Mouse Spinal Cord Dorsal Horn

The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate–responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase γ-1 (PLCγ-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCγ-1 but not extracellular signal–regulated kinase (ERK1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury–induced CREB and PLCγ-1 phosphorylation but had no effect on ERK1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCγ-1/CREB-signaling pathway. PerspectiveThis article demonstrates that long-term treatment with imipramine reverses some of the marked effects induced by peripheral nerve injury in the spinal dorsal horn that contribute to long-term maintenance of sensory disorder, providing a new view to the mechanisms of action of these drugs.

No changes in striatal dopamine transporter in antidepressant-treated patients with major depression

Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are the mainstay treatment for major depressive disorder, but whether their therapeutic mechanisms involve the dopaminergic system remains inconclusive. Eight participants with major depressive disorder were administered single-photon emission computed tomography with [(99m)Tc] TRODAT-1 both before and after 24 weeks of antidepressant treatment to evaluate the change in striatal dopamine transporter (DAT) availability. All participants were responders (≥50% reduction in Hamilton Depression Rating Scale score). The DAT availability did not change (P=0.58), as the Hamilton Depression Rating Scale score decreased (P=0.02). Striatal DAT availability remains intact during long-term antidepressant treatment in patients with major depressive disorder.

Achieving the Balance: Treating Depressed Pregnant Women With Antidepressants

Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.Major depressive disorder is a common, recurring, serious, and potentially life-threatening condition. The period prevalence for major depression during pregnancy appears to be 12.7% and for any depressive disorder, 18.4%. Women who have had 1 depressive episode are at risk for recurrence, and those having more than 3 episodes are candidates for long-term antidepressant treatment.

The impact of escitalopram on vagally mediated cardiovascular function to stress and the moderating effects of vigorous physical activity: a randomized controlled treatment study in healthy participants

Recent concerns over the impact of antidepressant medications, including the selective serotonin reuptake inhibitors (SSRIs), on cardiovascular function highlight the importance of research on the moderating effects of specific lifestyle factors such as physical activity. Studies in affective neuroscience have demonstrated robust acute effects of SSRIs, yet the impact of SSRIs on cardiovascular stress responses and the moderating effects of physical activity remain to be determined. This was the goal of the present study, which involved a double-blind, randomized, placebo-controlled, cross-over trial of a single-dose of escitalopram (20 mg) in 44 healthy females; outcomes were heart rate (HR) and its variability. Participants engaging in at least 30 min of vigorous physical activity at least 3 times per week (regular exercisers) showed a more resilient cardiovascular stress response than irregular vigorous exercisers, a finding associated with a moderate effect size (Cohen's d = 0.48). Escitalopram attenuated the cardiovascular stress response in irregular exercisers only (HR decreased: Cohen's d = 0.80; HR variability increased: Cohen's d = 0.33). HR during stress under escitalopram in the irregular exercisers was similar to that during stress under placebo in regular exercisers. These findings highlight that the effects of regular vigorous exercise during stress are comparable to the effects of an acute dose of escitalopram, highlighting the beneficial effects of this particular antidepressant in irregular exercisers. Given that antidepressant drugs alone do not seem to protect patients from cardiovascular disease (CVD), longitudinal studies are needed to evaluate the impact of exercise on cardiovascular stress responses in patients receiving long-term antidepressant treatment.

P-530 - Long-term antidepressant treatment with agomelatine: results of the non-interventional study vivaldi follow-up over 12 months

Agomelatine is the first melatonergic antidepressant working as MT 1 /MT 2 -agonist and 5-HT 2c -antagonist. Aim of VIVALDI Follow-up was to examine agomelatine-treatment over one year under routine conditions. To evaluate the antidepressant effectiveness and tolerability of agomelatine as well as its effects on sleep-wake-rhythms in depressed patients over one year in daily practice. Optional 9-months-follow-up of the 3-months non-interventional-study VIVALDI. 605 outpatients were observed by 208 psychiatrists over 12 months in Germany and treated with agomelatine 25–50 mg once daily at bedtime. Antidepressant effectiveness was evaluated by svMADRS (short version MADRS) and CGI scales, effects on sleep and daily activity by a patient questionnaire (CircScreen). At inclusion, patients had a moderate to severe depression (svMADRS total score 30.6), which improved markedly during the 12 months treatment with agomelatine (svMADRS total Score 9.8). The responder rate (≥50% reduction of svMADRS) rose steadily from 15.3% (2 weeks) to 69.7% (12 weeks) and 75.7% (12 months). 59.6% and 69.8% of patients were in remission (svMADRS ≤12) after 3 and 12 months, respectively. The CGI-S-Score improved from 4.7 to 2.6 after 12 months-treatment with agomelatine. Improvements in falling asleep and daily activities as well as decrease in repeated awakenings were observed after 12 months by 83.6%, 57% and 87.0% of patients, respectively. Adverse drug reactions (mainly headache, dizziness) were reported by only 4.3% of patients. Antidepressant effectiveness and good tolerability of agomelatine as well as its marked improvement of sleep-wake-rhythms observed in controlled studies were confirmed by this observational trial in daily psychiatric practice over 12 months.

Long-term prospective mood self-rating and antidepressant treatment.

The use of antidepressants in bipolar illness remains controversial. This controversy continues to be fuelled by short-term studies that inconsistently report efficacy or no benefit. However, long-term studies have been consistently unfavourable, suggesting that understanding the long-term course of the illness in the setting of antidepressant treatment is important. This is an extraordinary case in which prospectively collected daily mood ratings were available in a type I bipolar individual who had experienced minimal medication changes over a 21-year period was reviewed. Data regarding the number of euthymic days in the setting of antidepressant use and after antidepressant discontinuation were collected. Induction of cycling and increase in the number of depressed days occurred after five years of continuous serotonergic antidepressant administration. Discontinuation of antidepressants after 11 years of continuous use was associated with only a partial improvement which had a delayed onset. Cycling and increase in depression was noted after years of continuous use of serotonergic antidepressant treatment. Antidepressant-associated destabilisation may occur after long-term exposure and may be associated with prolonged worsening even after antidepressant discontinuation.

The continuum of unipolar depression - bipolar II depression - bipolar I depression: different treatments indicated?

Strakowski et al indicate that bipolar depression may need to be treated differently from unipolar depression because in bipolar depression antidepressants may be ineffective and may precipitate the risk of a switch to (hypo)mania (and induction of rapid cycling). While this could be a major argument to discriminate bipolar depression form unipolar depression, a critical appraisal of the available literature is indicated. First, are antidepressants ineffective in bipolar depression? Compared to around 1,500 randomized controlled trials (RCTs) with antidepressants in unipolar depression, there are around 15 RCTs in bipolar depression and only four of them exceeded 50 patients per treatment arm. Therefore, the main conclusion is that, compared to unipolar depression, bipolar depression is heavily understudied 1. Nevertheless, in a meta-analysis, antidepressants as a group appeared to be effective 1. Of the four larger studies, two reported positive results. The first study found that the combination of fluoxetine and olanzapine was more effective than placebo plus olanzapine 2. The second study reported response rates of 50-60% when sertraline, bupropion or venlafaxine was added to an ongoing treatment with mood stabilizers 3. The limitation of this study was the lack of a placebo arm. On the other hand, in a third study, paroxetine was not more effective than placebo, while two doses of quetiapine (300 and 600 mg/day) did separate from placebo 4. Finally, in the STEP-BD study, sertraline or bupropion as add-on to ongoing treatment with (among other medications) lithium or valproate was not found more effective than the addition of placebo 5. Although this is the largest study which investigated the efficacy of antidepressants in bipolar depression, it has major methodological limitations (e.g., patients were allowed to continue with another antidepressant during the first two weeks of the study; they could also use other drugs with an antidepressant effect, such as quetiapine, olanzapine and lamotrigine; 69% of the patients participated at the same time in a study comparing three different forms of psychotherapy with treatment as usual). It is clear that the conclusion that antidepressants are not effective cannot be drawn on the basis of this study. My overall conclusion is that, due to a lack of well designed RCTs, we can only state that it has not (yet) been proven that antidepressants are effective in bipolar depression. Second, do antidepressants cause a switch into (hypo)mania and rapid cycling? In our meta-analysis 1, we did not find that in the acute treatment of bipolar depression antidepressants were more often associated with a switch into (hypo)mania than placebo. However, in all studies comparing different antidepressants, the treatment arms with a tricyclic (TCA) were associated with a greater risk of switch into (hypo)mania than the treatment arms with other antidepressants, suggesting that TCAs have a greater risk of switch. Concerning the risk associated with long-term antidepressant treatment, we argued that there is a scarcity of randomized studies, and that the available studies all suffer from various forms of bias 6. Nevertheless, we concluded that antidepressants, when combined with a mood stabilizer, seemingly do not induce a switch into hypomania or mania. Ghaemi et al 7 presented a meta-analysis of seven RCTs in which antidepressants were used for at least 6 months. Three of these RCTs (total n=50) compared the effects of antidepressants monotherapy with placebo; five (total n=246) compared antidepressants plus a mood stabilizer versus a mood stabilizer alone (or in combination with placebo); and three (total n=108) compared antidepressants alone with a mood stabilizer alone. In most of the studies the antidepressant was a TCA. When combining all RCTs, the antidepressants yielded a significant 27% lower risk of a depressive recurrence versus control treatment without an antidepressant, but also a significant 72% greater risk for a manic recurrence. However, in RCTs with an antidepressant alone versus placebo, the only significant result was fewer depressive recurrences with the antidepressant, while in RCTs with an antidepressant alone versus a mood stabilizer alone (lithium), the only significant result was fewer manic recurrences with lithium. Therefore, my conclusion is that antidepressants do protect against depressive recurrences, while lithium does protect against manic recurrences. Whether antidepressants may accelerate episode frequency and/or cause other forms of destabilization in patients with bipolar disorder remains to be properly studied. In conclusion, there is not enough evidence to conclude that bipolar depression needs to be treated differently from unipolar depression. Especially in bipolar II depression, antidepressants still have a role even in monotherapy, as also suggested by recent guidelines 8,9. Therefore, bipolar I depression and unipolar depression should be seen as the ends of a continuum, with arbitrary demarcations and bipolar II depression in between.

Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: A 24-week follow-up study

Major depressive disorder (MDD) is a devastating disease that afflicts large populations and has also been accepted to be an independent risk factor for cardiovascular disease (CVD). Oxidative stress seems to play an essential role in the relationship of MDD and CVD. We aimed to determine the level of oxidative stress in patients with MDD and to investigate the effects of long-term antidepressant (AD) treatment on the oxidative-antioxidative system parameters and CVD risk factors. Fifty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for MDD and 44 healthy control subjects were included in the study. Control visits of the patients were repeated 6weeks, 12weeks and 24weeks after beginning of the AD treatment. Lipid profiles, oxidation and oxidizability of apolipoprotein B-containing lipoproteins (expressed as apo B-b-MDA and apo B-Δ-MDA, respectively), levels of plasma malondialdehyde (p-MDA), total antioxidative capacity (TAOC), antioxidant molecules and antioxidant enzyme activities including paraoxonase/arylesterase, red blood cell superoxide dismutase (RBC-SOD) and glutathione peroxidase were determined during 24-week of follow-up period. According to the results of the study, p-MDA, apo B-b-MDA and RBC-SOD activity were increased and arylesterase activity was decreased in MDD patients. Body mass index (BMI), vitamin A and total cholesterol levels in MDD patients increased after 24-weeks of AD treatment. RBC-SOD activity, TAOC, p-MDA and apo B-b-MDA levels were decreased; paraoxonase/arylesterase activities and apo B-Δ-MDA were increased at the end of 24th week. Oxidative stress, demonstrated in MDD patients, was partly improved during 24weeks of AD treatment. Increase in paraoxonase/arylesterase activities and decrease in p-MDA and apo B-b-MDA levels after 24weeks seem to be beneficial for reduction of CVD risk in MDD patients. However increased BMI and apo B-Δ-MDA levels are negative cardiovascular effects of long-term AD treatment.

P02-04 - Area-specific occupancy of the serotonin transporter by escitalopram and citalopram in major depressive disorder

IntroductionThe serotonin transporter (SERT) occupancy after long-term antidepressant treatment (steady-state) at minimum clinical doses has been reported to be approximately 80% (e.g., Meyer 2007, J.Psychiatry Neurosci;32(2):86-102, review). However, this value is mostly calculated in the striatum, therefore the occupancy values in other brain areas might be better associated to clinical parameters.ObjectivesTo compare the SERT occupancy of the striatum to occupancy values in six other brain areas.Methods18 patients with major depressive disorder (MDD) received either escitalpram (10mg/d) or citalopram (20mg/d) in a double-blind, longitudinal study. They underwent three PET scans using the radioligand [11C]DASB: PET1 baseline, PET2 six hours after the first drug intake and PET3 after three weeks of treatment. Occupancy of SERT at PET3 was analyzed in seven regions partly associated with alterations in MDD: striatum, subgenual part of the anterior cingulate cortex (sgACC), ACC, amygdala, inferior frontal cortex (IFC), superior frontal cortex (SFC), superior parietal cortex (SPC). ROI-based quantification was performed in PMOD.ResultsThere was a huge range in occupancy values of different areas: amygdala (93.5% ± 6.9%, mean ± SD), SPC (90.8% ± 8.0%), ACC (86.0% ± 13.2%), sgACC (79.1% ± 23.6%), striatum (78.8% ± 4.9%), SPF (64.0% ± 26.4%), IFC (54.4% ± 21.7%). We found significant differences in occupancy values between striatum and the ACC, amygdala, IFC, SFC, SPC (t-test, p < 0.05).ConclusionsIn this study we show significant differences in SERT occupancy between brain areas ranging between 54.4% and 93.5%. According to the area-specific effects of changes in serotonergic neurotransmission, regional occupancy values, especially in limbic areas, might be considered in the association to clinical response.

Pharmacogenetics of SSRIs and Sexual Dysfunction

Sexual dysfunction (SD) is a common and disconcerting side effect of selective serotonin reuptake inhibitors (SSRIs) that often influences a patient’s desire to continue long-term antidepressant treatment. Studies specifically assessing changes in sexual well-being over time illustrate that the incidence of sexual side effects from SSRIs ranges from 20% to 70%, depending on the characteristics of the study sample assessed. Developing strategies to predict who may be at the highest risk for adverse changes in their sexual well-being is an important step in improving the quality of life and treatment of patients who require antidepressant therapy. Pharmacogenetic studies of SSRI-associated SD have identified associations between serotonin and glutamate system genes with aspects of SD. The results of studies investigating genetic variations in drug metabolism enzymes and their relationships to antidepressant-associated adverse effects have been mixed. Continued efforts to characterize the relationships between genetic markers and antidepressant outcomes, and to translate this knowledge to patient care, have the potential to significantly improve the empiric selection of antidepressant agents and to minimize the risk for intolerable side effects.

Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment

Previous magnetic resonance imaging (MRI) studies of patients with major depressive disorder (MDD) have consistently shown bilateral and unilateral reductions in hippocampal volume relative to healthy controls. Recent structural MRI studies have addressed the question of whether changes in the volume of hippocampal subregions may be associated with MDD. We used a comprehensive and reliable 3-dimensional tracing protocol that enables delineation of hippocampal subregions (head, body, tail) to study changes in the hippocampus of patients with MDD. We recruited 39 MDD patients (16 medicated, 23 unmedicated) and 34 healthy age- and sex-matched controls. We acquired images using a magnetization-prepared rapid acquisition gradient echo sequence on a 1.5-T scanner with a spatial resolution of 1.5 mm x 0.5 mm x 0.5 mm. We performed volumetric analyses, blinded to diagnosis, using the interactive software package Display. All volumes were adjusted for intracranial volume. We found a significant reduction in the volume of the hippocampal tail bilaterally, right hippocampal head and right total hippocampus in MDD patients. Medicated MDD patients showed increased hippocampal body volume compared with both healthy controls and unmedicated patients. This study was cross-sectional. Further prospective studies are needed to determine the direct effect of antidepressant treatment. Our results suggest that decreased hippocampal tail and hippocampal head volumes could be trait changes, whereas hippocampal body changes may be dependent on treatment. We showed that long-term antidepressant treatment may affect hippocampal volume in patients with MDD.

Long-Term Duloxetine Treatment Normalizes Altered Brain-Derived Neurotrophic Factor Expression in Serotonin Transporter Knockout Rats through the Modulation of Specific Neurotrophin Isoforms

Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.

Frontal electroencephalogram changes in early phase antidepressant treatment predict clinical response in major depressive disorder

Evaluation of: Leuchter AF, Cook IA, Marangell LB et al.: Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in major depressive disorder: results of the BRITE-MD study. Psychiatry Res. 169, 124–131 (2009) and Leuchter AF, Cook IA, Marangell LB et al.: Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry Res. 169, 132–138 (2009). The investigators of the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD) study calculated the Antidepressant Treatment Response (ATR) index, a biomarker of frontal quantitative electroencephalogram changes, after 1 week of escitalopram treatment and examined whether the ATR had utility as a predictor of outcome after a further 7 weeks of treatment. The ATR index predicted response and remission at week 7, whereas the symptom reduction in Hamilton Depression Rating Scale scores by week 1 only predicted response at week 7. Other markers, such as genetic polymorphisms (5-HTTLPR and 5HT2A), the clinician-rated global impression of improvement and serum drug concentrations, did not provide significant predictive utility. Notably, high ATR values predicted response to escitalopram, while low ATR values predicted response to bupropion. The findings provocatively suggest that the ATR index may be a useful predictor for short-term antidepressant outcome. These results may encourage the future work that will be necessary to evaluate the role of the ATR index and clinical measures as predictors of both short- and long-term antidepressant treatment outcomes.

Antidepressants and dementia

Background It has been suggested that antidepressants may have neuroprotective abilities but it has newer been investigated lately whether treatment with antidepressants reduces the risk of dementia. Method Linkage of registers of all prescribed antidepressants and diagnoses of dementia in Denmark during a period from 1995 to 2005. Results Persons who purchased antidepressants once ( N = 687,552) had an increased rate of dementia compared to persons unexposed to antidepressants ( N = 779,831). Nevertheless, the rate of dementia changed over time; thus during the initial prescription periods the rate increased with the number of prescriptions but continued long-term antidepressants treatment was associated with a reduction in the rate of dementia, however, not to the same level as the rate for the general population. This pattern was found for all classes of antidepressants (SSRIs, newer non-SSRI antidepressants and older antidepressants). All findings were replicated in sub-analyses with Alzheimer's disease as outcome. Limitations Methodological reasons for the findings cannot be excluded due to the non-randomized nature of data. Conclusions Continued long-term antidepressant treatment was associated with a reduced rate of dementia, however, not to the same level as the rate for the general population.

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve--indicating the involvement of effects distant from reuptake inhibition. To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression. The behavioral response to long-term paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology. Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice. Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

Risk of Recurrence of Depression During Long-Term Antidepressant Treatment

Major depressive disorder (MDD) is widespread, costly, and frequently chronic. Internationally, the burden of depression is large and growing. By the year 2020, this disorder is projected to be the world's second leading cause of disease burden. The costs associated with depression are enormous; people with depression tend to have approximately double the health care costs of unaffected individuals. There are few other major disorders that have a negative health impact of the same magnitude.Early onset of depressive symptoms, along with underdiagnosis and undertreatment, contribute to the burden of MDD, which is also characterized by chronicity, frequent relapses, and recurrences. Risk factors for depressive recurrence include the presence of residual symptoms, >3 prior depressive episodes, chronic depression lasting more than 2 years, a family history of mood disorders, other comorbidities (eg, terminal illness, diabetes), and late onset (>60 years of age). Patients who have any of these factors should be candidates for maintenance treatment.Naturalistic studies have demonstrated that most patients with MDD without sustained treatment will eventually experience a relapse or recurrence. Furthermore, depressive episodes tend to become more autonomous over time, with decreased linkage to stressful life events, more severe, and potentially more refractory with each new relapse or recurrence. Researchers and clinicians have observed that rather than only treat or manage relapses or recurrences of MDD, the best strategy may be prevention of depressive episodes. As a result, current strategies seek to treat patients to remission, which translates to a lower overall risk of developing relapses or recurrences compared with those patients who continue to demonstrate residual symptoms. Thus, a consistent body of evidence now supports continuous pharmacotherapy for the prevention of depressive relapse and recurrence.