Antidepressant Strategies Research Articles

AS25-01 - Depression: to switch or to combine?

About 30 to 45% of adequately treated major depressive disorder (MDD) episodes in a psychiatric setting fail to achieve an adequate response, e.g. demonstrate an ‘insufficient response' for which the European Medicines Agency (EMA) recently granted indication. For this group of patients and also for the ones considered as ‘ treatment resistant depression ', ‘ treatment refractory ', and ‘chronic resistant depression' patients, the question emerges if switching strategies from one mechanism to another is the way to go. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained when a patient does not respond to one medication, the results of controlled studies and the European Study Group of Resistant Depression (GSRD) challenge this notion. Switching is associated with withdrawal symptoms in most cases and the antidepressant response needs to be built up again in another 3 to 4 weeks time frame. Another set of newly obtained evidence indicate that augmentation with an atypical antipsychotic, like quetiapine XR results in a quick and sustained response and remission rate. Antidepressant combination, lithium or T3 augmentation would be other options, although not thoroughly studied for augmentation therapy. It seems that switching the mechanism of action of antidepressant therapy should only be obtained as a first step when intolerably side effects are evident, but for efficacy it should be considered at a later step after antidepressant combination and augmentation strategies have been administered. There are as yet no biomarkers available to guide the strategy which medication to choose.

CS08-01 - Augmentation strategies in treatment resistant depression

Patients with major depressive episodes require effective treatment to reduce depressive symptoms and improve functional disability. Various alternative treatment strategies have been proposed for non- or partially responsive depressions in unipolar and bipolar disorder. However, achieving an adequate response in patients with MDD continues to be a challenge. Possible treatment strategies for patients with a depressive episode who are non-responsive to an adequate trial of any antidepressant treatment strategy include switching, combination with another antidepressant with a different mechanism of action, or augmentation with a non-antidepressant drug. Augmentation options include lithium, anticonvulsants, and the thyroid hormones, triiodothyronine, T3, and levothyroxine, T4. Add-on lithium as the first-choice augmentation strategy in treating patients with resistant depression is currently the most well-documented augmentation strategy, with more than 30 open-label studies and 10 placebo-controlled studies in the acute treatment of depressive episodes, and has been shown to augment the therapeutic effects of a broad spectrum of antidepressants. More recently, attention has turned to the atypical antipsychotics, e.g. aripiprazole, olanzapine, risperidone and quetiapine. Several controlled studies show favourable outcomes of augmentation treatment with these antipsychotics in unipolar and bipolar depression.

Strategic use of new generation antidepressants for depression, SUN(^_^)D : study design and rationale

Background After more than half a century of modern psychopharmacology, with billions of dollars spent on antidepressants annually world-wide, we lack good evidence to guide our everyday decisions in conducting antidepressant treatment of patients with major depression. First we did not know which antidepressant to use as first line treatment. Second we do not know which dosage we should be aiming at with that antidepressant. Because more than half of the patients with major depression starting treatment do not remit after adequate trial with the first agent, they will need a second line treatment. Dose escalation, augmentation and switching are the three often recommended second line strategies but we do not know which is better than the others. Moreover, we do not know when to start considering this second line treatment. The recently published multiple-treatments meta-analysis of 12 new generation antidepressants has provided some partial answers to the first question [1]. Starting with these findings, this proposed trial aims to establish the optimum 1 line and 2 line antidepressant treatment strategy among adult patients with a non-psychotic unipolar major depressive episode.

Duloxetine in the acute and continuation treatment of major depressive disorder

Duloxetine is a serotonin–noradrenaline reuptake inhibitor with indications for use in the short term, continuation and maintenance treatment of major depression. Although clinicians currently have access to a range of medications for the treatment of depression, a significant number of patients fail to respond or remit from their illness despite adequate trials of treatment with multiple agents. A developing concept is that antidepressant strategies that combine multiple mechanisms of action may have advantages over agents with single mechanisms (i.e., selective serotonin reuptake inhibitors). As a dual-acting agent, duloxetine offers the promise of advantages in terms of efficacy over selective serotonin reuptake inhibitors while retaining a favorable safety and tolerability profile in comparison to older agents. Likewise, duloxetine is of interest in the treatment of certain conditions commonly seen in conjunction with major depression, particularly anxiety and pain, both of which may respond more favorably to agents that act on both serotonin and noradrenaline neurotransmitter systems.

Circulating Glial-derived neurotrophic factor is reduced in late-life depression

BackgroundThe Glial Cell-line derived neurotrophic factor (GDNF) is part of the TGF-β superfamily and is abundantly expressed in the central nervous system. Changes in GDNF homeostasis have been reported in affective disorders. AimTo assess serum GDNF concentration in elderly subjects with late-life depression, before antidepressant treatment, as compared to healthy elderly controls. MethodsThirty-four elderly subjects with major depression and 37 age and gender-matched healthy elderly controls were included in this study. Diagnosis of major depression was ascertained by the SCID interview for DSM-IV and the severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale (HDRS-21). Serum GDNF concentration were determined by sandwich ELISA. ResultsPatients with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 scores (r = −0.343, p = 0.003). DiscussionOur data provide evidence that GDNF may be a state marker of depressive episode in older adults. Changes in the homeostatic control of GDNF production may be a target to development of new antidepressant strategies.

A New Anti-Depressive Strategy for the Elderly: Ablation of FKBP5/FKBP51

The gene FKBP5 codes for FKBP51, a co-chaperone protein of the Hsp90 complex that increases with age. Through its association with Hsp90, FKBP51 regulates the glucocorticoid receptor (GR). Single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased recurrence of depressive episodes, increased susceptibility to post-traumatic stress disorder, bipolar disorder, attempt of suicide, and major depressive disorder in HIV patients. Variation in one of these SNPs correlates with increased levels of FKBP51. FKBP51 is also increased in HIV patients. Moreover, increases in FKBP51 in the amygdala produce an anxiety phenotype in mice. Therefore, we tested the behavioral consequences of FKBP5 deletion in aged mice. Similar to that of naïve animals treated with classical antidepressants FKBP5−/− mice showed antidepressant behavior without affecting cognition and other basic motor functions. Reduced corticosterone levels following stress accompanied these observed effects on depression. Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies.

Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.

The Search for Improved Antidepressant Strategies: Is Bigger Better?

The Search for Improved Antidepressant Strategies: Is Bigger Better?

Chronobiological therapy for mood disorders

Alteration of the sleep–wake cycle and of the sleep structure are core symptoms of a major depressive episode, and occur both in course of bipolar disorder and of major depressive disorder. Many other circadian rhythms, such as the daily profiles of body temperature, cortisol, thyrotropin, prolactin, growth hormone, melatonin and excretion of various metabolites in the urine, are disrupted in depressed patients, both unipolar and bipolar individuals. These disrupted rhythms seem to return to normality with patient recovery. Research on circadian rhythms and sleep have led to the definition of nonpharmacological therapies of mood disorder that can be used in everyday practice. These strategies, named chronotherapeutics, are based on controlled exposures to environmental stimuli that act on biological rhythms, and demonstrate good efficacy in the treatment of illness episodes. They include manipulations of the sleep–wake rhythm (such as partial and total sleep deprivation, and sleep phase advance) and of the exposure to the light–dark cycle (light therapy and dark therapy). In recent years, an increasing literature about the safety and efficacy of chronobiological treatments in everyday psychiatric settings has supported the inclusion of these techniques among the first-line antidepressant strategies for patients affected by mood disorders.

Strategies to achieve clinical effectiveness: Refining existing therapies and pursuing emerging targets

Clinical effectiveness reflects a balance between efficacy and tolerability as well as patient satisfaction and overall improvement in quality of life and function. This is of particular importance when considering the long term use of antidepressant therapies for relapse prevention. The purpose of this review is to explore methods to enhance the modest efficacy and effectiveness outcomes reported with current antidepressant strategies. Two strategies are addressed: a) Doing better with existing treatments and b) pursuing novel targets beyond the monoamine system for new antidepressant drug development. In the first instance, it is important to consider the balance between antidepressant efficacy and tolerability for individual patients and also be aware of evidence supporting superiority of one agent over others. Both sequential and concurrent combination therapies with existing antidepressants are also reviewed. The second approach involves a review of emerging novel pharmacological treatments based on biomarker research. Unique targets where antidepressant treatments appear effective include the melatonergic, glutamatergic, neurotrophic, cytokine, and neuropeptide systems. While agomelatine represents an example of a clinically available antidepressant that targets melatonin receptors, drugs that act on other candidate systems are still in the development phase.

Pharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT(7)) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT(7) receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT(7) receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT(7) receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

2010 in Review.

2010 in Review.

Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats

Chronic treatment with antidepressants affects several proteins linked to neuroplasticity, particularly brain derived neurotrophic factor (BDNF): this leads eventually to their therapeutic effects. It is possible that also for putative early therapeutic onset, antidepressants may act by promoting cellular adaptations linked to neuroplasticity. Escitalopram, known to be already effective in preclinical models of depression after 7 days, allowed us to investigate whether two effective treatment regimens (7 and 21 days) may contribute to synaptic plasticity by acting on BDNF signalling. We focused our attention on two regulators of BDNF transcription, CREB and CaRF (calcium responsive factor), and on kinases, CaMKII, ERK1/2 and p38 MAPK, linked to BDNF that play a distinctive role in synaptic plasticity. We evaluated whether the effects of escitalopram on these targets may be different in brain areas involved in the depressive symptomatology (hippocampus, frontal and prefrontal cortex). Here we demonstrate that escitalopram regulates intracellular pathways linked to neuroplasticity at both the time points evaluated in an area-specific manner. While the two escitalopram-treatment regimens failed to affect gene expression in the rat frontal cortex, 7 days of treatment with escitalopram activated intracellular pathways linked to BDNF and increased the levels of Pro-BDNF in the rat prefrontal cortex. Moreover, 21 days of treatment with escitalopram decreased CREB/BDNF signalling while increasing p38 levels in the rat hippocampus. Even if further experiments with different antidepressant strategies will be needed, our data suggest that escitalopram efficacy may be mediated by early and late effects on synaptic plasticity in selective brain areas.

Acute Relapse After Successful Vagus Nerve Stimulation Therapy

To the Editor: Quite a number of patients suffering from major depression are resistant to several psychopharmacologic interventions, even when current treatment guidelines are applied.1,2 Electroconvulsive therapy (ECT) is considered a valid alternative treatment option with established efficacy in treatment-resistant depression (TRD),3 yielding response rates of up to 60%.4 When ECT nonresponse is confronted, treatment options are limited.5 In these cases, vagus nerve stimulation (VNS) has been proposed as a continuous antidepressant strategy.6–8 However, when patients who have achieved remission with VNS relapse, guidelines are absent. Case report. Mr A, a 64-year-old male patient, had a history of recurrent unipolar depressed episodes since 1990 (per DSM-IV-TR criteria and ICD-9-CM code 296.34). According to the Thase and Rush staging system for TRD (from 0 to 5), the patient was considered maximally treatment resistant, as multiple trials of psychopharmacologic agents and several adequately performed bilateral ECT applications were unsuccessful.9 At the end of 2004, it was decided to implement VNS. After titration of the VNS parameters (intensity: 1.25 mA, frequency: 20 Hz, pulse width: 500 ms, signal on time: 30 sec, signal off time: 3 min), the patient achieved complete remission after 1 year, and euthymia was sustained for another 2 years. Concomitant pharmacotherapy was venlafaxine 225 mg/d and mirtazapine 30 mg/d. During the spring of 2008, the patient unexpectedly relapsed. Because of the presence of severe psychotic features with suicidal risk and to avoid cognitive side effects, we decided to acutely treat the patient with unilateral ECT. After 11 sessions, the patient reached euthymia (parameters: 1.0 ms, 60 Hz, 3.00 s, 0.8 mA, and 288 mC during sessions 1 to 5; 1.0 ms, 70 Hz, 3.00 s, 0.8 mA, and 336 mC during sessions 6 to 8; and 1.0 ms, 70 Hz, 3.50 s, 0.8 mA, and 392 mC during sessions 9 to 11, for a total convulsion time of 333 s). This clinical remission was confirmed with a score of 0 on the 21-item Beck Depression Inventory (BDI)10 and a score of 5 on the 17-item Hamilton Depression Rating Scale (HDRS).11 Only during the administration of ECT was the VNS device turned off. After ECT was administered, we changed the VNS intensity to 1.50 mA and added olanzapine 10 mg/d to the ongoing treatment with mirtazapine and venlafaxine. With this treatment combination, the patient remains in full remission: BDI = 0, HDRS = 5 after 6 months and BDI = 4, HDRS = 6 after 1 year. Although ECT is considered the “gold standard” for efficacy in TRD, not all patients respond and further treatment options are limited. In addition, ECT relapse rates remain high, and relapse generally occurs in the first 6 months.12 Relapse rates during VNS therapy are not yet established.8,13 Husain and colleagues14 reported a similar case of relapse during VNS therapy in a female patient with TRD. Although remission was achieved with bilateral ECT, long-term efficacy data were not provided. In short, besides the fact that the concomitant use of ECT with VNS was found to be safe,15,16 our case indicates that, when severe relapses occur in patients previously treated successfully with VNS, ECT, even when previously associated with only moderate response, can be performed effectively with good long-term clinical outcome results.

Integrating science and clinical practice in the understanding and treatment of mood disorders

The Hippocratic humoral theory is upheld in modern neuropharmacologic investigations showing depressive relapse with catecholamine-depleting agents. Serotonin dysregulation is supported, especially in females, in reduced 5-HT2A receptors in PET studies. Furthermore, the ancient concept of temperament and its role in depression is supported by current psychometric research. Despite increasing clinical and public health recognition, sophisticated research strategies and the broad availability of relatively safer agents for treatment, depression continues to be a prevalent group of illnesses which often pursue a recurrent and chronically relapsing course with considerable morbidity and mortality. Etiology is multifactorial, involving, among others, familial-genetic, demographic, developmental, personality, seasonal-circadian, experiential, interpersonal, conjugal, cultural and economic factors. Grief, losses and other life events, emphasized in Freud's and Bowlby's writings, as well as current clinical research experience, together with Darwin's landmark work on evolution, place sadness and related emotions in an adaptive context. Current evidence indicates that experiencing life events depends on a familial diathesis for depression, and that temperament increases reactivity to the very life events that precipitate depression. Even social support, a factor that buffers the depressant effect of life events, appears to be dependent on familial factors. Finally, a positive family history of depression, seems to involve the amygdala. It is of great theoretical and clinical interest that the responsivity of the amygdala is mediated through such conditions as anxiety, bipolar II and related affective personality styles. Response of aversive stimuli, too, appears to be processed through the limbic structures. Many medically associated somatic complaints--fibromyalgia, irritable bowel syndrome and migraine--appear to be part of the foregoing affective spectrum. Depression may precede, follow or complicate such common diseases as diabetes, myocardial infarction, stroke, and treatment of the associated depression often improves the prognosis of the underlying disease. Another provocative development is the continuity of unipolar and bipolarI II doisorders, which may in selected patients necessitate the use of antidepressant augmentation strategies. Current treatment research involves complex methodologies in both the psychosocial and psychopharmacologic realms, which each clinician must practice as an art. Medications are best administered in the context of of an ongoing therapeutic alliance. Prototypes of modern mood stabilizers [lithium, carbamazepine, divalproex, topiramate, gabapentin, lamotrigene] are efficaceous via somewhat overlapping yet distinct mechanisms. Many antipsychotics [eg, perphenazine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole] exercise prominent mood stabilizing effects. Finally, prototypes of antidepressants exert thymoleptic action via putative noradrenergic [desipramine], serotoninergic [fluoxetine], or dual chemical action[ venlafaxine], possibly dopaminergic [bupropion?], and in the case of MAOIs such as tranylcypromine appear to involve all three neurotransmitters. Glutaminergic action represents a new fascinating vista beyond the scope of this presentation. Given that mood disorders do occur in a distinct minority of eminent and creative individuals, the clinician can appropriately weigh the relative advantages and limitations of these agents as well as their different side-effect profiles for a given patient in these populations.

Lesions of the basolateral amygdala reverse the long-lasting interference with shuttle box escape produced by uncontrollable stress

Exposure to an uncontrollable, but not a controllable, stressor produces a constellation of behaviors called learned helplessness. In rodents, uncontrollable stress interferes with the ability to learn to escape from escapable shocks delivered in a shuttle box. The stress-induced shuttle box escape deficit is a common screening tool for potential antidepressant strategies. Inconsistencies in the literature exist regarding the time-course of, and mechanisms underlying, stress-induced escape deficits. When no common cues are shared between the stressor and testing environment, the escape deficit is short lived and independent of conditioned freezing. In contrast, when stress and testing occur in the same or similar environments, the escape deficit is very long lasting. The current studies address the hypothesis that the long-lived escape deficit produced by uncontrollable stress is dependent upon conditioned fear and the basolateral amygdala (BLA). Rats received bilateral excitotoxic lesions of the BLA 2 weeks following uncontrollable foot shocks. One week after surgery, rats were tested for conditioned freezing and escape behavior in the same shuttle boxes in which prior foot shocks were delivered. Stressed rats with sham lesions displayed robust conditioned freezing and failed to escape during shuttle box testing. Lesions of the BLA eliminated conditioned freezing and completely restored stressed rats’ ability to perform the escape contingency. These data indicate that the long-lived stress-induced escape deficit produced under conditions in which the stressor and testing environments share common cues is dependent upon conditioned freezing elicited by the BLA. Results have important implications for the mechanisms underlying learned helplessness phenomena.

Creatine transporter expression after antidepressant therapy in rats bred for learned helplessness

In cells and tissues with a high demand of energy such as neurons the major pool of energy is supplied by phosphocreatine. The necessary supply with creatine is directly related to the expression level of the creatine transporter (CRT). To study possible interactions between this transporter and depressive like behavior we have used a congenitally learned helplessness (cLH) model. Because uptake via CRT is the only means to supply neurons with creatine, we hypothesized a rise in CRT expression following antidepressive treatment strategies. The hippocampus of the cLH animals exhibited a significantly lower CRT expression as compared to wild type (WT) animals. Treatment with escitalopram and ECS induced an elevation of CRT levels in the hippocampus and the prefrontal cortex. In WT animals there was no treatment effect. In summary, our data presented here suggest an association between depressive behavior and cellular energy metabolism in defined brain areas.

P01-84 - Deep brain stimulation, electroconvulsive therapy, or both? A two case report

BackgroundElectroconvulsive therapy (ECT) cannot always be effective for Treatment Resistant Depression. Deep brain stimulation (DBS), a procedure that involves the direct implantation of stimulation electrodes in localized brain regions with the aim of modulating local and connected abnormal activity, has recently been gaining momentum as an alternative treatment modality for the most severe TRD patients. However, there is minimal experience with ECT in patients who have undergone DBS procedures.MethodsWe present two cases of patients who remitted from TRD after SCG-DBS, and some months after they suffered a relapse that was treated with ECT.ResultsBefore DBS intervention, ECT was not capable to sustain response more than two weeks beyond and was even bad tolerated by these patients. DBS was effective for both patients until a severe relapse occurred (after 4 and 14 months, respectively). Optimization of medication did not elicit response, given the seriousness of symptoms and their previous treatment resistance. Therefore, neurostimulator was turned off in order to administer ECT to both patients. After usual series of sessions set at corresponding parameters over 3 weeks, using bitemporal electrode placement, the episode remitted. Deep brain stimulator was turned on again, and they were in remission until the present moment.ConclusionsThe use of ECT proved to be effective without adverse effects to the patients or to the DBS hardware. The modulation of SCG activity and its downstream targets might also serve as a trigger for the therapeutic effect of formerly useful or even never-effective antidepressant strategies.

Prognosis in Heart Failure and the Value of β-Blockers Are Altered by the Use of Antidepressants and Depend on the Type of Antidepressants Used

Depression worsens the prognosis in patients with cardiac disease, and treatment with antidepressants may improve survival. Guidelines recommend use of selective serotonin reuptake inhibitors (SSRIs), but knowledge of the prognostic effect of different classes of antidepressants is sparse. We studied 99 335 patients surviving first hospitalization for heart failure (HF) from 1997 to 2005. Use of HF medication and antidepressants (divided into tricyclic antidepressants [TCA] and SSRI) was determined by prescription claims. Risk of overall and cardiovascular death associated with antidepressants, HF medication, and coadministration of these 2 drug classes was estimated by Cox proportional hazard analyses. Propensity adjusted models were performed as sensitivity analysis. During the study period, there were 53 988 deaths, of which 83.0% were due to cardiovascular causes (median follow-up, 1.9 years; 5, 95% fractiles, 0.04 to 7.06 years). Use of beta-blockers was associated with decreased risk of cardiovascular death (hazard ratio [HR], 0.77; 95% CI, 0.75 to 0.79). Antidepressants were prescribed to 19 411 patients, and both TCA and SSRI were associated with increased risk of overall and cardiovascular death (TCA: HR, 1.33; CI, 1.26 to 1.40; and HR, 1.25; CI, 1.17 to 1.32; SSRI: HR, 1.37; CI, 1.34 to 1.40; and HR, 1.34; CI, 1.30 to 1.38, respectively). Coadministration of SSRI and beta-blockers was associated with a higher risk of overall and cardiovascular death compared with coadministration of beta-blockers and TCA (P for interaction <0.01). Use of antidepressants in patients with HF was associated with worse prognosis. Coadministration of SSRIs and beta-blockers was associated with increased risk of overall death and cardiovascular death compared with coadministration of TCAs and beta-blockers. To further clarify this, clinical trials testing the optimal antidepressant strategy in patients with HF are warranted.

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

BackgroundSerotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain.Methodology/Principal FindingsCitalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition.Conclusions/SignificanceTaken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies.