Effects Of Selective Serotonin Reuptake Inhibitors Treatment Research Articles

Altered Serotonin 1B Receptor Binding After Escitalopram for Depression Is Correlated With Treatment Effect.

Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale. We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P = .021) and 6-7 (r = 0.94, P < .001) weeks' treatment. Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.

(021) Sexual Function in Patients with Major Depressive Disorder before and after Treatment with Selective Serotonin Reuptake Inhibitor (SSRI)

Abstract Introduction Major Depressive Disorder (MDD) is closely associated with sexual dysfunction, which may worsen during treatment with SSRIs due to side-effects of pharmacological treatment. This can potentially aggravate the depressed state or result in non-compliance with the treatment. Currently, little is known about the interplay between effects of SSRI treatment, patient characteristics and sexual function. Objective To examine the association between sexual function and the severity of MDD in drug-naïve patients compared to healthy controls and how treatment with SSRIs affects sexual function over time in individuals with MDD. Interaction with gender and treatment response was examined. Methods In 92 patients with MDD, we measured MDD severity with Hamilton Depression Rating Scale (HDRS) and level of sexual function with the Changes in Sexual Function Questionnaire (CSFQ) at baseline and 4, 8, and 12 weeks after initiating treatment with escitalopram. Baseline sexual function was compared to sexual function of 73 healthy controls. Results Patients had worse sexual function at baseline than healthy controls, which was not associated with severity of MDD. Patients’ sexual function improved significantly during treatment. Improvement in sexual function was coupled with amelioration of symptoms of depression, but treatment response groups did not predict change in sexual function. Gender had no effect on sexual dysfunction symptoms during treatment. Conclusions Sexual dysfunction was strongly associated with MDD and improved in parallel with improvement in overall symptoms of depression across a standard 12-week SSRI antidepressant treatment. Disclosure Yes, this is sponsored by industry/sponsor: The Lundbeck Foundation alliance BrainDrugs, Sahakian: Lundbeck Foundation Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: FREYA, Novo Nordic

The effects of selective serotonin reuptake inhibitors on memory functioning in older adults: A systematic literature review.

Introduction:Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to older adults. In contrast to young subjects, it is unclear whether older adults may be vulnerable to cognitive side effects. Serotonin is involved in cognitive functions (e.g. memory). It is of great importance to examine the effects of SSRIs on memory functioning in older adults.Objectives:The objective of this systematic literature review is to summarize studies in which the effects of SSRI treatment on all aspects of memory functioning in older adults are investigated.Methods:PubMed, PsycINFO, CINAHL, and Embase were searched for all studies published until 18th of October 2021. Articles were included if they fulfilled the inclusion criteria as follows: (1) study design is (randomized) controlled trial, cross-sectional, or prospective cohort study; (2) study population consists of older adults (mean age ⩾65 years), or results for this age-group are reported separately; (3) intervention is use of an SSRI; and (4) effects on performance of any memory domain are measured and clearly described.Results:The search yielded 1888 articles, of which 136 were included for the full-text review. Eventually, 40 articles were included. Most studies reported no association between SSRI use and memory functioning. The studies that found a positive association mainly investigated older adults with mental or neurological disorders (e.g. depression or stroke). A few studies found a negative association in the following subgroups: non-responders (depression), patients with frontal brain disease, and women.Conclusion:Overall, no consistent negative effects of SSRIs on memory functioning in older adults were found after SSRI treatment. Most studies reported no change in memory functioning after SSRI use. Some studies even showed an improvement in memory performance. Positive effects of SSRIs on memory functioning were especially found in older adults with mental or neurological disorders, such as subjects with depression or stroke.

Effects of SSRI treatment on GABA and glutamate levels in an associative relearning paradigm

Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI).In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis.A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found.Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.

Selective serotonin reuptake inhibitor use in hip fracture patients: a Danish nationwide prevalence study

Background and purpose — Selective serotonin reuptake inhibitors (SSRIs) are often used in the elderly and are associated with adverse effects. Therefore, it is important to ascertain the prevalence of SSRI use in fragile and surgery-treated hip fracture patients.Methods — This population-based prevalence study included Danish hip fracture patients aged ≥ 65 years operated in 2006–2016 (n = 68,607) and matched individuals from the background population (n = 343,020). Using Poisson regression, prevalence risk ratios (PRRs) with 95% confidence intervals (CIs) were estimated to compare hip fracture patients with the general population, and to estimate the association between hip fracture patient characteristics and SSRI prescriptions.Results — The prevalence of SSRI use among hip fracture patients was 23% compared with 12% in the general population. During 2006–2016, the prevalence decreased from 26% to 18% among hip fracture patients and from 13% to 10% in the general population. Factors associated with SSRI use in hip fracture patients were age 75–84 years (PRR 1.18, CI 1.13–1.23), age ≥ 85 years (PRR 1.17, CI 1.11–1.22), female sex (PRR 1.13, CI 1.09–1.17), unmarried status (PRR 1.15, CI 1.11–1.19), living in a residential institution (PRR 2.30, CI 2.19–2.40), Charlson comorbidity index (CCI) score 1–2 (PRR 1.50, CI 1.45–1.55), CCI score 3+ (PRR 1.62, CI 1.55–1.69), and several medications.Interpretation — The prevalence of SSRI use was high among hip fracture patients compared with the general population. Our data stress the importance of continued clinical awareness of frailty, comorbidity, and polypharmacy of hip fracture patients and the potentially adverse drug effects of SSRI treatment.

Neuroticism predicts the impact of serotonin challenges on fear processing in subgenual anterior cingulate cortex

The personality trait neuroticism is associated with increased vulnerability to anxiety and mood disorders, conditions linked with abnormal serotonin neurotransmission and emotional processing. The interaction between neuroticism and serotonin during emotional processing is however not understood. Here we investigate how individual neuroticism scores influence the neural response to negative emotional faces and their sensitivity to serotonergic tone. Twenty healthy participants performed an emotional face task under functional MRI on three occasions: increased serotonin tone following infusion of a selective serotonin reuptake inhibitor (SSRI), decreased serotonin tone following acute tryptophan depletion (ATD) protocol, and no serotonin challenge (control). During the task, participants performed a gender-discrimination task of neutral, fearful or angry facial expressions. Individual variations in neuroticism scores were associated with neural response of subgenual anterior cingulate cortex to fearful facial expressions. The association was however opposite under the two serotoninergic challenges. The fear-related response in this region and individual neuroticism scores correlated negatively during citalopram challenge and positively during ATD. Thus, neuroticism scores were associated with the relative impact of serotonin challenges on fear processing in subgenual anterior cingulate cortex. This finding may link to a neural mechanism for the variable therapeutic effect of SSRI treatment observed in clinical populations.

Effect of Citalopram on Emotion Processing in Humans: A Combined 5-HT1A [11C]CUMI-101 PET and Functional MRI Study

A subset of patients started on a selective serotonin reuptake inhibitor (SSRI) initially experience increased anxiety, which can lead to early discontinuation before therapeutic effects are manifest. The neural basis of this early SSRI effect is not known. Presynaptic dorsal raphe neuron (DRN) 5-HT1A receptors are known to have a critical role in affect processing. Thus we investigated the effect of acute citalopram on emotional processing and the relationship between DRN 5-HT1A receptor availability and amygdala reactivity. Thirteen (mean age 48±9 years) healthy male subjects received either a saline or citalopram infusion intravenously (10 mg over 30 min) on separate occasions in a single-blind, random order, crossover design. On each occasion, participants underwent a block design face-emotion processing task during fMRI known to activate the amygdala. Ten subjects also completed a positron emission tomography (PET) scan to quantify DRN 5-HT1A availability using [11C]CUMI-101. Citalopram infusion when compared with saline resulted in a significantly increased bilateral amygdala responses to fearful vs neutral faces (left p=0.025; right p=0.038 FWE-corrected). DRN [11C]CUMI-101 availability significantly positively correlated with the effect of citalopram on the left amygdala response to fearful faces (Z=2.51, p=0.027) and right amygdala response to happy faces (Z=2.33, p=0.032). Our findings indicate that the initial effect of SSRI treatment is to alter processing of aversive stimuli and that this is linked to DRN 5-HT1A receptors in line with evidence that 5-HT1A receptors have a role in mediating emotional processing.

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.

Is increased antidepressant exposure a contributory factor to the obesity pandemic?

Major depressive disorder (MDD) and obesity are both common heterogeneous disorders with complex aetiology, with a major impact on public health. Antidepressant prescribing has risen nearly 400% since 1988, according to data from the Centers for Disease Control and Prevention (CDC). In parallel, adult obesity rates have doubled since 1980, from 15 to 30 percent, while childhood obesity rates have more than tripled. Rising obesity rates have significant health consequences, contributing to increased rates of more than thirty serious diseases. Despite the concomitant rise of antidepressant use and of the obesity rates in Western societies, the association between the two, as well as the mechanisms underlying antidepressant-induced weight gain, remain under explored. In this review, we highlight the complex relationship between antidepressant use, MDD and weight gain. Clinical findings have suggested that obesity may increase the risk of developing MDD, and vice versa. Hypothalamic–pituitary–adrenal (HPA) axis activation occurs in the state of stress; concurrently, the HPA axis is also dysregulated in obesity and metabolic syndrome, making it the most well-understood shared common pathophysiological pathway with MDD. Numerous studies have investigated the effects of different classes of antidepressants on body weight. Previous clinical studies suggest that the tricyclics amitriptyline, nortriptyline and imipramine, and the serotonin norepinephrine reuptake inhibitor mirtazapine are associated with weight gain. Despite the fact that selective serotonin reuptake inhibitor (SSRI) use has been associated with weight loss during acute treatment, a number of studies have shown that SSRIs may be associated with long-term risk of weight gain; however, because of high variability and multiple confounds in clinical studies, the long-term effect of SSRI treatment and SSRI exposure on body weight remains unclear. A recently developed animal paradigm shows that the combination of stress and antidepressants followed by long-term high-fat diet results, long after discontinuation of antidepressant treatment, in markedly increased weight, in excess of what is caused by high-fat diet alone. On the basis of existing epidemiological, clinical and preclinical data, we have generated the testable hypothesis that escalating use of antidepressants, resulting in high rates of antidepressant exposure, might be a contributory factor to the obesity epidemic.

Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials.

It has been suggested that the efficacy of antidepressants has been overestimated in clinical trials owing to unblinding of drug treatments by adverse events. To investigate the association between adverse events and the efficacy of selective serotonin reuptake inhibitors (SSRIs). The literature was searched to identify randomised, double-blind, placebo-controlled trials of SSRIs in the treatment of major depression. Efficacy outcomes were response to treatment and change in depressive symptoms. Reporting of adverse events was used as an indicator of tolerability. Random effects meta-analyses were used to calculate pooled estimates. Meta-regression analyses were performed to investigate the association between adverse events and efficacy. Potential mediation was investigated with the Baron & Kenny approach. A total of 68 trials (n = 17 646) were included in the analyses. In meta-analysis SSRIs were superior to placebo in terms of efficacy (odds ratio, OR = 1.62, 95% CI 1.51-1.72). More patients allocated to SSRIs reported adverse events than did patients receiving placebo (OR = 1.73, 95% CI 1.58-1.89). Meta-regression analyses did not find an association between adverse events and efficacy (P = 0.439). There was no indication of adverse events mediating the effect of SSRI treatment. Our results do not support, but also do not unequivocally disprove, the hypothesis that adverse events lead to an overestimation of the effect of SSRIs over placebo.

Citalopram and sertraline exposure compromises embryonic bone development.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.

TALOS: a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of citalopram in patients with acute stroke.

Selective Serotonin Reuptake Inhibitors (SSRI) are effective in the treatment of post-stroke depression and may have potential neuroprotective and vascular effects. Data from registry studies have further indicated a protective effect against recurrent ischemic events, but also an increased risk of bleeding in patients with ischemic stroke. Therefore, prospective studies are needed to determine the effects of SSRI treatment after acute ischemic stroke. TALOS is an investigator-initiated, national multicenter randomized- and placebo-controlled, double-blind trial testing citalopram in acute ischemic stroke. We hypothesize that citalopram treatment initiated in the acute phase after ischemic stroke will improve outcome assessed by the modified Rankin Score (mRS) and reduce the risk of death from vascular causes, transient ischemic attack (TIA)/stroke and myocardial infarction. There are two co-primary effect variables: (i) Functional status at six-months, measured by the modified Rankin Scale, and (ii) Vascular death, TIA/stroke and myocardial infarction. Secondary effect variables include: (i) Single primary outcomes; (ii) The Barthel Index; (iii) Mini Mental State Examination at six-months; (iv) Final infarct size (Magnetic Resonance Imaging). SSRI treatment is well tolerated and overall beneficial in the wake of stroke; it may also be neuroprotective and prevent new vascular events.

Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men.

Background:Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV).Methods:The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 µg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequency-domain HRV parameters, assessed at both baseline and immediately after CCK-4 application.Results:Results showed substantial effects for the treatment × CCK-4 challenge interaction with respect to heart rate (p < 0.001; pη2 = 0.499), SDNN (p < 0.001; pη2 = 576), RMSSD (p = 0.015; pη2 = 194), NN50% (p = 0.008; pη2 = 0.224), and LF% (p = 0.014; pη2 = 0.196), and moderate effects with respect HF% (p = 0.099; pη2 = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5-HTTLPR polymorphism on CCK-4-induced autonomic response.Conclusions:Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men.

Antenatal depression and antidepressants during pregnancy: Unraveling the complex interactions for the offspring

During pregnancy the risk for a woman to develop a depressive episode is as high as 20%. Antenatal depression is not harmless for the developing child as several changes, including neurodevelopmental alterations, have been reported. Sometimes it is unavoidable to treat a pregnant mother with antidepressants, especially when she is suicidal. Currently, selective serotonin reuptake inhibitors (SSRIs) are the pharmacological choice of antidepressant treatment. SSRIs do not cause gross teratogenic alterations and are generally considered safe for use in pregnancy. However, although SSRIs may relieve the maternal symptoms, they definitively cross the placenta partially influencing the neurodevelopment of the fetus. In this review an overview is given of the effects on the offspring of maternal antenatal depression and the putative neurodevelopmental effects of SSRI treatment during pregnancy. Although we primarily focus on human data, some animal data are discussed to describe possible mechanisms on how SSRIs are affecting underlying biological mechanisms associated with depression. In summary, maternal depression may have long-lasting effects on the offspring, whereas prenatal SSRI exposure also increases the risk for long-lasting effects. It remains to be determined whether the effects found after SSRI treatment in pregnant women are only due to the SSRI exposure or if the underlying depression is also contributing to these effects. The possibility of epigenetic alterations as one of the underlying mechanisms that is altered by SSRI exposure is discussed. However much more research in this area is needed to explain the exact role of epigenetic mechanisms in SSRI exposure during pregnancy.

“When I Want to Cry I Can’t”: Inability to Cry Following SSRI Treatment

IntroductionWe describe seven cases of patients with an inability to cry after treatment with selective serotonin re-uptake inhibitor (SSRI) medication, even during sad or distressing situations that would have normally initiated a crying episode, in the light of the role of the serotonergic system in emotional expression. MethodCase series drawn from patients attended in a secondary care psychiatry service. ResultsWhile excessive crying without emotional distress has been previously reported in the literature, and is associated with reduced serotonin function, these reports suggest cases of the reverse dissociation, where emotional distress and an urge to cry was present, but crying was impaired. DiscussionAlthough the case series presented here is new, these cases are consistent with the neuroscience of crying and their relationship with serotonergic function, and provide preliminary evidence for a double dissociation between subjective emotional experience and the behavioural expression of crying. This helps to further illuminate the neuroscience of emotional expression and suggests the possibility that the phenomenon is an under-recognised adverse effect of SSRI treatment.

Antidepressant Treatment Reduces Serotonin-1A Autoreceptor Binding in Major Depressive Disorder

Chronic selective serotonin reuptake inhibitor (SSRI) administration to rodents desensitizes or downregulates raphe 5-hydroxytryptamine 1A (5-HT1A) autoreceptors. We previously found elevated 5-HT1A binding in antidepressant-naive and not recently medicated major depressive disorder (MDD) and now report the effect of SSRI treatment on 5-HT1A autoreceptors in depressed patients. 5-HT1A binding (BPF) was quantified in medication-free subjects using positron emission tomography (PET) with [11C]-WAY-100635 before and after treatment of MDD with an SSRI for 5 to 9 weeks (mean 47 ± 8 days). Nineteen subjects without recent history of antidepressant pharmacotherapy completed both [11C]WAY-100635 PET scans with a metabolite-corrected arterial input function and depression severity was rated before and after the treatment course. 5-HT1A autoreceptor BPF in the raphe was reduced 18% on SSRI treatment (df = 1,18; F = 5.12; p = .036). However, the degree of reduction in 5-HT1A autoreceptor BPF was unrelated to improvement in depression (df = 1,16; F = 1.27; p = .276). Downregulation of 5-HT1A autoreceptor binding by SSRI treatment of major depression is consistent with animal studies. This may be a necessary but insufficient requirement for clinical response to SSRIs. A PET agonist ligand that binds selectively to the high-affinity conformation of this receptor can determine whether SSRIs also cause desensitization of the autoreceptor as reported by some rodent studies and whether that effect may be related to clinical response.

Sertraline-Induced Hypersexuality in a Patient Taking Bupropion

To the Editor: Sertraline is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Estimates of sexual dysfunction with SSRIs have been suggested to be between 30% and 50%, with some reporting up to 80%.1,2 Interestingly, there are a few reports of heightened sexual activity with SSRIs.3–7 We report the first case of sertraline-induced hypersexuality in a patient taking bupropion for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Case report. Mr A, a 55-year-old married white man, presented in 2006 for management of DSM-IV PTSD and MDD. His symptoms were inadequately controlled with bupropion (extended release 100 mg daily). Due to limited evidence on benefit of bupropion in PTSD, the bupropion dose was not increased further. Instead, sertraline was added per US Food and Drug Administration (FDA) recommendation for PTSD, and the dose was titrated to 100 mg daily. On a return visit, Mr A reported improvement, but his wife expressed concern about his having heightened sexual desire and increased demands to have sexual intercourse, resulting in spousal distress to the point of marital discord. The patient confirmed this and added that his erections had been lengthier and firmer than ever before. There was no evidence of priapism. Both the patient and his wife strongly attributed this heightened sexual desire to introduction of sertraline, since this increased desire was nonexistent when he took bupropion alone. There was no evidence of hypomania/mania. Substance use, medical conditions, and medicines used to enhance sexual functioning were ruled out. The patient discontinued sertraline, and hypersexuality gradually resolved over a span of 1 month without concomitant worsening in his PTSD and MDD symptoms. He was then maintained on bupropion monotherapy. The mechanism of SSRI-induced sexual dysfunction is not clear, but serotonin receptors 5-HT2 and 5-HT3, neurotransmitters such as dopamine, and prolactin have been implicated.8,9 Intriguingly, SSRIs, including fluoxetine and paroxetine, have been associated with hypersexuality in previous case reports.4,5,7,10–13 Dose-dependent incidence of hypersexuality has been described in a patient taking fluoxetine, for whom symptoms emerged within 2 days of increasing the fluoxetine dose from 20 mg to 40 mg daily and subsided completely with reduction to 20 mg daily.10 The hypersexuality resolved after discontinuation of SSRI treatment in other cases.4,5,7 Our patient never complained of sexual stimulation on bupropion monotherapy despite the favorable effect of bupropion on sexual functioning.14 The emergence of hypersexuality in our patient on the addition of sertraline may be an independent side effect of sertraline or may be due to the synergistic action of bupropion and sertraline. Sertraline is not an exclusively serotonergic agent but also acts on norepinephrine and dopamine receptors.15 A recent preclinical study showed that sertraline increases extracellular levels of dopamine in the nucleus accumbens and striatum of rats.16 Similarly, fluoxetine has been shown to increase synaptic dopamine level.17 These data may support hypersexuality as an independent side effect of certain SSRIs, most likely due to their prodopaminergic action. There is 1 previous case report of hypersexuality caused by combination of bupropion and sertraline18 resulting after bupropion was added for sertraline-induced sexual dysfunction. Our case had the reverse sequence. Inhibition of metabolism of bupropion by sertraline19 can potentially explain hypersexuality. There is also evidence of inhibition of metabolism of sertraline by bupropion involving cytochrome P450 2D6.20 Hence, blood levels of both bupropion and sertraline can potentially rise in a patient receiving this particular combination. Although the mechanism of SSRI-induced hypersexuality is still speculative, SSRIs have been associated with hypersexuality both independently and in combination with bupropion. Clinicians should be aware of hypersexuality as a rare but distressing side effect of SSRI treatment.

Clinical and neurocognitive changes with modafinil in obsessive–compulsive disorder: a case report

There are limited treatment options for co-occurring sleep disorders and obsessive–compulsive disorder (OCD). We postulated that Modafinil (Provigil) [2-{(diphenylmethyl) sulfinyl acetamide}], a non-amphetamine wakefulnesspromoting agent, might be of value in patients with excessive daytime sleepiness (EDS). Randomized double-blind placebo-controlled depression trials have investigated the effects of modafinil co-administered with selective serotonin re-uptake inhibitors (SSRIs) and found improvement in clinical global scores, and aside from effects on sleep and mood, modafinil has exhibited cognitive enhancing effects in some subjects (Minzenberg and Carter 2008). In a doubleblind placebo-controlled crossover challenge, Turner et al. (2004) demonstrated decreased motor impulsivity as measured on laboratory tests in adult attention-deficit/ hyperactivity disorder patients treated with single doses of modafinil (100 mg and 200 mg). To date, studies examining the neuropsychological effects of treatment are rare in OCD and have generally failed to show a positive effect of SSRI treatment on cognition (Nielen and den Boer 2003). In this context, we considered a new approach for treating neurocognitive impairments in treatment-resistant OCD. Modafinil’s effects on clinical symptoms and on a selected range of neurocognitive functions previously reported to be impaired in OCD (Chamberlain et al. 2005) are examined. We report the case of a patient with treatment-resistant OCD and EDS treated with adjunctive modafinil. DW is a 33-year-old unemployed man with a 13-year history of aggressive obsessions, panic anxiety, low mood, and EDS. Past treatment with dothiepin, venlafaxine, and several SSRIs had produced little benefit. A primary diagnosis of SSRI-resistant, DSM-IV OCD (defined as less than 25% improvement on the Yale-Brown Obsessive– Compulsive Scale (Y-BOCS) despite adequate treatment trials) was made, with DSM-IV panic disorder and DSM-IV dysthymia as subsidiary diagnoses. His sleep schedule was chaotic, with sleeping periods during the day, though he tended to get up at 8 am irrespectively. At initiation of modafinil, DW (right-handed, no sensory impairments) had been receiving escitalopram (40 mg) for at least 12 weeks being administered unchanged throughout the trial. A single morning dose of modafinil (100 mg) was prescribed and increased after 3 weeks to 200 mg (in two divided doses), and after 4 weeks to 400mg (in two divided doses). Treatment adherence was checked verbally. Clinical assessments were W. H. Dittrich (*) Medical School, Office of the Dean, Goethe-University Frankfurt am Main, Haus 15B, Zi. 418, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany e-mail: winand.dittrich@kgu.de

Reversible escitalopram-induced hypothyroidism

Some drugs can cause alterations in the concentration of thyroid hormones in blood even without clinical signs of dysfunction or pathology of the thyroid gland. Apart from the well-known relationship between depression and hypothalamic-pituitary-thyroid (HPT) axis, and the impact of selective serotonin reuptake inhibitors (SSRIs) on thyroid indices, hypothyroidism is a very rare adverse effect of SSRI treatment. However, the case presented here demonstrates that escitalopram may have the potential to induce hypothyroidism without any significant clinical signs and symptoms. Therefore, the possibility of SSRI-induced asymptomatic hypothyroidism presented here may help clinicians in this regard.

Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze

The elevated T-maze (ETM) is an animal model of anxiety-like behavior that assesses two different defensive behavioral tasks in the same animal—acquisition of inhibitory avoidance and latency to escape from an open and elevated arm. In rats, cute and chronic treatments with anxiolytic-like drugs impair avoidance acquisition while only chronic administration of panicolytic-like drugs impairs open arm withdrawal. To date, only the acute effects of anxiolytic/anxiogenic or panicolytic/panicogenic drugs have been tested in the mouse ETM and the results have partially corroborated those found in the rat ETM. This study investigated the effects of acute (a single intraperitoneal injection 30 min before testing) and chronic (daily i.p. injections for 15 consecutive days) treatment with imipramine or fluoxetine, non-selective and selective serotonin reuptake inhibitors, respectively, on inhibitory avoidance and escape tasks in the mouse ETM. Neither acute nor chronic treatment with imipramine (0, 1, 5 or 10 mg/kg, i.p.) significantly changed the behavioral profile of mice in the two ETM tasks. Interestingly, while acute fluoxetine (0, 5, 10, 20 or 40 mg/kg, i.p.) facilitated inhibitory avoidance and impaired escape latency, chronic treatment (0, 5, 20 or 40 mg/kg, i.p.) with this selective serotonin reuptake inhibitor (SSRI) produced an opposite effect, i.e., it impaired inhibitory avoidance acquisition and facilitated open arm withdrawal. Importantly, acute or chronic treatment with imipramine (except at the highest dose that increased locomotion when given acutely) or fluoxetine failed to alter general locomotor activity in mice as assessed in an ETM in which all arms were enclosed by lateral walls (eETM). These results suggest that inhibitory avoidance acquisition is a useful task for the evaluation of acute and chronic effects of SSRI treatment on anxiety in mice. However, as open arm latency was actually increased and reduced by acute and chronic fluoxetine, respectively, this does not seem to be a useful measure of escape from a proximal threat in this species.