Stimulus novelty and emotion perception: the near absence of habituation in the visual cortex

In rapid serial visual presentation of pictures, an early event-related brain potential component shows enlarged negativity over occipital regions for emotional pictures compared with neutral pictures. The present study examined whether the processing of emotional target pictures varies as a function of stimulus repetition. Accordingly, pictures of erotica, neutral contents, and mutilations were repeatedly presented (90 times) while the electroencephalogram was recorded with a 129 dense sensor array. As in previous studies, emotional pictures were associated with a larger posterior negativity than neutral pictures. Furthermore, differential emotion processing did not vary as a function of stimulus repetition and was similarly expressed across blocks of picture presentation. These findings suggest the near absence of habituation in differential emotion processing during perceptual processing.     

The adverse skeletal effects of selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are a widely used group of antidepressants (ADs) with reported potential detrimental effects on bone mineral density (BMD) and increased fracture risk. Here, a comprehensive review of the in vitro, in vivo and clinical studies to date was carried out using the medical search engines MEDLINE (1950 to September 2010) and EMBASE (1980 to September 2010). Serotonin (5-HT) receptors have been identified on osteoclast, osteoblast and osteocyte cell lines. The effect of SSRIs on bone formation and resorption appears to be governed by the activation of a number of 5-HT receptors on osteoblasts and osteoclasts via endocrine, autocrine/paracrine and neuronal pathways. In vitro, in vivo and clinical collective data appears to indicate that SSRIs have a negative effect on bone at the therapeutic dose levels widely used for the treatment of depression in current clinical practice. Caution may therefore have to be employed with the use of SSRIs in patients at an increased risk of falls and osteoporosis. Further studies are needed in order to fully elicit the role of SSRIs in bone formation and their effects in the low oestrogen state.     

The emotional power of music: how music enhances the feeling of affective pictures

Music is an intriguing stimulus widely used in movies to increase the emotional experience. However, no brain imaging study has to date examined this enhancement effect using emotional pictures (the modality mostly used in emotion research) and musical excerpts. Therefore, we designed this functional magnetic resonance imaging study to explore how musical stimuli enhance the feeling of affective pictures. In a classical block design carefully controlling for habituation and order effects, we presented fearful and sad pictures (mostly taken from the IAPS) either alone or combined with congruent emotional musical excerpts (classical pieces). Subjective ratings clearly indicated that the emotional experience was markedly increased in the combined relative to the picture condition. Furthermore, using a second-level analysis and regions of interest approach, we observed a clear functional and structural dissociation between the combined and the picture condition. Besides increased activation in brain areas known to be involved in auditory as well as in neutral and emotional visual-auditory integration processes, the combined condition showed increased activation in many structures known to be involved in emotion processing (including for example amygdala, hippocampus, parahippocampus, insula, striatum, medial ventral frontal cortex, cerebellum, fusiform gyrus). In contrast, the picture condition only showed an activation increase in the cognitive part of the prefrontal cortex, mainly in the right dorsolateral prefrontal cortex. Based on these findings, we suggest that emotional pictures evoke a more cognitive mode of emotion perception, whereas congruent presentations of emotional visual and musical stimuli rather automatically evoke strong emotional feelings and experiences.     

Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents.

A frontal lobe syndrome has previously been reported in adults treated with selective serotonin reuptake inhibitors (SSRIs), but not in children. Five typical cases of apathy and lack of motivation, one accompanied by disinhibition, are described in a child and four adolescents. Symptoms were dose related and reversible. The subtlety of symptoms, lack of insight in patients, disabling effects, and delayed onset indicate a need for clinicians to inform families of these potential symptoms when SSRIs are prescribed.     

Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability

BACKGROUND: Awareness of the impact and prevalence of autism spectrum disorders has significantly increased in recent years. Given the dearth of reliable interventions, there is great interest in demonstrating efficacy of the various treatment options. A growing body of evidence links autism spectrum disorders to abnormalities in serotonin function, and the selective serotonin reuptake inhibitors (SSRIs) have been utilized to target various symptoms of the disorders. This article reviews the available data on the efficacy and tolerability of SSRIs in individuals with autism spectrum disorders. Objectives for future research in this area will also be suggested. DATA SOURCES AND STUDY SELECTION: The entire PubMed database including MEDLINE (1966-July 2005) was searched for English-language biomedical articles. Search terms included autism, autism spectrum disorder, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, pervasive developmental disorder, selective serotonin reuptake inhibitors, and sertraline. All clinical trials evaluating treatment outcomes associated with the use of SSRIs in managing symptoms of autism that were identified in the search were reviewed. All randomized controlled trials and open-label trials were included in this review. Case reports and case series were excluded. DATA SYNTHESIS: We identified 3 randomized controlled trials and 10 open-label trials or retrospective chart reviews on the use of SSRIs in autism and autism spectrum disorders. The SSRIs that have been studied in autism spectrum disorders are citalopram, escitalopram, fluoxetine, fluvoxamine, and sertraline. Most studies demonstrate significant improvement in global functioning and in symptoms associated with anxiety and repetitive behaviors. While side effects were generally considered to be mild, increased activation and agitation occurred in some subjects. CONCLUSIONS: Although SSRIs may demonstrate therapeutic benefit in autism spectrum disorders, methodological weaknesses of many of the clinical trials suggest the need for additional randomized controlled trials. Furthermore, given the increased awareness of the dangers associated with SSRI-induced activation and agitation, the presence of these side effects in the autistic population warrants closer attention to dosage, titration, and subject selection issues.     

Dual reuptake inhibitors incur lower rates of tachyphylaxis than selective serotonin reuptake inhibitors: a retrospective study

BACKGROUND: The notion that selective serotonin reuptake inhibitors (SSRIs) may be associated with higher relapse rates than other antidepressants during maintenance treatment (tachyphylaxis) has been discussed for years, but to date there is little or no empirical evidence confirming this phenomenon. In this study, we systematically assessed prior anti-depressant treatment history in a cohort of depressed patients who presented for outpatient psychiatric treatment. Rates of tachyphylaxis were compared in venlafaxine and tricyclic antidepressants (TCAs), which act as dual reuptake inhibitors, versus SSRIs. METHOD: 237 patients who presented for treatment at the Rhode Island Hospital Department of Psychiatry's outpatient practice and were diagnosed with DSM-IV major depressive disorder were interviewed with the semistructured Treatment Response to Antidepressant Questionnaire. This cohort reported having undergone 326 prior SSRI trials, 47 prior venlafaxine trials, and 35 prior trials with a TCA. Rates of tachyphylaxis as a function of antidepressant class were compared. RESULTS: Rates of tachyphylaxis were significantly lower (chi(2) = 6.77, df = 1, p = .01) with the dual reuptake inhibitors venlafaxine and TCAs (3 [3.7%] of 82) compared to rates of tachyphylaxis with SSRIs (46 [14.1%] of 326). CONCLUSION: These results provide preliminary evidence that dual reuptake inhibitors may incur lower rates of tachyphylaxis than SSRIs. By virtue of the retrospective and non-random design of the study, these results warrant confirmation.     

Persistent pulmonary hypertension of the newborn and selective serotonin reuptake inhibitors: lessons from clinical and translational studies

Two recent studies linking in utero exposure to selective serotonin reuptake inhibitors (SSRIs) with persistent pulmonary hypertension of the newborn (PPHN), a potentially serious but rare respiratory illness, have made clinicians and patients more reluctant to use SSRIs during pregnancy. However, additional clinical studies have associated maternal depression rather than SSRI exposure as a risk factor for PPHN. This review summarizes the current knowledge regarding PPHN pathophysiology, including the role of serotonin and genetic risk factors; the effects of SSRIs on pulmonary vasculature; the possible link between SSRIs and PPHN; and the diagnosis, clinical management, and prognosis of PPHN.     

Distinguishing roles for norepinephrine and serotonin in the behavioral effects of antidepressant drugs

Antidepressant drugs have typically been classified into sets of compounds with actions targeted at serotonin (selective serotonin reuptake inhibitors [SSRIs]), norepinephrine (norepinephrine reuptake inhibitors [NRIs]), or both neurotransmitters (serotonin-norepinephrine reuptake inhibitors). Their classification has been based predominantly on their acute pharmacologic effects, usually determined by in vitro radioligand binding assays. The pharmacologic selectivity of antidepressants can be altered after their systemic administration, however, by dose, drug metabolism, physiologic interactions between neurotransmitters, and adaptive effects that emerge after chronic administration. This review examines whether pharmacologic selectivity is maintained by different types of antidepressants in vivo and whether pharmacologic selectivity matters for the production of their behavioral effects. Antidepressants increase extracellular levels of neurotransmitters according to their ability to inhibit presynaptic transporters, although physiologic interactions among neurotransmitters can influence antidepressants' selectivity in certain brain regions. Chronic administration of many antidepressants also causes down-regulation of postsynaptic and presynaptic receptors. The pattern of responses of presynaptic markers suggests that pharmacologic selectivity is maintained after chronic administration of many antidepressants. Behavioral tests indicate that depletion of serotonin (5-HT) is capable of preventing the effects produced by SSRIs but not NRIs. The depletion of catecholamines also inhibits the effects of NRIs, although test results can be complicated by inhibition of motor activity. Depletion of norepinephrine may also inhibit the effects of some SSRIs, but not highly selective SSRIs like citalopram. Although the pattern of results from in vivo tests supports the concept that parallel neurotransmitter mechanisms lead to antidepressant activity, norepinephrine may participate in the effects of some SSRIs. It is also possible that compounds with dual actions at 5-HT and norepinephrine systems may be effective under circumstances in which selective antidepressants are ineffective.     

Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear. METHODS: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory. RESULTS: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist. CONCLUSIONS: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.     

Selective serotonin reuptake inhibitors for children and adolescents

The controlled studies of selective serotonin reuptake inhibitors (SSRIs) in pediatric psychopharmacology research lag behind the controlled studies of SSRIs in adults. As a result, widespread use of SSRIs in the treatment of child and adolescent psychiatric disorders is in stark contrast to the paucity of research data. Recent changes in the research climate (including support from the National Institute of Mental Health, the Food and Drug Administration, and industry) have encouraged welldesigned SSRI studies in pediatric psychopharmacology, and will ultimately provide needed information to guide treatment. This paper reviews the best available data from pediatric SSRI trials, including 10 double-blind placebo-controlled trials, and two abstracts of open-label continuation studies of SSRIs associated with large pediatric efficacy studies. Adverse events (AEs) of SSRIs in children and adolescents are discussed in reference to available pediatric studies. Recent pharmacokinetic studies of SSRIs in children and adolescents are reviewed. Future SSRI research strategies are also discussed.     

Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: A critical review

OBJECTIVE: To critically review the antiobsessional properties of serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine and clomipramine) in the treatment of obsessive-compulsive disorder (OCD) as an alternative to selective serotonin reuptake inhibitors (SSRIs), which are currently considered the first-line treatment of OCD. DATA SOURCES: A MEDLINE search was performed to identify clinical trials with the SNRIs venlafaxine and clomipramine published from 1996 to 2004 (keywords: SNRIs, venlafaxine, duloxetine, and clomipramine, each matched individually with the term OCD), focusing on the best-designed studies for inclusion. DATA SYNTHESIS: Much of the literature about SNRIs in OCD supports the efficacy of these compounds in the treatment of OCD. However, double-blind, placebo-controlled studies with venlafaxine are lacking, and the most relevant studies consist of active comparison trials between SNRIs and SSRIs. In these studies, SNRIs seem to be as effective as SSRIs in OCD; SNRIs might be preferred for patients with certain types of treatment-resistant OCD or those with particular comorbid conditions. A large number of placebo-controlled and active comparison trials with clomipramine document efficacy in OCD, and meta-analytic studies suggest a small superiority over SSRIs. Compared with clomipramine, the SNRI venlafaxine showed fewer side effects and better tolerability. CONCLUSION: The SNRIs may represent a valid alternative to the SSRIs, particularly in specific cases. Double-blind, placebo-controlled studies are, however, needed to confirm the positive findings reported by several studies with venlafaxine.     

Use of bupropion in combination with serotonin reuptake inhibitors.

Incomplete symptom remission and sexual side effects are common problems for which bupropion often is added to treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs) for patients with major depressive disorder (MDD). This article reviews the literature on combining bupropion with SSRIs or SNRIs. We used MEDLINE to select studies that included patients diagnosed with MDD treated with any combination of bupropion and an SSRI or SNRI, either to enhance antidepressant response or to ameliorate antidepressant-associated sexual dysfunction. Bibliographies of located articles were searched for additional studies. Controlled and open-label studies support the effectiveness of bupropion in reversing antidepressant-associated sexual dysfunction, whereas open trials suggest that combination treatment with bupropion and an SSRI or SNRI is effective for the treatment of MDD in patients refractory to the SSRI, SNRI, or bupropion alone. The available data suggest that, although not an approved indication, the combination of bupropion and either an SSRI or an SNRI is generally well tolerated, can boost antidepressant response, and can reduce SSRI or SNRI-associated sexual side effects. Additional randomized controlled studies are needed to answer important questions, such as those regarding optimal dose and duration of treatment.     

Treatment of severe depression with the selective serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are recognized as effective as and better tolerated than older antidepressant therapies and have become the drugs of choice in the treatment of mild to moderate depression. However, there is a clinical impression that the SSRIs are less effective than older therapies in the severely depressed patient. A limited number of trials have attempted to address this issue. This review assesses 16 controlled studies of SSRIs in severe depression. The findings from a majority of studies found the SSRIs to be superior to placebo and as effective as but better tolerated than the tricyclic antidepressants (TCAs) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRIs in this patient population. Depression and Anxiety 4:182–189, 1996/1997. © 1997 Wiley-Liss, Inc.     

Differential effects of the 5-HT2 receptor antagonist on the anti-immobility effects of noradrenaline and serotonin reuptake inhibitors in the forced swimming test

The effects of the 5-HT(2) receptor antagonist, LY 53857 on the effects of noradrenaline and serotonin reuptake inhibitors were investigated using the forced swimming test. LY 53857 enhanced anti-immobility effects of clomipramine and maprotiline, which can inhibit reuptake of noradrenaline. However, LY 53857 did not affect the immobility time of mice treated with the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine. These results suggest that antagonism of the 5-HT(2) receptor leads to potentiation of the antidepressant effects of noradrenaline reuptake inhibitors but not SSRIs and that LY 53857 may modify the activity of noradrenergic neurons.     

Effects of left and right medial temporal lobe resections on hemodynamic correlates of negative and neutral scene processing

Enhanced visual cortex activation by negative compared to neutral stimuli is often attributed to modulating feedback from the amygdala, but evidence from lesion studies is scarce, particularly regarding differential effects of left and right amygdala lesions. Therefore, we compared visual cortex activation by negative and neutral complex scenes in an event‐related fMRI study between 40 patients with unilateral temporal lobe resection (TLR; 19 left [lTLR], 21 right [rTLR]), including the amygdala, and 20 healthy controls. We found preserved hemodynamic emotion modulation of visual cortex in rTLR patients and only subtle reductions in lTLR patients. In contrast, rTLR patients showed a significant decrease in visual cortex activation irrespective of picture content. In line with this, healthy controls showed small emotional modulation of the left amygdala only, while their right amygdala was activated equally by negative and neutral pictures. Correlations of activation in amygdala and visual cortex were observed for both negative and neutral pictures in the controls. In both patient groups, this relationship was attenuated ipsilateral to the TLR. Our results support the notion of reentrant mechanisms between amygdala and visual cortex and suggest laterality differences in their emotion‐specificity. While right medial temporal lobe structures including the amygdala seem to influence visual processing in general, the left medial temporal lobe appears to contribute specifically to emotion processing. Still, effects of left TLR on visual emotion processing were relatively subtle. Therefore, hemodynamic correlates of visual emotion processing are likely supported by a distributed cerebral network, challenging an amygdalocentric view of emotion processing.     

The use of selective serotonin reuptake inhibitors in autism and related disorders

This paper reviews the published literature on the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of symptoms associated with autistic disorder and other pervasive developmental disorders (PDDs) in both children and adults. To date, placebocontrolled studies of SSRIs have involved only fluvoxamine (in children and adults) and fluoxetine (in children). Open-label and retrospective studies of all other SSRIs in PDDs have also been published that suggest effectiveness. Despite these positive reports, there continues to be questions about the tolerability and appropriate dosing of SSRIs in children with PDDs. Because of the limited number of placebo-controlled studies, definitive conclusions about the role SSRIs should play in the clinical treatment of children with PDDs cannot be drawn. Larger, placebo-controlled studies of SSRIs are needed to guide clinical treatment.     

Role of presynaptic alpha2-adrenoceptors in antidepressant action: recent findings from microdialysis studies

The therapeutic effect of an antidepressant drug takes at least 2 to 3 weeks to develop and a significant proportion of patients have no or only partial benefit regardless of the class of antidepressant used. Research into the neurobiological basis of antidepressant action has suggested new strategies to improve the antidepressant effect. Recent microdialysis studies show that hypofunction of the presynaptic autoreceptors enhances the increase of extracellular serotonin (5-HT) induced by selective serotonin reuptake inhibitors (SSRIs) so it has been suggested that the antidepressant effect may be speeded up by blockade of the autoreceptors. The similarity between the synaptic mechanisms controlling serotonergic and noradrenergic transmission has stimulated preclinical research into the role of presynaptic alpha(2)-adrenoceptors in the effect of noradrenaline (NA) reuptake inhibitors (NRIs) on NA availability at central synapses. The microdialysis studies reviewed here indicate that NRIs including desipramine, reboxetine and atomoxetine, the mixed 5-HT/NA reuptake inhibitors sibutramine, duloxetine, venlafaxine or the NA/DA reuptake inhibitor amineptine, increased extracellular NA in various regions of the rat brain. The effect was enhanced by chronic treatment and even more by the co-administration of alpha(2)-adrenoceptor antagonists. The results support the theory that desensitization of the alpha(2)-adrenoceptor contributes to enhancing the effect of NRIs seen after chronic administration and may account for the slow onset of the antidepressant effect. Finally, they suggest that co-administration of an alpha(2)-adrenoceptor antagonist may improve the therapeutic effect of NRI.     

Regulation of the norepinephrine transporter by chronic administration of antidepressants.

BACKGROUND: Downregulation of serotonin transporter was observed previously after chronic treatment with selective serotonin reuptake inhibitors (SSRIs) but not selective norepinephrine reuptake inhibitors (NRIs). This study investigated if chronic treatment of rats with selective NRIs or SSRIs also affected the norepinephrine transporter (NET). METHODS: Rats were treated for 3 to 6 weeks by osmotic minipumps with either the selective NRIs, desipramine, or the SSRI paroxetine. RESULTS: [(3)H]nisoxetine binding sites as well as [(3)H]norepinephrine uptake were decreased in hippocampus and cortex after treatment with desipramine. By contrast, paroxetine-treated rats showed no alteration in either [(3)H]nisoxetine binding or [(3)H]norepinephrine uptake. NET messenger RNA levels in the locus coeruleus were unchanged by desipramine treatment. CONCLUSIONS: These results demonstrate that the marked decrease in NET density 1) is not a consequence of a decrease in gene expression; 2) was caused only by a selective NRI; and 3) was associated with a parallel decrease in norepinephrine uptake.     

Postmenopausal hormone use impact on emotion processing circuitry

Despite considerable evidence for potential effects of estrogen on emotional processing, several studies of postmenopausal women who began hormone therapy (HT) remote from menopause report no effects of HT on emotional measures. As early HT initiation may preserve brain mechanisms, we examined effects of HT on emotional processing in postmenopausal women who started HT early after menopause. We performed a cross-sectional comparison of 52 postmenopausal women 66 ± 5 years old, including 15 users of conjugated equine estrogen, 20 users of conjugated equine estrogen plus medroxyprogesterone acetate, and 17 who never used hormones (NT). All hormone users started therapy within two years of menopause, and received at least 10 years of continuous therapy. Outcomes were fMRI-detected brain activity and behavioral measures during an emotional processing picture rating task. During processing of positive pictures, NT women had greater activation than estrogen treated women in medial prefrontal cortex extending to the anterior cingulate, and more activation than estrogen plus progestin treated women in the insula. During processing of negative pictures, estrogen treated women had higher activation than NT women in the entorhinal cortex. Current compared to past HT users showed greater activation in the hippocampus and higher emotion recognition accuracy of neutral stimuli. Estrogen plus progestin treated women had slower response time than NT women when rating all pictures. In conclusion, hormone use was associated with differences in brain functional responses during emotional processing. These fMRI effects were more prominent than those observed for behavioral measures and involved brain regions implicated in cognitive-emotional integration.