Chronic SSRI Treatment Research Articles

Ongoing Use of SSRIs Does Not Alter Outcome in Hospitalized COVID-19 Patients: A Retrospective Analysis.

SARS-CoV-2 continues to have devastating consequences worldwide. Though vaccinations have helped reduce spread, new strains still pose a threat. Therefore, it is imperative to identify treatments that prevent severe COVID-19 infection. Recently, acute use of SSRI antidepressants in COVID+ patients was shown to reduce symptom severity. The aim of this retrospective observational study was to determine whether COVID+ patients already on SSRIs upon hospital admission had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Electronic medical records of 9044 patients with laboratory-confirmed COVID-19 from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. In this sample, no patients admitted on SSRIs had them discontinued. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs. those not taking SSRIs, after controlling for age category, gender, and race. This study shows the utility of large clinical databases in determining what commonly prescribed drugs might be useful in treating COVID-19. During pandemics due to novel infectious agents, it is critical to evaluate safety and efficacy of drugs that might be repurposed for treatment.

Expression and impact of Lsamp neural adhesion molecule in the serotonergic neurotransmission system

Limbic system associated membrane protein (Lsamp) is a neural adhesion protein which has been recently found to be differentially expressed between serotonergic neuron subtypes. We have previously shown elevated serotonin (5-HT) turnover rate in Lsamp-deficient mice. The purpose of the current study was to elucidate the role of Lsamp in serotonergic neurotransmission.Chronic (18 days) administration of serotonin reuptake inhibitor (SSRI) escitalopram (10 mg/kg) significantly increased general activity in wild-type mice in the open field and protected exploration in Lsamp−/− mice in the elevated-plus maze. An important psychopathology-related endophenotype, elevated 5-HT turnover in the brain of Lsamp-deficient mice, was reproduced in the saline group. Escitalopram restored the elevated 5-HT turnover of Lsamp-deficient mice to a level comparable with their wild-type littermates, suggesting that high 5-HT turnover in mutants is mediated by the increased activity of serotonin transporter (SERT protein encoded by Slc6a4 gene). The baseline level of Slc6a4 transcript was not changed in Lsamp-deficient mice, however, our immunohistochemical analysis showed partial co-expression of Lsamp with both SERT and Tph2 proteins in raphe. Overactivity of SERT in Lsamp−/− mice is further supported by significant elevation of Maoa transcript and increase of DOPAC, another Mao A product, specifically in the raphe. Again, elevation of DOPAC was reduced to the level of wild-type by chronic SSRI treatment. The activity of Lsamp gene promoters varied in 5-HT producing nuclei: both Lsamp 1a and 1b promoters were active in the dorsal raphe; most of the expression in the median raphe was from 1b promoter, whereas Lsamp 1a promoter was almost exclusively active in the caudal subgroup of raphe nuclei. We suggest that Lsamp may have an impact on the integrity of serotonergic synapses, which is possibly the neurochemical basis of the anxiety- and sociability-related phenotype in Lsamp-deficient mice.

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT−/−) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT−/− rats. SERT−/− showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT−/− results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT−/− during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT−/− resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear.

Robust presynaptic serotonin 5-HT(1B) receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment.

The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT(1B)Rs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT(1B)Rs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT(1B)R agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT(1B)R-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT(1B)Rs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5-HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT(1B)R-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment.

The tryptophan hydroxylase 2 (Tph2) polymorphism C2432T mediates mRNA expression and responses to antidepressant treatment in a sex‐specific manner

The mechanisms behind successful treatment response in Major Depressive Disorder remain unclear. We examined whether a novel single nucleotide polymorphism (SNP) C2432T in the Tph2 gene mediates differences in response to SSRIs between two mouse strains: MRL/MpJ (MRL; SSRI‐responding, T/T) versus C57Bl/6J (C57; SSRI‐nonresponding, C/C) (Balu et al, 2009). We cross‐bred the MRL and C57 strains to isolate C2432T in the F2 generation and determined functionality using the response to SSRIs in the tail suspension test (TST). F2 T/T females showed an enhanced citalopram response (p<0.001, n=10), while males showed no genotype‐specific effects. The C2432T SNP also mediated Tph2 mRNA expression, with T/T animals showing increased expression in the midbrain (p<0.05, n=11–16). However, in response to chronic SSRI treatment, there was no difference by genotype in F2 generation animals in measures of hippocampal neurogenesis or novelty‐induced hypophagia behavior. The C2432T SNP may mediate serotonin involvement to acute antidepressant response in a sex‐specific manner, but did not mediate the effects of chronic antidepressant treatment.

P-1117 - Paroxetine and herpes zoster

Paroxetine is a selective serotonin reuptake inhibitor antidepressant. We present a case of a patient who developed herpes zoster 4 weeks after initiating paroxetine. A 35 year old female was referred to our hospital due to obsessive compulsive disorder. She complained of intrusive thoughts of being contaminated and repetitive behaviors. After a thorough laboratory and imaging tests she was prescribed paroxetine 40 miligrams daily. Four weeks later she complained of pain followed by rash along the same dermatomal distribution in the lower abdominal area. The involved area was tender to palpation. A detailed dermatologic evaluation was performed and the rash was attributed to herpes zoster. Despite the potential association of paroxetine with herpetic rash the patient continued treatment and was prescribed acyclovir and pain killers. One month later herpetic rash had fully remitted. This is the first report of herpes zoster attributed to paroxetine therapy. The pathophysiological mechanism governing the effects of SSRIs in immune function is controversial. In vitro studies have shown that SSRIs decreased splenic lymphocyte proliferation while other studies have shown that chronic SSRI treatment is associated with a reduction of the number of leucocytes and neutrophils. It has been suggested that the immune effects of SSRIs are mediated by endogenously released serotonine, while T leymphocytes express 5HT receptors. Although a casual association of herpes zoster and paroxetine therapy cannot be attributed with the described case, further studies are needed to clarify under which circumstances, paroxetine could trigger herpetic rash.

The Serotonin Transporter Plays an Important Role in Male Sexual Behavior: A Study in Serotonin Transporter Knockout Rats

Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels. To investigate the putative role of the SERT in male sexual behavior. After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist ± 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/-) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined. Male rat sexual behaviors of mounts, intromissions, and ejaculations. SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. ± 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of ± 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by ± 8-OH-DPAT of the sexual inhibitory effects of WAY100635. Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of ± 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido.

P.1.e.017 Chronic SSRI treatment induces adaptive changes in brain 5-HT phMRI responses

No study has examined the effect of cognitive-behavioral therapy (CBT) on moderate–severe major depressive disorders (MDD) in China. The objective of this study was to evaluate the effect of CBT, antidepressants alone (MED), combined CBT and antidepressants (COMB) and standard treatment (ST; i.e., receiving psycho-educational intervention and/or medication treatment determined by treating psychiatrists) on depressive symptoms and social functioning in Chinese patients with moderate–severe MDD.A total of 180 patients diagnosed with MDD according to ICD-10 were randomly allocated to one of the four treatment regimens for a period of 6 months. Depressive symptoms were measured using the Hamilton Rating Scale for Depression (HAMD) and the Quick Inventory of Depressive Symptomatology-Self-Report (C-QIDS-SR). Remission threshold was defined as a C-QIDS-SR total score of <5. Social functioning was evaluated with the Work and Social Adjustment Scale (WSAS). All outcome measures were evaluated at entry, and at 3- and 6-months follow-up.At the 6-months assessment, the remission rates in the whole sample (n=96), the MED, the CBT, the COMB and the ST groups were 54.2%, 48%, 75%, 53.5% and 50%, respectively. Following the treatment periods, there was no significant difference in any of the study outcomes between the four groups. However, the CBT showed the greatest effect in the HAMD total score with the effect size=0.94, whereas the ST has only a moderate effect size in the WSAS total score (effect size=0.47).The findings support the feasibility and effectiveness of CBT as a psychosocial intervention for Chinese patients with moderate–severe MDD. We also found that single treatment using MED or CBT performed equally well as the combined CBT-antidepressant treatment in controlling the remission. The study provided important knowledge to inform the mental health care planning in China.

Influence of Sex and Corticotropin-Releasing Factor Pathways as Determinants in Serotonin Sensitivity

Stress sensitivity and sex are predictive factors in affective disorder susceptibility. Serotonin (5-HT) pathway recruitment by corticotropin-releasing factor (CRF) during stress is necessary in adaptive coping behaviors, but sex differences in such responses have not been investigated. Using selective 5-HT reuptake inhibitor (SSRI) administration to acutely elevate 5-HT in a genetic model of stress sensitivity, we examined behavioral and physiological responses in male and female stress-sensitive CRF receptor-2-deficient (R2KO) mice. Chronic SSRI treatment was used to confirm outcomes were specific to acute 5-HT elevation and not antidepressant efficacy. We hypothesized that R2KO mice would show a greater sensitivity to acute changes in 5-HT and that, because females typically are more stress sensitive, R2KO females would be the most responsive. Our results supported this hypothesis because females of both genotypes and R2KO males showed a greater sensitivity to an acute 10 mg/kg dose of citalopram in a tail suspension test, displaying decreased immobile time and increased latency to immobility. Furthermore, acute citalopram promoted significant anxiogenic-like effects that were specific to R2KO females in the elevated plus maze and light-dark box tests. Chronic citalopram did not produce these behavioral changes, supporting specificity to acute 5-HT modulation. Mechanistically, females had decreased hippocampal 5-HT transporter (SERT) levels, whereas R2KO mice showed reduced SERT in the prefrontal cortex, supporting a possible intersection of sex and genotype where R2KO females would have the lowest SERT to be blocked by the SSRI. This sensitivity to 5-HT-mediated anxiety in females may underlie a heightened vulnerability to stress-related affective disorders.

A Silver Bullet for the Treatment of Depression?

The search for a rapid-acting antidepressant has been a subject of intense research interest for several decades. The article by Lucas and colleagues in this issue of Neuron provides compelling evidence from preclinical animal models that drugs acting at the serotonin 5-HT(4) receptor could finally achieve this goal. However, caution is warranted, as results from animal studies are not always predictive of therapeutic actions in humans.

The Role of the Selective Serotonin Reuptake Inhibitor Fluoxetine in Temperature Regulation in Ovariectomized Rat Models

Thermoregulation is an integrated network of neuroendocrine, autonomic and somatosensory responses. Thermoregulatory dysfunction occurs during fluctuations or decline of gonadal hormone levels and results in vasomotor symptoms such as hot flushes and/or night-time sweating. The neurotransmitter serotonin (5-HT), has been reported to play a role in thermoregulation via changes in extracellular 5-HT levels and/or activation of various 5-HT receptors. The purpose of this study was to evaluate the role of the selective 5-HT reuptake inhibitor (SSRI), fluoxetine (FLX), on temperature regulation using ovariectomized (OVX) rodent models of thermoregulation. Single, subcutaneous (s.c.) administration of FLX (3, 10, 30 and 60 mg/kg) dose-dependently reduced core body temperature (CBT). FLX at 3 and 10 mg/kg s.c. showed no statistically significant decrease on tail-skin temperature (TST), whereas at higher doses (30 and 60 mg/kg) a significant decrease in TST was noted in the telemetry model. To mimic chronic SSRI treatment, a 5-HT_1A antagonist (WAY-100635; 0.3 mg/kg) was administered 20 min prior to FLX (10 mg/kg). This combination showed no significant improvement on temperature dysfunction compared to FLX alone. Similarly, in a morphine-dependent model of temperature dysfunction FLX, was inactive at 10 mg/kg whereas the 30 and 60 mg/kg s.c. dose abated the naloxone-induced increase in TST by 55 and 81%, respectively. In summary, FLX affected CBT at all doses, but alleviated thermoregulatory dysfunction only at higher doses that are non-selective for the 5-HT system.

The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are efficacious in the treatment of a variety of fear or anxiety disorders. Although they inhibit the reuptake of serotonin within hours of administration, therapeutic improvement only occurs after several weeks. In this study, we used fear conditioning to begin to understand how acute and chronic SSRI treatment might differentially affect well-characterized fear circuits. MethodsWe evaluated the effects of acute and chronic treatment with the SSRI citalopram on the acquisition of auditory fear conditioning. To further understand the role of serotonin in modulating fear circuits, we compared these effects with those of acute and chronic administration of the antidepressant tianeptine, a purported serotonin reuptake enhancer. ResultsWe found that acute administration of the SSRI citalopram enhanced acquisition, whereas chronic treatment reduced the acquisition of auditory fear conditioning. In comparison, treatment with tianeptine had no effect acutely but also reduced the acquisition of tone conditioning when administered chronically. ConclusionsOur findings with citalopram are consistent with the clinical effects of SSRI treatment seen in patients with anxiety disorders, in which anxiety is often increased during early stages of treatment and decreased after several weeks of treatment. The findings also indicate that auditory fear conditioning can be a useful tool in understanding differences in the effects of short-term and long-term antidepressant treatment with serotonergic medications.

Differential Regulation of 5-HT1A Receptor-G Protein Interactions in Brain Following Chronic Antidepressant Administration

Changes in 5-HT1A receptor function or sensitivity following chronic antidepressant treatment may involve changes in receptor-G protein interaction. We have examined the effect of chronic administration of the SSRI fluoxetine or the tricyclic antidepressant amitriptyline on 5-HT1A receptor-stimulated [35S]GTPγS binding in serotonergic cell body areas, and cortical and limbic structures using quantitative autoradiography. Treatment of rats with fluoxetine, but not amitriptyline, resulted in an attenuation of 5-HT1A receptor-stimulated [35S]GTPγS binding in the dorsal and median raphe nuclei. The binding of the antagonist radioligand [3H]MPPF to 5-HT1A receptor sites was not altered, suggesting that the observed changes in 5-HT1A receptor-stimulated [35S]GTPγS binding were not due to changes in receptor number. Thus, the desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal and median raphe following chronic SSRI treatment appears to be due to a reduced capacity of the 5-HT1A receptor to activate G protein. By contrast, no significant change in postsynaptic 5-HT1A receptor-stimulated [35S]GTPγS binding was observed in any of the forebrain areas examined following chronic antidepressant treatment. Thus, changes in postsynaptic 5-HT1A receptor-mediated responses reported to follow chronic SSRI or tricyclic antidepressant administration most likely occur distal to receptor-G protein interaction, perhaps at the level of effector, or involving changes in neuronal function at the system or circuit level.

Chronic fluvoxamine treatment reduces platelet MAO activity in medicated chronic schizophrenics

AbstractThe effect of add‐on fluvoxamine on platelet MAO activity was studied in nine chronic schizophrenic patients on steady antipsychotic treatment. Platelet MAO activity decreased significantly after 5 weeks of treatment and remained depressed. Since fluvoxamine does not inhibit MAO activity in vitro, the findings, which are preliminary, raise the possibility that chronic SSRI treatment may modify MAO production.