Abstract: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine are prescribed to relieve clinical depression and a variety of other disorders. Recently tardive dyskinesia, as well as other movement disorders, have been found to be a clinical side effect of SSRIs. In light of these emerging side effects, we asked if motor neurons were affected by SSRI. Motor neurons were challenged with fluoxetine and paroxetine at clinically relevant doses as well as at lesser and greater doses. Ethanol was used as a negative control and another group of cells was left untreated. As expected, in alcohol-treated cells, there was significant decrease in cell survival and neurite outgrowth. In untreated cells there was no effect in either cell survival or neurite outgrowth. In fluoxetine-treated motor neurons there was ∼52% cell death while in paroxetine-treated cells there was 14% cell survival and both SSRIs caused significant loss of the percentage of neurite-bearing cells. Both SSRIs decreased cell survival in a dose-dependent manner. This study is provocative enough to call for further in vivo studies.
Selective serotonin reuptake inhibitors (SSRIs) are amongst the most widely prescribed class of antidepressants worldwide. Their extensive use is due to their better safety and effectiveness profile when compared to other classes of antidepressants. Several differences in pharmacology of the various SSRIs may affect the treatment choice in individual patients. This article summarises the role of SSRIs in the management of psychiatric and other disorders.
Major depressive disorder (MDD) is a complex disorder associated with various monoaminergic disturbances, abnormalities of endocrine regulation, alterations in sleep physiology, neuroanatomic abnormalities, and neurophysiologic changes (Drevets 1998; Thase 1998; Manji et al 2001; Ordway et al 2002; Moretti et al 2003; Sheline 2003; Buysse 2004). Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat MDD; however, it is now clear that a large percentage of patients suffering from MDD may not benefit from SSRI treatment (Thase 2003). Evidence from family studies indicates that response to specific antidepressant treatments can be affected by genetic differences (Pare and Mack 1971; O’Reilly et al 1994; Serretti et al 1998). Pharmacogenetics holds the potential to genetically predict who will and will not benefit from SSRIs (Catalano 1999; Pickar and Rubinow 2001; Serretti et al 2002). Moreover, delineating the genes that are associated with poor response to an SSRI may be valuable in identifying alternative patient-specific treatments, such as novel treatments or currently known and available therapies.
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Six selective serotonin reuptake inhibitors (SSRIs) are on the Norwegian market today, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram (the pure S-enantiomer of citalopram). SSRIs are typically used as antidepressants and are used to treat conditions such as depression, anxiety disorders and some personal- ity disorders. The total consumption of SSRIs has slowly increased in Norway the last years, although when ad- justed to population growth, the number of SSRI users has been relatively stable at just below 4% of the popula- tion. Citalopram/escitalopram is most widely distributed and constitutes approximately 591 kg of the total amount, while sertraline with its higher defined daily dosage is sold in the largest amounts contributing with approximately 621 kg . SSRIs have been found in wastewater in Norway [8,14], and it is reasonable to believe that not all pharmaceuticals are used or delivered back to the pharma- cies but might end up on landfill sites through private gar- bage disposal. Contaminants from landfill sites might reach the environment through leachate water run-off, and water soluble chemicals can reach the aquatic ecosys- tems or the groundwater. SSRIs have been shown to have a number of unwanted effects on aquatic organisms, such as the behavioural effect fluoxetine has on fish  and the induction of spawning and parturition in bivalves [16,17]. Fluoxetine is probably the most studied SSRI when it comes to effects on nontarget organisms, but ef- fects from the other SSRIs have been found as well.
OBJECTIVES: Adolescent depression and attempted and completed suicide are increasing in the United States. Because suicide is often impulsive, the means of self-harm are frequently items of convenience like medication. Authors of a recent study compared tricyclic antidepressant overdose to bupropion overdose. Fluoxetine and escitalopram are the only agents with Food and Drug Administration approval for pediatric depression, but off-label bupropion prescriptions are common. We sought to compare the effects of selective serotonin reuptake inhibitors (SSRIs) and bupropion in overdose.
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With regard to changes in BP caused by SSRIs versus SNRIs, WMDs were significantly different, though the exact numerical values were small with variations of ,3 mmHg. A conclusion that fluctuations in BP were not significantly different in groups of SSRIs compared with placebo may be drawn from our meta-analysis, it may be inferred that SNRIs could lead to higher BP than SSRIs. Both in short-term and long-term duration, SNRIs were associated with escalation of SBP and DBP to some extent. These findings are consistent with conclusions drawn in the previous reports focusing on venlafaxine. 13,14 Mean BP 13 and supine DBP 14 increase with
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alize to children and adolescents in primary care. Future pediatric studies need to examine the use of SSRIs to treat attention-deficit/hyperactivity disorder and other diagnoses, safety of combination pharmacotherapy, and outcomes for children treated in primary care. In addition to considerations of potential overuse or inappropriate use of SSRIs, we must conversely evaluate issues of underdiagnosis and undertreatment of mental disorders. The lack of training and comfort of care of pediatric depression and mental illnesses cannot be overlooked. Training and continuing education must improve and change as new pharmacotherapies emerge. Finally, phy- sician specialty differences must be explored further to determine whether differences in physician SSRI pre- scription practices translate into different health out- comes for children and adolescents with mental illnesses. Pediatrics 2000;105(6). URL: http://www.pediatrics.org/ cgi/content/full/105/6/e82; serotonin uptake inhibitors, de- pression, primary health care, physician’s practice pat- terns, mental health services.
Duration of use for all SSRIs combined was based on the total number of SSRI prescriptions dispensed in each of the SSRI exposure time windows of interest (two or more years, two to seven years or more than seven years prior to index date). Since SSRI prescrip- tions in Saskatchewan are typically dispensed to accommodate a 34-day treatment period, this measure of SSRI use approximated the number of months exposed. For each exposure time period, duration of SSRI use was categorized on the basis of clinically rele- vant cut-offs with the intention of creating an upper- most category of SSRI users that included an adequate number of subjects. For the time periods two or more years and two to seven years prior to the index date, duration of SSRI was categorized as never, 1 to 35 pre- scriptions and ≥36 prescriptions. Due to the smaller number of subjects who had used SSRIs in the period of time more than seven years prior to index date, exposure categories chosen were never, 1 to 23 and ≥24 prescriptions.
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Despite many advances in SSRI therapies, as many as 30-40% of patients treated for depression with these drugs typically do not respond. 74-77 In addition, nearly 50% of those patients that do respond never fully achieve complete remission of their depressive symptoms. Moreover, many patients using SSRIs experience adverse side effects. These side effects include sexual dysfunction, 85 increased anxiety, gastrointestinal effects (nausea) 101 and insomnia. 76 Many patients also terminate their medication regiment due to slow-onset of action of the SSRIs. 102 In clinical environments it can take 2-6 weeks of continuous SSRI administration before antidepressant activity can be observed. In late 2004 media attention was given to a proposed link between SSRI use and juvenile suicide. 103,104
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This study had several strengths. The study cohort was col- lated using data from a computerized database on randomly sampled HBV-infected patients from all the HBV-infected patients in Taiwan, thus eliminating the possibility of selection bias. In addition, because the data on SSRIs and other medica- tion use were obtained from a historical database from which all the prescription information for the study period were available, the possibility of recall bias can be eliminated. We also clarified possible confounders from different medications. Furthermore, we conducted a sensitivity analysis by using case-control study design. The results showed that SSRI use had a potential protective effect on HCC development in a dose-responsive manner.
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sample size. However, when the most commonly used SSRIs were compared, citalopram or escitalopram were associated with the largest increase in body composition measures, whereas sertraline was no different from no SSRI treatment. Fluoxetine, on the other hand, was associated with significant increases, albeit of smaller magnitude. The citalopram and escitalopram results are consistent with findings from the Treatment of Resistant Depression in Adolescence (TORDIA) study in which citalopram and paroxetine showed a larger increase in BMI over 24 weeks when compared with fluoxetine and venlafaxine. 9 However, the magnitude
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With reference to “Overall completeness and applicability of evidence”, the review concludes that: “The data that inform this review are few and generally poor, in terms of the quality of the trials that ori- ginated them. Only five studies reported data on the most relevant clinical outcome, migraine frequency (two placebo and three amitriptyline-controlled) for a total of fewer than 300 participants. Reporting was often incomplete, making some studies uninformative. The applicability of this scarce evidence is also an issue, mainly because the analyzed studies used short follow-up and outcomes with a small clinical value. However, the findings of this review suggest that SSRIs and SNRIs do not show benefits for the outcomes that may matter to patients” .
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The finding that fluoxetine, and to a lesser extent, citalopram, increase noradrenaline efflux and inhibit [^H]noradrenaline uptake was interesting as these drugs are considered to selectively inhibit the uptake of 5-HT. It is conceded that the effects of citalopram (~50 |iM) and fluoxetine (~5 pM) on the noradrenergic system occurred at concentrations higher than their K\ s for inhibition of 5-HT reuptake in vitro (2.6 & 25 nM respectively; Thomas et al., 1987). However, the concentrations at which the SSRIs affected noradrenergic transmission were within a physiologically relevant range. As mentioned in earlier chapters, the extracellular concentration of fluoxetine after a single anticonvulsant dose (45 mg / kg) has been measured using microdialysis to be ~2- 3 pM (Dailey et a l, 1992). Other groups have also measured the brain concentration of fluoxetine to be -1 0 pM (Goodnough & Baker, 1994; see Chapter 3, Discussion). More recently, the plasma concentration of fluoxetine in depressed patients being treated with this drug has been reported to be between 0.2-1.5 pM (see Baumann, 1996). These findings suggest that the SSRIs, fluoxetine and citalopram at least, are merely preferential inhibitors of 5-HT uptake, which are unlikely to affect 5-HT uptake exclusively when these drugs are used clinically for the treatment of depressive illness.
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that frontal alpha asymmetry was related to metabolic activity in the amygdala (part of the limbic system), which was linked to emotion regulation. In the existing study, we found no significant correlation between EEG findings and the clinical manifestation of PMS [Tables 4-6 and Figures 4 and 5]. Numerous treatment modalities have been shown to be effective in the treatments of PMS, and counseling, including psychotherapy, medications as SSRIs (selective serotonin reuptake inhibitors). SSRIs are the most effective medication available at the present for treating PMDD, hormonal therapies, including oral contraceptive pills, danazol, GnRh analogue, progesterone, progestogens and surgical removal of the ovaries  . Selective serotonin reuptake inhibitors (SSRIs)
TCAs and Selective serotonin reuptake inhibitors metabolize majorly by cytochrome P 450 enzymes. Actually the drugs taken in combination and metabolise by the same enzyme produce potential for competitive inhibition. So in this way they increase the unexpected plasma level. For example fluoxetine and paroxetine (CYP 2D6), fluoxetine and nefazodone (CYP 3A4) cause the adverse effects and reduce the metabolic breakdown of co-prescribed drug. Antidepressants are usually prescribed in combination with antipsychosis drugs e.g. paroxetine + thioridazine (CYP 2D6), fluvoxamine + sertindole (CYP 3A4) and fluoxetine + olanzapine (CYP 1A2). There is inhibition of zuclopenthixol metabolism (CYP 2D6) due to fluoxetine or paroxetine and enhacement of this effect by the antipsychotic (CYP 2D6) cause to induce the over sedation and respiratory depression. Co-prescription of β adrenocptors with enzyme inhibiting antidepressants can cause to induce the antihypertensive effects. The inhibition of P 450 enzyme by Selective serotonin reuptake inhibitors increase the effects of alcohol, tramadol, methadone, terfenadine (risk of cardiac arryrhmia), and theophylline. [46-67]
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outcome measures, and medication efficacy across 12 clinical trials of selective serotonin reuptake inhibitors (paroxetine, fluvoxamine, fluoxetine, and sertraline) and clomipramine, finding a modest aggregate effect size relative to placebo (d = 0.46; 95% confidence interval 0.37–0.55). Clomipramine was significantly more effective in reducing obsessive- compulsive symptoms than paroxetine, fluvoxamine, fluox- etine, and sertraline, which were not significantly different from one another. However, clomipramine is not recom- mended as the first line of pharmacotherapeutic treatment for pediatric OCD due to side effects (eg, dry mouth, dizziness, fatigue, tremors, and cardiac complications). 20,46,47
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Theoretically, antidepressants such as selective serotonin reuptake inhibitors may have effects on coagulation, and some studies have explored their car- dioprotective effect. These studies have tended to be underpowered and explored outcomes in secondary care or other selected populations. Randomised con- trolled trials of antidepressants tend to be short term and underpowered to detect effects on cardiovascular outcomes, and observational studies of cardiovascular outcomes show conflicting results and many have not accounted for depression and so are susceptible to indication biases. The observational studies have either been restricted to or predominantly included older people, so uncertainty exists about associations in a younger age group, although antidepressants are often prescribed for depression in adults of working age. Antidepressants may have differential effects on cardiovascular outcomes according to age. A meta-analysis of 13 observational studies found that use of selective serotonin reuptake inhibitors was asso- ciated with a 40% increased risk of stroke, but this was significant only in studies restricted to older age groups and no significantly increased risk was seen in studies with no age restriction, although none of the studies specifically focused on a younger age group. 9 Simi-
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Anxiety disorders are some of the most frequently occurring mental disorders in South Africa and can negatively impact on a patient`s quality of life and disrupt important activities of daily living. They are a result of abnormal neurotransmitter function within the central nervous system. Abnormal functioning of neurochemicals as well as abnormal chemoreceptor activity lead to anxiety. There are various neurotransmitters that are involved in anxiety such as serotonin, glutamate, gamma-amino butyric acid. Treatment options for anxiety disorders include lifestyle modifications, psychotherapy and pharmacotherapy. Several drug classes are indicated for the management of anxiety disorders with selective serotonin reuptake inhibitors considered as first-line therapy. Benzodiazepines are effective in reducing anxiety symptoms, but their use is often limited by the risk of abuse and adverse-effect profile. Pharmacists should be aware of adverse drug reactions and drug interaction for the various medications used in the treatment of anxiety disorders. Lifestyle modifications are as important as pharmacotherapy.
89 potentially serious DDI pairs were identified, with bleed- ing risk as the most common, particularly with selective serotonin-reuptake inhibitors (SSRIs). Other potential DDIs included lithium toxicity with SSRIs, ventricular arrhyth- mias with tricyclic antidepressants (TCAs), and central nervous system toxicity with TCAs and monoamine oxidase inhibitors (MAOIs).
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(n=165); the depression observation group (n=121); the anxiety control group (n=100); and the anxiety observation group (n=72). The two control groups only received treatment with SSRIs, while the two observation groups received treatment with mirtazapine in combi- nation with SSRIs. The diagnosis of patients with depression and/or anxiety was based on criteria from the Chinese Classification and Diagnostic Standard for Mental Diseases, Edition 3 . All patients had single depres- sion or anxiety, with no antidepressant treat- ment history before admission, had no allergic reactions to mirtazapine or SSRIs, and had no familial mental disease or organic psychosis. Patients with repeated suicidal thoughts or self-injurious behaviors, and those unable to communicate due to serious dementia, apha- sia, consciousness disturbance, or alcohol abu- se, were excluded. This study was approved by the Ethics Committee of the authors’ hospital, Table 1. General Information