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Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats Role of serotonin synthesis

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Abstract

We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance.

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... As an example of the problem, we are aware of just two preclinical studies that directly address the behavioural effects of SSRI discontinuation. One study reported an enhanced acoustic startle response in rats 2 days after discontinuation from repeated treatment with citalopram (Bosker et al., 2010). Another study reported increased locomotor behaviour 4 h after the first 'missed dose' of repeated fluoxetine in rats, and this effect dissipated within 4 days (Bjork et al., 1998). ...
... Testing commenced either 18 h (once daily) or 6 h (twice daily) after the last injection. The 5-day discontinuation period was based on previous rodent experiments reporting discontinuation effects (Bosker et al., 2010;Trouvin et al., 1993) and aimed to capture the timeframe when paroxetine and citalopram fall to undetectable levels in the blood plasma (Benmansour et al., 1999;Cremers et al., 2000). An initial exploratory investigation of paroxetine used mixed sex groups (six males, six females per group) and revealed sexually dimorphic effects. ...
... The evidence of altered EPM performance within 2 days of discontinuation from paroxetine and citalopram is consistent with the short half-lives of these drugs in rodents (6.3 h and 1.5 h, respectively) (Fredricson Overø, 1982;Kreilgaard et al., 2008), and an abrupt fall in brain levels of the drug once drug administration has stopped. Moreover, a rapid appearance of a discontinuation effect on the EPM is consistent with earlier evidence of heightened startle responsivity in rats 2 days after discontinuation from repeated treatment with citalopram (Bosker et al., 2010). Our finding also fits with the clinical picture that SSRIs such as paroxetine, which have a short half-life in humans, are particularly problematic with patients often experiencing discontinuation effects within 2 days of treatment cessation (Fava et al., 2015;Michelson et al., 2000;Rosenbaum et al., 1998). ...
Article
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Background Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals. Aim Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice. Methods Experiments were based on a three-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5-day period using the elevated plus maze (EPM) and other anxiety tests. Results An exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open-arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open-arm exploration but this was dissociable from the effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days of treatment but was absent after 7 days of treatment. A discontinuation response was not discernible in other anxiety and fear-learning tests applied 3–5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity. Conclusion Overall, this study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.
... As an example of the problem, we are aware of just two preclinical studies that directly address the behavioural effects of SSRI discontinuation. One study reported enhanced acoustic startle response in rats 2 days after discontinuation from repeated treatment with citalopram (Bosker et al., 2010). Another study reported increased locomotor behaviour 4 h after the first "missed dose" of repeated fluoxetine in rats, and this effect dissipated within 4 days (Bjork et al., 1998). ...
... Testing commenced either 18 h (oncedaily) or 6 h (twice-daily) after the last injection. The 5 day discontinuation period was based on previous rodent experiments reporting discontinuation effects (Bosker et al., 2010;Trouvin et al., 1993), and aimed to capture the timeframe when paroxetine and citalopram fall to undetectable levels in the blood plasma (Benmansour et al., 1999;Cremers et al., 2000). An initial exploratory investigation of paroxetine used mixed sex groups (6 males, 6 females per group) and revealed sexually dymorphic effects. ...
... The evidence of increased anxiety-like behaviour within 2 days of discontinuation from paroxetine and citalopram is consistent with the short half-lives of these drugs in rodents (6.3 h and 1.5 h, respectively) (Kreilgaard et al., 2008;Fredricson Overø, 1982), and an abrupt fall in brain levels of the drug once drug administration has stopped. Moreover, a rapid appearance of an anxiogenic effect would be consistent with earlier evidence of heightened startle responsivity in rats 2 days after discontinuation from repeated treatment with citalopram (~24 mg/kg per day for 15 days) (Bosker et al., 2010). Our finding also fits with the clinical picture that SSRIs like paroxetine which have a short half-life in humans are particularly problematic in terms of discontinuation effects which can onset within days of treatment cessation (Rosenbaum et al., 1998;Michelson et al., 2000;Fava et al., 2015). ...
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Background Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is often associated with a discontinuation syndrome, typified by numerous disabling symptoms including elevated anxiety, which is of unknown cause. Aim Here, the effect of SSRI discontinuation on anxiety-like behaviour was investigated in mice. Methods Mice were treated repeatedly with paroxetine, citalopram or saline using a 3-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed over 5 days after SSRI discontinuation using the elevated plus maze (EPM) and other anxiety tests. Results In an exploratory experiment mice discontinued (2 days) from paroxetine (12 days) showed evidence of increased anxiety on the EPM, although this effect was observed in male and not female mice. Follow-up studies confirmed the EPM findings in male mice discontinued (2 days) from paroxetine (12 or 28 days) or citalopram (12 days) compared to saline controls. Continued treatment with paroxetine was also anxiogenic on the EPM but this was not the case for citalopram. Paroxetine exposure for more than a week was required to elicit evidence of a discontinuation response, which did not obviously strengthen with increased frequency or duration of dose. Finally, SSRI discontinuation effects were not resolvable from continued treatment in other anxiety tests applied between 3 and 5 days post-discontinuation. Conclusion Overall, the current study provides evidence for a short-lasting increase in anxiety-like behaviour in mice following SSRI discontinuation, and offers a means for the investigation of the neurobiological mechanisms involved.
... This distinction is important to consider in the field of experimental models, where ADS-and withdrawal-like symptoms also overlap. While substance abuse typically impairs central dopaminergic reward circuits (Renoir, 2013), ADS is mainly associated with serotonin deficits (Bosker et al., 2010) (note that ADS-related mania may stem from abnormal subcortical activity modulated by the frontolimbic circuits (Kwok and Lim, 2017)). Nevertheless, both ADS and drug withdrawal evoke similar clinical symptoms, including sleep disturbances, anxiety, fretfulness, gastrointestinal and other problems (Schlienz et al., 2017), as well as sweating, tremor and vomiting (Rastegar et al., 2017). ...
... Its multiple mental and body symptoms ( (Renoir, 2013). Antidepressants tend to reduce serotonin and 5-HIAA levels and SERT binding, and mRNA responses during treatment, with a reduction of effect back to control conditions within a 2-14-day washout (Benmansour et al., 2002;Bosker et al., 2010;Caccia et al., 1993;Horschitz et al., 2001;Neumaier et al., 1996;Trouvin et al., 1993). The downregulation of 5-HT 1B mRNA in rat dorsal raphe nucleus by chronic 8-week paroxetine and fluoxetine exposure is reversed 3 days after discontinuation, also consistent with the timeline of ADS symptoms occurring clinically (Anthony et al., 2000). ...
... Exaggerated acoustic startle (likely resembling anxiety/agitation in ADS), increased serotonin turnover (Bosker et al., 2010) Imipramine/TCA (rats) 7 days Increased swim immobility "despair" (may also be relevant to clinical ADS-related weakness and fatigue) (Harvey et al., 2002) (mice) 7 days Increased stress vulnerability associated with lowered IL-4 and IL-10 levels (likely resembling anxiety/agitation in ADS) (Han et al., 2015) 3 or 7 days Elevated IL-2 and IL-4 levels 3 days after acute treatment, affected levels of IL-1α, IL-5, IL-10 and IL-12 after a 7-day discontinuation from acute or chronic treatment (Kusmider et al., 2017) Tianeptine/Atypical + fluoxetine/SSRI (mice) 21 days Increased anxiety and immobility time in selectively bred HAB mice (likely resembling ADS catatonia) (Sah et al., 2012) ...
... This distinction is important to consider in the field of experimental models, where ADS-and withdrawal-like symptoms also overlap. While substance abuse typically impairs central dopaminergic reward circuits (Renoir, 2013), ADS is mainly associated with serotonin deficits (Bosker et al., 2010) (note that ADS-related mania may stem from abnormal subcortical activity modulated by the frontolimbic circuits (Kwok and Lim, 2017)). Nevertheless, both ADS and drug withdrawal evoke similar clinical symptoms, including sleep disturbances, anxiety, fretfulness, gastrointestinal and other problems (Schlienz et al., 2017), as well as sweating, tremor and vomiting (Rastegar et al., 2017). ...
... Its multiple mental and body symptoms ( (Renoir, 2013). Antidepressants tend to reduce serotonin and 5-HIAA levels and SERT binding, and mRNA responses during treatment, with a reduction of effect back to control conditions within a 2-14-day washout (Benmansour et al., 2002;Bosker et al., 2010;Caccia et al., 1993;Horschitz et al., 2001;Neumaier et al., 1996;Trouvin et al., 1993). The downregulation of 5-HT 1B mRNA in rat dorsal raphe nucleus by chronic 8-week paroxetine and fluoxetine exposure is reversed 3 days after discontinuation, also consistent with the timeline of ADS symptoms occurring clinically (Anthony et al., 2000). ...
... Exaggerated acoustic startle (likely resembling anxiety/agitation in ADS), increased serotonin turnover (Bosker et al., 2010) Imipramine/TCA (rats) 7 days Increased swim immobility "despair" (may also be relevant to clinical ADS-related weakness and fatigue) (Harvey et al., 2002) (mice) 7 days Increased stress vulnerability associated with lowered IL-4 and IL-10 levels (likely resembling anxiety/agitation in ADS) (Han et al., 2015) 3 or 7 days Elevated IL-2 and IL-4 levels 3 days after acute treatment, affected levels of IL-1α, IL-5, IL-10 and IL-12 after a 7-day discontinuation from acute or chronic treatment (Kusmider et al., 2017) Tianeptine/Atypical + fluoxetine/SSRI (mice) 21 days Increased anxiety and immobility time in selectively bred HAB mice (likely resembling ADS catatonia) (Sah et al., 2012) ...
Article
Antidepressant drugs are currently one of the most prescribed medications. In addition to treatment resistance and side effects of antidepressants, their clinical use is further complicated by antidepressant discontinuation syndrome (ADS). ADS is a common problem in patients following the interruption, dose reduction, or discontinuation of antidepressant drugs. Clinically, ADS resembles a classical drug withdrawal syndrome, albeit differing from it because antidepressants generally do not induce addiction. The growing clinical importance and prevalence of ADS necessitate novel experimental (animal) models of this disorder. Currently available preclinical models of ADS are mainly rodent-based, and study mostly serotonergic antidepressants and their combinations. Here, we systematically assess clinical ADS symptoms and discuss current trends and challenges in the field of experimental (animal) models of ADS. We also outline basic mechanisms underlying ADS pathobiology, evaluate its genetic, pharmacological and environmental determinants, and emphasize how using animal models may help generate important translational insights into human ADS condition, its prevention and therapy.
... The resulting increase of monoamines at synaptic sites may cause an initial increase in anxiety levels (Browning et al., 2007;Grillon et al., 2007). As chronic treatment persists, adaptive changes seem to occur and therapeutic anxiolytic effects can be seen (Bosker et al., 2010). While many monoaminergic re-uptake inhibitors have a limited selectivity and affect serotonergic, norepinephrinergic and dopaminergic systems, clomipramine has a high potency as a serotonin and norepinephrine re-uptake inhibitor, but very limited effects on the dopaminergic system. ...
... Previous studies have seen either no change in baseline startle by serotonergic modulation in rats (Geyer and Tapson, 1988;Martinez and Geyer, 1997) or an increase of baseline startle in humans after acute modulations (Liechti et al., 2001;Browning et al., 2007;Grillon et al., 2007). Quednow et al. (2004) also found a trend for an increase in baseline startle in humans after two weeks of SSRI administration, however, studies on chronic SSRI administration in rats showed a reduced startle response (Bosker et al., 2010;Homberg et al., 2011). Serotonergic raphe neurons have been shown to directly project to startle neurons in the caudal pontine reticular formation (PnC) (Steinbusch, 1981;Kolta Figure 3 Prepulse inhibition with 75 dB prepulse intensity. ...
... Chronic administration of the SSRI sertraline decreased habituation in patients with major depression (Quednow et al., 2004). Accordingly, studies on chronic SSRI administration in rats showed a reduced startle response, and reduced habituation (Bosker et al., 2010;Homberg et al., 2011). Norepinephrine has also been suggested to oppose habituation by increasing sensitization (Adams and Geyer, 1981). ...
Article
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Many patients with depression have comorbidities associated with an impairment of sensorimotor gating, such as e.g. schizophrenia, Parkinson Disease, or Alzheimer disease. Anti-depressants like clomipramine that modulate serotonergic or norepinephrinergic neurotransmission have been shown to impact sensorimotor gating, it is therefore important to study potential effects of clomipramine in order to rule out an exacerbation of sensorimotor gating impairment. Prior studies in animals and humans have been inconclusive. Since serotonin and norepinephrine levels are closely related to anxiety and stress levels and therefore to the social status of an animal, we tested the hypothesis that acute and chronic effects of clomipramine on sensorimotor gating are different in dominant versus subordinate rats, which might be responsible for conflicting results in past animal studies. We used habituation and prepulse inhibition (PPI) of the acoustic startle response as operational measures of sensorimotor gating. After establishing the dominant animal in pair-housed male rats, we injected clomipramine for two weeks and measured acute effects on baseline startle, habituation and PPI after the first injection and chronic effects at the end of the two weeks. Chronic treatment with clomipramine significantly increased habituation in subordinate rats, but had no effect on habituation in dominant animals. Furthermore, PPI was slightly enhanced in subordinate rats upon chronic treatment while no changes occurred in dominant animals. We conclude that the social status of an animal, and therefore the basic anxiety/stress level determines whether or not clomipramine has a beneficial effect on sensorimotor gating and discuss possible underlying mechanisms.
... One such change is a decline in extracellular serotonin during chronic SSRI treatment that eventually comes back to the premedication equilibrium (Fig. 4) (Popa et al., 2010;Smith et al., 2000). This decline is due to the fact that all ADM classes inhibit the synthesis of serotonin (Bosker et al., 2010;Esteban et al., 1999;Honig et al., 2009;Moret and Briley, 1996;Muck-Seler et al., 1996;Siesser et al., 2013;Yamane et al., 1999Yamane et al., , 2001. Over chronic treatment, the cumulative effects of the inhibition of synthesis cause total (intracellular + extracellular) serotonin levels to decline (Fig. 5) (Bosker et al., 2010;Honig et al., 2009;Marsteller et al., 2007;Siesser et al., 2013). ...
... This decline is due to the fact that all ADM classes inhibit the synthesis of serotonin (Bosker et al., 2010;Esteban et al., 1999;Honig et al., 2009;Moret and Briley, 1996;Muck-Seler et al., 1996;Siesser et al., 2013;Yamane et al., 1999Yamane et al., , 2001. Over chronic treatment, the cumulative effects of the inhibition of synthesis cause total (intracellular + extracellular) serotonin levels to decline (Fig. 5) (Bosker et al., 2010;Honig et al., 2009;Marsteller et al., 2007;Siesser et al., 2013). ...
... By 28 days, fluoxetine exposed rats were statistically indistinguishable from control rats. Reprinted with permission from Bosker et al. (2010). (Mitchell, 2005). ...
... However, since several clinical observations point to the existence of tolerance phenomena during antidepressant treatment in some cases (Fava and Offidani, 2011), further animal research is required to determine the dependence potential of the various types of antidepressant drugs. In an attempt to compare and contrast the mechanisms underlying the effects of continuous SSRI administration against abrupt SSRI discontinuation, Bosker and colleagues measured the acoustic startle response of rats that had either been receiving 2 weeks of citalopram or had undergone 48 h of discontinuation from citalopram treatment (Bosker et al., 2010 ). Behavioral assessments started 2 days after the removal of osmotic mini pumps filled with either saline or 50 mg/ml citalopram. ...
... Exaggerated acoustic startle response has been previously linked to anxiety-like behaviors in rodents (Plappert and Pilz, 2002 ). Therefore , the findings of Bosker et al. (2010) suggest a higher level of anxiety in the citalopram discontinuation group, which is similar to the increased incidence of anxiety in patients with the SSRI discontinuation syndrome. An increased reactivity to acoustic stimuli in rats has been linked to long-term depletion of serotonin in the brain (Tanke et al., 2008). ...
... An increased reactivity to acoustic stimuli in rats has been linked to long-term depletion of serotonin in the brain (Tanke et al., 2008). Consistent with that notion, Bosker et al. (2010) found that an index of serotonin turnover [the ratio of 5-hydroxyindoleacetic acid to serotonin (5-HIAA/5-HT)] was increased after the 48-h washout period following chronic citalopram treatment, while chronic treatment exerted no significant effect on serotonin turnover. This finding is in agreement with an earlier study reporting that levels of the serotonin metabolite 5-HIAA are increased during withdrawal from chronic fluoxetine (30 mg/kg/days for 21 days), and are sustained at levels exceeding control levels (by 30–50%) for at least 14 days after cessation of chronic fluoxetine treatment (Trouvin et al., 1993). ...
Article
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Besides demonstrated efficacy, selective serotonin reuptake inhibitors (SSRIs) hold other advantages over earlier antidepressants such as greater tolerability and a wider range of clinical applications. However, there is a growing body of clinical evidence which suggests that SSRIs could, in some cases, be associated with a withdrawal reaction upon cessation of regular use. In addition to sensory and gastrointestinal-related symptoms, the somatic symptoms of the SSRI discontinuation syndrome include dizziness, lethargy, and sleep disturbances. Psychological symptoms have also been documented, usually developing within 1-7 days following SSRI discontinuation. The characteristics of the discontinuation syndrome have been linked to the half-life of a given SSRI, with a greater number of reports emerging from paroxetine compared to other SSRIs. However, many aspects of the neurobiology of the SSRI discontinuation syndrome (or SSRI withdrawal syndrome) remain unresolved. Following a comprehensive overview of the clinical evidence, we will discuss the underlying pathophysiology of the SSRI discontinuation syndrome and comment on the use of animal models to better understand this condition.
... Numerous studies show that total serotonin content in brain regions decrease (rather than increase) during chronic antidepressant therapy [60][61][62][63][64][65][66][67][68][69]. Because extracellular serotonin does not go below the premedication equilibrium level during SSRI exposure, the decline in total brain serotonin content must be caused by a reduction in the intracellular serotonin pool ( Figure 2). ...
... Because extracellular serotonin does not go below the premedication equilibrium level during SSRI exposure, the decline in total brain serotonin content must be caused by a reduction in the intracellular serotonin pool ( Figure 2). All classes of effective antidepressants inhibit the synthesis of serotonin, which reduces the intracellular pool of serotonin available for neurotransmission [62,66,[70][71][72]. One study showed the dose-dependent inhibition of serotonin synthesis, with higher doses of fluoxetine causing greater inhibition [73]. ...
Article
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Antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) have complex temporal effects. They may worsen symptoms during early treatment, they may reduce depressive symptoms over several weeks of treatment, and they may lose effectiveness over more prolonged treatment or after repeated treatment trials. Conceptually, these effects fall within the domain of hormesis, which refers to a biphasic or multiphasic response to a drug or toxin. Hormetic effects are commonly triggered when a drug interacts with homeostatic mechanisms. We develop and evaluate a theoretical framework for understanding how adaptations to SSRIs that restore synaptic homeostasis may partially contribute to their hormetic effects. Specifically, the serotonin system adapts to SSRIs by suppressing the firing of serotonergic neurons, inhibiting the synthesis of serotonin, and reducing the overall content of serotonin in the brain. Moreover, rodent models such as inescapable shock show that serotonin neurotransmission to specific forebrain regions is a necessary, but insufficient cause of depressive symptoms. Our review suggests: (1) early worsening of symptoms may be related to the direct effects of SSRIs on synaptic serotonin; (2) the symptom-reducing effects could be related to the loss of serotonin content in the brain during SSRI exposure; (3) the loss of efficacy over prolonged exposure could be related to the central nervous system equilibrating to the SSRIs. The serotonin system’s adaptations to SSRIs may play a clinically meaningful role in their hormetic effects on depressive symptoms. A complete understanding of SSRIs’ hormetic effects will require exploring temporal dynamics in other neurotransmitter systems.
... The increase in locomotor activity suggests a withdrawal phenomenon that is not unlike the agitation and anxiety experienced in patient with ADS (Table 1). Similarly, rats chronically treated with citalopram for 2 weeks, or following citalopram discontinuation for 48 h, displayed an exaggerated acoustic startle response, also a surrogate marker of anxiety-like behaviour (Bosker et al., 2010). Interestingly, these authors also found that 5-HT turnover (the ratio of 5-hydroxy indole acetic acid vs 5-HT) increased after the 48-h washout period following the chronic treatment period, while chronic treatment did not affect the 5-HT turnover (Bosker et al., 2010). ...
... Similarly, rats chronically treated with citalopram for 2 weeks, or following citalopram discontinuation for 48 h, displayed an exaggerated acoustic startle response, also a surrogate marker of anxiety-like behaviour (Bosker et al., 2010). Interestingly, these authors also found that 5-HT turnover (the ratio of 5-hydroxy indole acetic acid vs 5-HT) increased after the 48-h washout period following the chronic treatment period, while chronic treatment did not affect the 5-HT turnover (Bosker et al., 2010). Some authors have proposed that ADS symptoms such as anxiety, low mood and tearfulness (Table 1), as well as negative mood states (see Lane, 2014), reflect an adverse effect of the SRI on the DA reward system (Gardier et al., 1994;Renoir, 2013). ...
Article
Objective Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology.DesignThe relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS.ResultsAltered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems.Conclusions This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome. Copyright © 2014 John Wiley & Sons, Ltd.
... Notably, many of these changes persisted for up to 2 weeks in rodent models [16], with 17 days in rats equivalent to a human year [34]. Consistent with this, in animals, long-term treatment with antidepressants produces a reduction in endogenously synthesised levels of serotonin detected [35] after an initial increase [36], although this phenomenon has not been studied in humans. In one study that measured changes for longer, 14 days of fluoxetine treatment in rats produced a reduced oxytocin response that was still present 60 days after drug cessation-four times longer than the period of treatment [16,37]. ...
Article
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Adaptation of the brain to the presence of a drug predicts withdrawal on cessation. The outcome of adaptation is often referred to as ‘physical dependence’ in pharmacology, as distinct from addiction, although these terms have unfortunately become conflated in some diagnostic guides. Physical dependence to antidepressants may occur in some patients, consistent with the fact that some patients experience withdrawal effects from these medications. It is thought that longer duration of use, higher dose and specific antidepressants affect the risk of antidepressant withdrawal effects as they might cause greater adaptation of the brain. We searched PubMed for relevant systematic reviews and other relevant analyses to summarise existing data on determinants of antidepressant withdrawal incidence, severity and duration. Overall, data were limited. From survey data, increased duration of use was associated with an increased incidence and severity of withdrawal effects, consistent with some evidence from data provided by drug manufacturers. Duration of use may be related to duration of withdrawal effects but data are heterogenous and sparse. Serotonin and noradrenaline reuptake inhibitors and paroxetine are associated with higher risks than other antidepressants, though data for some antidepressants are lacking. Higher doses of antidepressant has some weak association with an increased risk of withdrawal, with some ceiling effects, perhaps reflecting receptor occupancy relationships. Past experience of withdrawal effects is known to predict future risk. Based on these data, we outline a preliminary rubric for determining the risk of withdrawal symptoms for a particular patient, which may have relevance for determining tapering rates. Given the limited scope of the current research, future research should aim to clarify prediction of antidepressant withdrawal risk, especially by examining the risk of withdrawal in long-term users of medication, as well as the severity and duration of effects, to improve the preliminary tool for predictive purposes. Further research into the precise adaptations in long-term antidepressant use may improve the ability to predict withdrawal effects for a particular patient.
... These findings suggest that in the long-term antidepressants might produce compensatory changes [72] that are opposite to their acute effects [73,74]. Lowered serotonin availability has also been demonstrated in animal studies following prolonged antidepressant administration [75]. Further research is required to clarify the effects of different drugs on neurochemical systems, including the serotonin system, especially during and after long-term use, as well as the physical and psychological consequences of such effects. ...
Article
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The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
... Arguably, the strongest evidence for a pharmacological mechanism is inferred by rapid resolution of discontinuation symptoms by reinitiation of SSRI medication or, when symptoms emerge with a decrease in the dosage, by an increase in dosage. This is supported by animal studies in which discontinuation of chronic SSRI treatment has been associated with increased turnover of serotonin and reduced extracellular serotonin levels, along with an increased acoustic startle reflex, suggesting that reduced serotonin levels may account for anxiety-like discontinuation symptoms (72). ...
... For example, several lines of evidence suggest that regulation of serotonin synthesis through the modulation of TPH2 enzyme activity, which can be assessed using the decarboxylase inhibition method, is important for the therapeutic effects of SSRIs. Using this method, chronic treatment with the SSRI citalopram decreased 5-HTP accumulation, thereby indicating decreased TPH2 activity, in forebrain regions (Honig et al., 2009;Bosker et al., 2010). Alternatively, a role for modulation of serotonergic neuronal firing rates in the dorsal raphe nucleus (DR), which contains the majority of the forebrain-projecting serotonergic neurons, has been suggested. ...
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Although the neurobiological mechanisms underlying autism spectrum disorder (ASD) are still unknown, dysregulation of serotonergic systems has been implicated in the etiology of ASD and serotonergic antidepressant drugs are often prescribed to treat some symptoms of ASD. The BALB/c strain of mice, express a dysregulated serotonergic system and a phenotype that is relevant to ASD. In this study, juvenile male BALB/c mice were exposed to the selective serotonin reuptake inhibitor fluoxetine either chronically (18 mg/kg/day in drinking water, post-natal day (PND) 28 to 39) or acutely (18 mg/kg, i.p.; PND40), or to vehicle control conditions (0.9% sterile saline, i.p.; PND40), prior to being exposed to the three-chambered sociability test (SAT; PND40). One cohort of mice then received an injection of the aromatic amino acid decarboxylase inhibitor, NSD-1015, and, one hour later, brain tissue was collected for quantification of 5-hydroxytryptophan accumulation in the dorsal raphe nucleus (DR) as a measure of TPH2 activity. For the second cohort, brain tissue was collected ninety minutes after the onset of the social phase of the SAT and prepared for immunohistochemical staining for c-Fos and TPH2 to measure the activation of serotonergic neurons within subregions of the DR. Acute fluoxetine decreased social behavior, while chronic fluoxetine increased social behavior compared with vehicle-treated controls. Furthermore, acute and chronic fluoxetine treatments were without effect on TPH2 activity but differentially affected populations of serotonergic neurons in the DR. These data are consistent with the hypothesis that serotonergic systems are implicated in social behavior that is relevant for ASD.
... One article even hypothesized that depression is a result of elevated 5-HT concentration rather than deficiency of 5-HT (Andrews et al., 2015). The evidence challenging the low 5-HT hypothesis may be summarized as the following three categories: first, the rapid increase of 5-HT concentration in the synaptic cleft of neurons is inconsistent with the clinical delayed onset of antidepressant efficacy; second, lowering the concentration of 5-HT in synaptic cleft through tryptophan depletion (Ruhé et al., 2007) or serotonin transporter (SERT) enhancer (i.e., Tinaptine; Kasper and McEwen, 2008) failed to induce depression in healthy subjects, actually long-term antidepressants treatment had been detected to downregulating the total 5-HT concentration in the brain (Marsteller et al., 2007;Bosker et al., 2010;Siesser et al., 2013), which was contrary to the common sense of low 5-HT in depression; and third, genetic variants associated with potentiated SERT function (l allele of 5-HTTLPR) have been repeatedly found to be related with reduced risk of depression or better prognosis than variants associated with decreased SERT function (s allele of 5-HTTLPR; Karg et al., 2011). A timeline of historical publications or events supporting or opposing the monoamine hypothesis is shown in Figure 1. ...
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... This condition may further be deteriorated with SSRI administration, as long-term administration of SSRIs has been reported to decrease serotonin synthesis by 60%, although synaptic serotonin levels were elevated. It is the endogenous mechanism that leads to reduced synthesis of serotonin when its uptake is blocked [38]. As treatment of depression requires long-term administration, administering ADs such as SSRIs may further decrease overall serotonin levels, which may lead to a proconvulsant effect with prolonged therapy. ...
... Our previous study exposed bass to higher concentrations of venlafaxine and found a similar lack of effect on norepinephrine [15]. Although venlafaxine is marketed as a serotonin and norepinephrine reuptake inhibitor, it has an order of magnitude lower affinity for the norepinephrine transporter when compared with the serotonin transporter in mammalian systems [25,26]. This translates into needing an order of magnitude higher concentration of venlafaxine to have a similar effect on norepinephrine as that seen on serotonin. ...
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... Interestingly, in this simulation we did observe a constant synthesis of 5-HT when administering SSRIs ( Figure 4B). This result suggests that other pathways might be interacting with 5-HT, as has also been implied by the results of other studies [37,38]. However, care should be taken when considering this possibility because the model cannot consider the effects of 5-HT concentration on its homeostasis. ...
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This chapter resumes applications of PET in neurological and psychiatric disease and research. Routine applications and recent developments in [18F]FDG-PET are dealt with, followed by the role of amyloid PET as inclusion parameter in clinical trials. A large series of PET tracers do target neurotransmitter signaling at various steps. This serves as a tool to decipher the pathophysiology of disease as well as to conduct pharmacokinetic and dose-finding studies of new drug candidates. After presenting the different types of experimental approaches, an overview of targets is given that had been imaged thus far by PET in the human brain. Taken together, PET imaging always accompanied and catalyzed the emergence of new technologies – may it be deep brain stimulation or new biomarkers – at the threshold to routine.
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Selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, are widely used to treat depressive disorders in pregnant women. These antidepressants effectively penetrate through the placental barrier, affecting the fetus during the critical phase of neurodevelopment. Some clinical studies have linked prenatal exposure to SSRIs with increased neonatal mortality, premature birth, decreased fetal growth and delay in psychomotor development. However, the effects of prenatal exposure to SSRIs remain unknown. The administration of SSRIs in rodents during the first postnatal weeks is considered as an model for studying the effects of prenatal SSRIs exposure in human. The aim of this work was to study the acute effects of chronic fluvoxamine (FA) administration in white rat pups. The study was carried out in male and female rat pups treated with FA (10 mg/kg/day, intraperitoneally) from postnatal days 1 to 14. The lethality level, body weight, age of eye opening, and motor reflex maturation were recorded. The contents of biogenic amines and their metabolites in different brain structures were also determined. It was shown that neonatal FA administration led to increased lethality level, reduced body weight, and delayed maturation of motor reflexes. Furthermore, increased noradrenalin level in hypothalamus, serotonin level in hippocampus and serotonin metabolite 5-HIAA level in frontal cortex, hypothalamus, hippocampus, and striatum were observed in drug-treated animals compared to the control group. We can conclude that the altered activity of the serotoninergic system induced by fluvoxamine administration at early developmental stages leads to a delay in physical and motor development.
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We questioned: what kind of relationships between mental and neurobiological levels of complexity is or could become useful in the psychiatric practice? The concept of mind and associated mood states defended here is that they are physically emergent, subjective, qualitative, unified features of the brain. We compared our neurobiological assessment also to psychoanalytical practice (first person's perspective). ARGUMENT: Applied to recent work on major depressive disorder (MDD), our ideas are among other supported by clinical and experimental studies on sleep deprivation, deep brain stimulation and epidemiological assessments of time-to-recovery. We suggest that depression is a transient state of the brain, that is mutually exclusive to the state of pleasure (in the Freudian context), rather than a disorder or disease with a characteristic time course (like many reversible somatic diseases). MDD can best be described with stochastic transition models, which is discussed in the context of a presumed brain serotonin dysfunction in depression. Our ideas invite a reconsideration of some concepts underlying current diagnostic and therapeutic approaches in the clinical practice.
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Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. Individual patient-level data were obtained from study authors. Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.
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The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.
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Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain. Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition. Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies.
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Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)gamma and tumor necrosis factor (TNF)alpha in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNgammaR(-/-) mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNgammaR(-/-) mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNgammaR(-/-) mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFNgamma, interleukin(IL)-1beta, TNFalpha, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNgammaR(-/-) mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNFalpha mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNgammaR(-/-) mice compared with WT controls. Pretreatment of mice with the TNFalpha antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFNgamma and TNFalpha synergized to induce IDO in primary microglia. Together, these data demonstrate that IFNgamma, with TNFalpha, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection.
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The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the α2C-autoreceptor modulating dopa/noradrenaline synthesis, and the α2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1–10 mg/kg), protriptyline (0.3–10 mg/kg) and nisoxetine (3–10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%–40%) and hippocampus (20%–53%). Fluoxetine (1–10 mg/kg) and zimelidine (1–10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%–43%) and hippocampus (27%–54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1–21 days) or fluoxetine (3 mg/kg for 3–21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1–21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%–37%, days 1–14) followed by recovery to control values (day 21). Fluoxetine (3–21 days) did not alter brain dopa synthesis. To further assess the desensitization of α2C-autoreceptors, α2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at α2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory α2C-autoreceptors, α2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.
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In major depression in humans and in animal models of depression, there is a defect in serotonergic neurotransmission that can be relieved by chronic antidepressant treatment. One possibility is that this pathologic state is caused by excessive presynaptic autoreceptor activity in serotonergic neurons, and that antidepressants down-regulate the number of these inhibitory receptors, allowing more normal serotonin release to occur. To evaluate this hypothesis, we measured the effects of the antidepressant fluoxetine on neuronal levels of 5-HT1B receptor mRNA, the putative serotonin terminal autoreceptor in rat brain, and on serotonin transporter mRNA, the direct site of fluoxetine binding. Fluoxetine reduced serotonin transporter mRNA briefly, but this was not sustained after 21 days of treatment. However, fluoxetine reduced dorsal raphe 5-HT1B mRNA levels in a time-dependent and washout-reversible manner. This reduction in 5-HT1B mRNA was specific to dorsal raphe nucleus and was not found in several postsynaptic (nonserotonergic) regions. These results suggest that chronic fluoxetine may increase serotonin release from axonal terminals by down-regulating the messenger RNA coding for presynaptic 5-HT1B autoreceptors while causing only transient effects on serotonin transporter mRNA. © 1996 American College of Neuropsychopharmacology
Article
The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.
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• Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, lowtryptophan diet followed the next morning by a 16—amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.
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Discontinuation symptoms are recognised with tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and miscellaneous antidepressants. A wide variety of symptoms have been described, differing somewhat between antidepressant classes, and several symptom clusters or discontinuation syndromes appear to exist. A common feature is onset within a few days of stopping the antidepressant or, less commonly, reducing the dosage. Discontinuation syndromes are clinically relevant as they are common, can cause significant morbidity, can be misdiagnosed leading to inappropriate treatment and can adversely effect future antidepressant compliance. Preventative strategies include tapering antidepressants prior to stoppage and educating patients and healthcare professionals to ensure that antidepressants are taken consistently and not stopped abruptly. Most reactions are mild and short-lived and require no treatment other than patient reassurance. Severe cases can be treated symptomatically or the antidepressant can be reinstated before being gradually withdrawn. Reinstatement usually leads to symptom resolution within 24 hours. Some individuals require very conservative tapering schedules to prevent the re-emergence of symptoms. With SSRIs and venlafaxine another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself. Neonatal discontinuation symptoms can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and doctor must take this into consideration when making prescribing decisions. Discontinuation symptoms have received little systematic study with the result that most of the recommendations made here are based on anecdotal data or expert opinion. Research is needed to provide a firm evidence base for future recommendations.
The monoamine hypothesis has dominated almost forty years the psychopathology of depression. Yet this has not lead to antidepressants that are significantly more efficacious than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic-pituitaryadrenal- axis are either too premature or have not lead to drugs with improved antidepressant activity. Antidepressants may not be perfect, both in terms of efficacy and side effects, however their performance may be improved by making use of so-called augmentation strategies. Augmentation strategies that have potential to hasten and/or improve the therapeutic effect of antidepressants, in particular serotonin reuptake inhibitors, can have different forms. They can be aimed at reducing comorbid symptoms, such as anxiety, or they may be directed to processes that counteract the effect of serotonin reuptake inhibitors. Examples of the latter are those involving 5-HT1A and 5-HT1B autoreceptors, 5-HT 2C receptors and the availability of tryptophan. Another option could be exploring neuropeptide/serotonin interactions. The various augmentation strategies are reviewed in the context of literature data regarding neurobiology and pharmacotherapy of major depression.
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In the first experiment raphe lesioned, sham operated and nonoperated rats were presented with 150 tones (50 at each of 3 intensities) a day for 5 days. No differences were found among the groups in the rate of startle response habituation either within or between sessions. However, overall levels of startle were much greater following raphe lesions and a tone by tone analysis indicated that this was caused by heightened tone-elicited sensitization in the raphe group. Further tests of startle sensitization in Experiment 2 found the raphe group to be more sensitized than the other groups by loud tones and footshocks but not by different levels of background white noise. The results support the theory that repetitive stimulus exposure produces both habituation and sensitization and that different neural systems may underly these two processes.
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Prior efforts to assess the impact of antidepressant use on risk of suicide attempt focused on antidepressant initiation or duration of use. Gaps remain in understanding risks associated with antidepressant discontinuation in the context of the drug regimen. We assessed the effects of antidepressant discontinuation on the risk of suicide attempt. We report a nested case-control study of suicide attempt with at least 12 months of prior observation. A retrospective cohort of 2.4 million patients with depression (ICD-9 codes 296.2, 296.3, 300.4, and 311), aged 5-89 years, was created using standard Healthcare Effectiveness Data and Information Set (HEDIS) criteria; from this cohort, cases (n = 10,456) and controls (n = 41,815) were selected for study. Data were from a large, national, longitudinal, integrated claims database of managed care enrollees in the United States from calendar years 1999 through 2006. Compared to controls, cases were more likely to have used antidepressants, to have had multiple antidepressants, and to have had prior depressive episodes and inpatient stays that involved depression. After adjusting for confounding due to depression severity, comorbidities, and other medications, antidepressant use showed a protective effect for suicide attempt (OR = 0.62, P < .001). Compared to prior therapy, antidepressant discontinuation had a significant risk for suicide attempt (OR = 1.61, P < .05). Antidepressant initiation had the highest risk for suicide attempt (OR = 3.42, P < .05), followed by titration (titration up, OR = 2.62; down, OR = 2.19; P < .05). Substantial confounding exists in examining the link between antidepressant use and suicide attempt, specifically regarding those factors associated with characteristics of depression. Antidepressant discontinuation showed a significant risk for suicide attempt, as did the period of an abbreviated trial, that is, stopping before a therapeutic regimen of 56 days had been reached. The highest risk was associated with initiation, a finding consistent with other studies, closely followed by periods of dosing changes and discontinuation. Patients should be closely monitored during these periods.
Article
Inflammation-induced activation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) causes depressive-like behavior in mice following acute activation of the innate immune system by lipopolysaccharide (LPS). Here we investigated the mechanism of IDO expression induced by LPS in primary cultures of microglia derived from neonatal C57BL/6J mice. LPS (10 ng/ml) induced IDO transcripts that peaked at 8h and enzymatic activity at 24h, resulting in an increase in extracellular kynurenine, the catabolic product of IDO-induced tryptophan catabolism. This IDO induction by LPS was accompanied by synthesis and secretion of the proinflammatory cytokines TNFalpha and IL-6, but without detectable IFNgamma expression. To explore the mechanism of LPS-induced IDO expression, microglia were pretreated with the c-Jun-N-terminal kinase (JNK) inhibitor SP600125 for 30 min before LPS treatment. We found that SP600125 blocked JNK phosphorylation and significantly decreased IDO expression induced by LPS, which was accompanied by a reduction of LPS-induced expression of TNFalpha and IL-6. Collectively, these data extend to microglia the property that LPS induces IDO expression via an IFNgamma-independent mechanism that depends upon activation of JNK. Inhibition of the JNK pathway may provide a new therapy for inflammatory depression.
Article
The influence of citalopram on regional 5-hydroxytryptamine (serotonin, 5-HT) synthesis, one of the most important presynaptic parameters of serotonergic neurotransmission, was studied. Sprague-Dawley (SPD) rats were used as the controls, and Flinders Resistant Line (FRL) rats were used as auxiliary controls, to hopefully obtain a better understanding of the effects of citalopramon Flinders Sensitive Line (FSL; "depressed") rats. Regional 5-HT synthesis was evaluated using a radiographic method with a labelled tryptophan analog tracer. In each strain of rats, the animals were treated with citalopram (10 mg/(kg day)) or saline for 14 days. The groups consisted of between fourteen and twenty rats. There were six groups of rats with citalopram (CIT) and saline (SAL) groups in each of the strains (SPD-AL, SPD-IT, FRL-AL, FRL-IT, FSL-AL and FSL-IT). A two-factor analysis of variance was used to evaluate the effect of the treatment c., SPD-SAL relative to SPD-CIT) followed by planned comparisons to evaluate the effect in each brain region. In addition, the planned comparison with appropriate contrast was used to evaluate a relative effects in SPD relative to FSL and FRL, and FSL relative to FRL groups. A statistical analysis was first performed in the a priori selected regions, because we had learned, from previous work, that it was possible to select the brain regions in which neurochemical variables had been altered by the disorder and subsequent antidepressant treatments. The results clearly show that citalopram treatment does not have an overall effect on synthesis in the control SPD rats; there was no significant (p > 0.05) difference between the SPD-SAL and SPD-CIT rats. In "depressed" FSL rats, citalopram produced a significant (p < 0.05) elevation of synthesis in seventeen out of thirty-four regions, with a significant (p < 0.05) reduction in the dorsal and median raphe. In the FRL rats, there was a significant (p < 0.05) elevation in the synthesis in twenty-two out of thirty-four brain regions, with a reduction in the dorsal raphe. In addition to these regions magnus raphe was different in the SPD and FSL groups, but it was on the statistical grounds identified as an outlier. There were significant changes produced in the FSL and FRL rats in thirteen out of seventeen a priori selected brain regions, while in the SPD rats, citalopram produced significant changes in only four out of seventeen a priori selected regions. The statistical evaluation also revealed that changes produced by citalopram in the FSL and FRL rats were significantly greater than those in the SPD rats and that there was no significant difference between the effect produced in the FSL and FRL rats. The presented results suggest that in "depressed" FSL rats, the antidepressant citalopram elevates 5-HT synthesis, which probably in part relates to the reported improved in behaviour with citalopram.
Article
In Experiment 1, body weights of rats fed a powdered tryptophan-free (TF) diet decreased monotonically during a 13-day period. Control animals fed the same diet supplemented with 0.5% L-tryptophan gained weight. The groups did not differ significantly in acoustic startle amplitude measured at 2, 4, 6, 7, 9, 11, and 13 days despite a 28% decrease in whole-brain serotonin in the TF rats. In Experiment 2, daily intubation of rats with a syrup form of each diet maintained the two groups' body weights at comparable levels. TF diet intubation decreased whole-brain serotonin by 64% and produced significantly elevated startle amplitudes, which returned to control levels when 0.5% L-tryptophan was added to the diet. Changes in whole-brain serotonin level preceded changes in startle amplitude by several days. In Experiment 3, acute injections of 125 mg/kg L-tryptophan significantly reduced the startle amplitude of TF diet intubated rats and significantly raised their brain serotonin levels. The results show that acoustic startle reflex is increased by a TF diet, provided the animals receive adequate nourishment, and suggest that this facilitation may result from depletion of brain serotonin.
Article
The activity of tryptophan and tyrosine hydroxylase were estimated in vivo by measuring the accumulation during 30 min of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA), respectively, after inhibition of aromatic amino acid decarboxylase by administration of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). Whereas the activity of tyrosine hydroxylase in the dopamine-rich striatum was sensitive to haloperidol, which caused a significant increase in accumulation of DOPA, there was no effect of haloperidol in the predominantly noradrenergic frontoparietal cortex, confirming that the activity of tyrosine hydroxylase, measured in the frontoparietal cortex, is essentially localized in noradrenergic neurones. In the frontoparietal cortex of the rat the in vivo activity of tryptophan and tyrosine hydroxylase were equipotently attenuated by imipramine, while the selective blocker of the uptake of noradrenaline, desipramine and the selective blocker of the uptake of serotonin, citalopram, reduced only tyrosine or tyrosine hydroxylase respectively. Milnacipran, an antidepressant which inhibits the uptake of both monoamines to a similar extent, decreased the synthesis of both monoamines equipotently. The monoamine oxidase inhibitor, clorgyline, also reduced the synthesis of both monoamines. Thus, the in vivo inhibition of the synthesis of monoamines would appear to be mediated by an increase in synaptic concentration of monoamines, resulting from the inhibition of the uptake or catabolism of monoamines. Chronic administration of citalopram led to a significant increase of the basal synthesis of 5-hydroxytryptamine (5-HT). Milnacipran, given chronically, significantly enhanced the basal synthesis of both 5-HT and noradrenaline (NA).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The pharmacokinetics and clinical properties of clomipramine, the classic 5-HT uptake inhibiting antidepressant is well known. Within the last years, several new and more selective serotonin uptake inhibitors have been introduced in clinical practice, including trazodone, citalopram, paroxetine, femoxetine, fluvoxamine and fluoxetine. They differ by their chemical structure, and therefore, important differences can be expected with respect to their metabolism and kinetics in man. In this presentation, the following points will be addressed: Present knowledge about their metabolism and their kinetics, taking into account that most of them are racemates, whose clinical role is only partially understood, including that of the metabolites. It will further be examined whether they are candidates for a genetic polymorphism of metabolism of the debrisoquine-spartein-dextromethorphan type. This may e.g. be suspected for fluoxetine which interferes strongly with the metabolism of tricyclic antidepressants. Finally, data of the literature will be analysed about a possible relationship between the clinical efficacy of these drugs and their plasma levels, including those of their active metabolites.
Article
The neurobiologic mechanisms whereby the long-term administration of different antidepressant treatments enhance the efficacy of 5-HT synaptic transmission was investigated using an electrophysiologic paradigm in chloral hydrate anesthetized rats. Repeated electroconvulsive shocks (ECS; administered every other day for 14 days) as well as the sustained 21-day administration of the tricyclic antidepressant imipramine (10 mg/kg/day) and of the selective 5-hydroxytryptamine (5-HT) reuptake blocker paroxetine (5 mg/kg/day), increased the suppressant effect of the electrical stimulation of the afferent 5-HT pathway on the firing activity of CA3 hippocampus pyramidal neurons. The long-term treatments with imipramine and ECS, but not with paroxetine, increased the responsiveness of postsynaptic CA3 hippocampus pyramidal neurons to the microiontophoretic application of 5-HT and to that of the selective 5-HT1A receptor ligand 8-OH-DPAT. In contrast, the long-term treatment with paroxetine, but not with imipramine or ECS, attenuated the negative feedback exerted by terminal 5-HT autoreceptors on 5-HT release. This was indicated by two series of experiments. First, the capacity of the acute intravenous injection of the terminal 5-HT autoreceptor antagonist methiothepin to increase the efficacy of the stimulation was abolished in paroxetine-treated rats. Second, the decreased suppressant effect on pyramidal neuron firing activity usually obtained by increasing the frequency of the stimulation from 1 to 5 Hz (shown to be due to an increase in terminal 5-HT autoreceptor activation at the higher frequency) was also reduced in paroxetine-treated rats. The present data confirm and extend those of previous electrophysiologic studies showing that an enhanced 5-HT synaptic transmission is a common end result of long-term administration of various types of antidepressant treatments. Furthermore, they suggest that the mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Tricyclic antidepressants and ECS enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers produce this effect by reducing the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.
Article
Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.
Article
Release of [3H]serotonin elicited by electrical stimulation from rat hypothalamus and its modulation through autoreceptors has been studied after chronic administration of two antidepressants, citalopram, specific inhibitor of serotonin uptake, and milnacipran (previously called midalcipran, F 2207) which blocks the uptake of serotonin and noradrenaline to the same extent. The amount of [3H]serotonin released by electrical stimulation was enhanced and the inhibitory effect of the agonist, LSD (lysergic acid diethylamide), reduced in rats treated with citalopram at 10 and 50 mg/kg per day for 21 days. These effects existed at both doses but were accentuated at the higher dose. Thus a chronic treatment with citalopram provokes a down-regulation of the serotonergic autoreceptor, allowing an increase of serotonin neurotransmission. After 21 days treatment with milnacipran, at 50 mg/kg per day, none of the parameters studied were modified. These data suggest that down-regulation of the serotonin autoreceptor is not a universally applicable hypothesis to explain the action of all antidepressants acting on the uptake of serotonin.
Article
The effects of chronic clomipramine administration (15 mg/kg daily for 23 days) on changes in serotonin (5-hydroxytryptamine, 5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and noradrenaline (NA) induced by chronic stress have been studied in the rat brain. Chronic stress increased 5-HT in midbrain, pons and hippocampus, 5-HIAA in frontal cortex, midbrain, pons and hippocampus, and NA in midbrain and striatum. Chronic clomipramine significantly decreased the levels of 5-HT in most regions. In hypothalamus, hippocampus and perhaps in frontal cortex this effect possibly reflects decreased synthesis caused by an action on presynaptic 5-HT receptors. However, in midbrain, pons and striatum decreased 5-HT could not be attributed to a decrease in its synthesis since 5-HIAA also increased. This drug treatment also reduced NA in all regions except the striatum. Nevertheless, conclusions on NA synthesis or turnover cannot be drawn since only NA levels were measured. When administered concurrently, chronic clomipramine prevented the increases in 5-HT, 5-HIAA and NA produced by chronic stress. These results are in good accordance with previous findings showing that chronic antidepressant treatment also prevented behavioural disturbances induced by chronic stress.
Article
The purpose of the experiments reported were to determine whether chronic treatment with either a monoamine oxidase (MAO) inhibitor or an uptake inhibitor would increase extracellular levels of 5-HT in vivo and whether such treatment resulted in a down-regulation of the 5-HT1B-mediated decrease in extracellular levels of 5-HT. Rats were given either saline, (E)-beta-fluoromethyline-m-tyrosine (MDL 72394 0.25 mg/kg p.o.) or amitriptyline (10 mg/kg p.o.) once a day for 21 days. Twenty-four hr after the final injection, dialysis loops were implanted into the frontal cortices of these rats and basal extracellular levels of 5-HT were measured. The effect of the 5-HT1 receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole succinate (RU 24969 10 mg/kg i.p.) on the extracellular level of 5-HT was then studied. Basal levels of 5-HT in saline-treated rats was found to be 27.9 +/- 3.9 fmol/20 microliters perfusate. Chronic treatment with amitriptyline had no effect on extracellular levels of 5-HT but chronic treatment with MDL 72394 significantly increased extracellular levels of 5-HT. Chronic treatment with either MDL 72394 or amitriptyline had no significant effect on the ability of RU 24969 to reduce extracellular levels of 5-HT. These results suggest that 5-HT1B receptors are not down-regulated in response to chronically raised extracellular levels of 5-HT.
Article
The effects of a series of tricyclic and non-tricyclic antidepressants on the transport of [3H]-serotonin into synaptosomal fractions from rat brain in vitro and in vivo are summarized. Differences in potency in vitro and in vivo would appear to be due partly to the presence of active metabolites, formed in vivo, that show different selectivities for the serotonin transport site. Evidence suggests that the initial reduction in serotonin turnover after acute administration of serotonin reuptake inhibitors is followed by a return to control values after the drug has been administered for at least 2 weeks. These changes in amine turnover are associated with normalization of both the serotonergic and beta-adrenergic receptor systems. Evidence suggests that changes in neurotransmitter receptor numbers and function of blood cells (platelets and lymphocytes) in depressed patients are possible state markers of the illness and that antidepressant efficacy may not be directly associated with specificity of amine reuptake inhibition. Studies also show that the bilaterally bulbectomized rat exhibits deficits in platelet and synaptosomal serotonin transport that resemble those shown in depressed patients. This animal model of depression may be useful not only for detecting putative antidepressants but also for studying the mode of action of such drugs during chronic administration.
Article
Ligand binding studies indicate that multiple serotonin (5-HT) binding sites exist in the brain. To relate these putative receptor subtypes to startle reactivity and habituation, compounds with varying specificities for 5iHT1 and 5-HT2 binding sites were administered to rats prior to the presentation of 201 startling tactile stimuli. The 5-HT2 antagonists cyproheptadine, cinanserin, ritanserin, and ketanserin increased the rate of tactile startle habituation without affecting initial levels of reactivity. The 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, and 5-methoxy-N,N-dimethyltryptamine, the 5-HT1B agonist m-trifluoromethylphenylpiperazine, and the 5-HT2 agonist quipazine affected startle reactivity rather than having specific effects on habituation. The effects of the exogenous 5-HT2 antagonists were consistent with the effects of manipulations of endogenous 5-HT. Specifically, the serotonin depleting agents parachlorophenylalanine and parachloroamphetamine accelerated startle habituation. Conversely, the serotonin reuptake inhibitor fluoxetine decreased startle habituation. These findings support the hypothesis that serotonergic systems modulate the habituation of tactile startle via actions at 5-HT2 receptors.
Article
Results of electrophysiological single-cell recording studies suggest that most, if not all, types of antidepressant treatments increase 5-hydroxytryptamine (5-HT) neurotransmission. Tricyclic antidepressants, electroconvulsive shock treatment, mianserin, adinazolam, and possibly sleep deprivation may exert their therapeutic effect through sensitization of postsynaptic neurons to 5-HT. Serotonin reuptake blockers may relieve depression through an increased efficacy of the presynaptic element resulting from a desensitization of somatodendritic and terminal 5-HT autoreceptors. Similarly, monoamine oxidase inhibitors may act by increasing the efficacy of 5-HT neurons. Intensification of 5-HT function appears to be a common denominator to antidepressant treatments; however, evidence suggests that this modification may only be a link in a chain of events leading to an antidepressant response.
Article
A direct comparison was made of the effects of serotonin 5-HT1A and 5-HT1B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the 5-HT1A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the 5-HT1B selective compounds, m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the 5-HT1A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP; dose-response relationships for the 5-HT1B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-HT1A compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-HT1A, but not to 5-HT1B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe neurons.
Article
The effects of prolonged treatment of rats with zimelidine, 5, 12.5, and 25 mol/kg PO twice daily for 2 weeks, on the accumulation of 14C-5-hydroxytryptamine (14C-5-HT) and 3H-noradrenaline (3H-NA) in hypothalamic slices were studied. The concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in whole brain, the concentration of 5-HT in whole blood and the in vitro labelling of receptors in cerebral cortex with 3H-5-HT, 3H-dihydroalprenolol (3H-DHA) and striatum with 3H-spiroperidol were also determined, and the concentrations of zimelidine and its demethylated metabolite norzimelidine in plasma and hypothalamus were analysed. The degree of inhibition of the accumulation of 14C-5-HT and 3H-NA was not changed or only slightly increased by prolonged treatment as compared to acute treatment with zimelidine, i.e. the 5-HT accumulation was more inhibited than the NA accumulation. The inhibition of 14C-5-HT accumulation was significantly correlated to the plasma and hypothalamic concentration of norzimelidine 14 h after the last repeated administration. The 5-HT concentration in whole blood was markedly reduced at the same doses which produced inhibition of 5-HT uptake in brain, which indicates that the inhibition of 5-HT uptake in platelets and in neurons are similarly affected. The concentration of 5-HIAA in whole brain was reduced by both single and repeated administration of zimelidine, whereas the concentration of 5-HT was decreased only after prolonged treatment. The density of -adrenoceptors (binding of 3H-DHA) was significantly reduced by zimelidine, whereas 5-HT receptor binding (3H-5-HT) and dopamine receptor binding (3H-spiroperidol) were unchanged. It is concluded that the effects on 5-HIAA and 5-HT levels in brain and on the -adrenoceptors in cerebral cortex reflect pre-and post-synaptic regulation resulting from the uptake inhibition.
Article
The kinetics of citalopram were studied in a group of volunteers after oral (8 subjects) and intravenous (4 subjects) single doses and repeated oral administration (7 subjects). Inter- and intraindividual variation was limited and linearity of kinetics indicated. Systemic and apparent oral clearance estimates (mean 0.42 l plasma/min.) were similar, indicating roughly complete systemic availability. The presence of unchanged drug in urine, corresponding to 1/7 of the dose, suggests elimination by renal as well as hepatic processes. The data from the intravenous test revealed two compartment kinetics; the total volume of distribution was estimated to about 1150 l and that of the central compartment to 175 l. Upon repeated administration steady-state conditions were generally achieved after one week in agreement with the 33 hrs half-life of elimination. Citalopram peak concentrations were reached within 2-4 hours after the daily dose and maximally two-fold variation was recorded in the 24 hrs dose interval. The levels of a main pharmacodynamically active metabolite were roughly half as high as the drug levels.
Article
A high-performance liquid chromatographic method is described for the determination of citalopram [1-(3-(dimethylaminopropyl)-1-(4-fluorophenyl)-5-phthalancarbonitrile] and its two main metabolites (the methylamino and amino derivatives). The compounds were extracted from alkaline plasma with diethyl ether. The combined ether layers were evaporated after addition of 50 microliter of 0.1 N HCl. The residual extracts were purified with diethyl ether and 20 microliter were injected into a Spherisorb ODS 5-micrometer column with acetonitrile--0.6% phosphate buffer pH 3 (55:45, v/v) as the mobile phase. Using a fluorescence detector the detection limits are 1 ng/ml of plasma for citalopram and the methylamino metabolite and 0.5 ng/ml for the amino metabolite.
Article
1. Plasma levels of citalopram and its metabolites were assayed after single oral and intravenous doses to baboons (4 mg/kg), dogs (1, 4, 5, and 10 mg/kg), rats (8 mg/kg), and mice (24 mg/kg). Kinetic parameters were estimated. 2. Half-lives were short (estimate for baboon 3, dog 3 1/2-8, rat 3, and mouse 1 1/2 hours) and systemic plasma clearance high (baboon 39, dog 37-14, male rat 82, female rat 103, male mouse 87, and female mouse 116 ml/min/kg body weight). Considerable first-pass metabolism was demonstrated. 3. Drug level data were obtained in long-term safety studies in dogs (1, 3, and 8 mg/kg), rats (32 and 320 mg/kg), and mice (640 mg/kg). The high-dose citalopram level in dogs and rats exceeded that of patients by a factor of 10; the factor for mice was 40.
Article
Following a 5-week maintenance on a low-tryptophan diet, brain 5-HT content was reduced to 75%, whereas NA and DA levels remained unchanged as compared to controls. Reactivity to air-puffs as well as to the novelty of the open-field was increased. Incidence of mouse-killing was examined in 2 groups of Wistar rats maintained on the tryptophan-deficient diet for 2 and 4 weeks, respectively, before being tested with a mouse: 70% and 60% of them killed mice, compared to 20% killers in rats given free access to standard food, and 20% killers in rats given a limited access to standard food so as to reproduce the suppression of weight gain observed in the tryptophan-deficient animals. Prior non-aggressive interactions with mice significantly reduced later incidence of mouse-killing following a 4-week tryptophan-poor diet, thus confirming the suppressant effect of prior familiarization with mice on elicitation of mouse-killing as a result of brain 5-HT depletion. Once initiated, mouse-killing persisted even when the rats were returned to standard food, demonstrating that reduced 5-HT activity is not necessary for the maintenance of this behavior.
Article
Serotonin infused into the lateral ventricle in rats produced a dose-dependent depression of the acoustic startle reflex. When infused onto the spinal cord, serotonin produced a dose-dependent increase in startle. Thus the same neurotransmitter can modulate the same behavior in opposite ways, depending on which part of the central nervous system is involved.
Article
The effects of repeated fluoxetine (Flx) administration (5, 10, or 15 mg/kg i.p., twice daily for 21 days) on serotonin and 5-HIAA metabolism were examined in the hypothalamus, hippocampus, pons medulla and cerebral cortex of rats killed 1-28 days after the last dose. Dose-dependent weight loss was observed during treatment, followed by gradual and complete recovery of body weight over the following two weeks. Chronic Flx treatment caused a dose-dependent decrease in brain 5-HT levels (by between 10 and 50% depending on the region examined), lasting for 3-7 days after cessation of treatment with the lowest and intermediate doses, and for 7-14 days after cessation of the highest dose. 5-HIAA levels decreased more markedly (-20; -60% depending on the region examined) than those of 5-HT, and tended to overshoot during the recovery period. The prolonged reduction in brain 5-HT levels after chronic Flx treatment was similar to that seen in rats given very high doses of dexfenfluramine (d-fen), a drug which both blocks 5-HT uptake and increases its release. These data suggest that brain 5-HT and 5-HIAA depletion may reflect similar dose-related expressions of the drug's mechanisms of action.
Article
1. The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite. 2. Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex. 3. The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus). 4. Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose. 5. One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing. 6. Further studies on the relationship between the long-term neurochemical changes and anorectic activity are required but it appears from these results that anorectic drugs with similar acute effects on 5-HT uptake may differ in their long-term effects on 5-HT mechanisms.
Article
This study investigated the alterations of the 5-HT1A and 5-HT1B autoreceptor function following chronic treatment with fluvoxamine using osmotic minipumps. The 5-HT1A and 5-HT1B autoreceptor function were studied using microdialysis in the dorsal hippocampus. The effect of the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, SC) and the 5-HT1B receptor agonist RU-24969 (100 nM through the dialysis probe for 30 min) on 5-HT release was compared with rats chronically treated with saline. 8-OH-DPAT decreased 5-HT release to 55% and 60% of baseline, while RU-24969 decreased 5-HT release to 66% and 70% of baseline value in the saline and fluvoxamine group, respectively. In both cases, differences between the saline and fluvoxamine groups were not statistically significant. Plasma levels of fluvoxamine after 21 days of treatment ranged from 3 to 5 ng/ml. Fluvoxamine concentration in rat brain during treatment was estimated between 100 and 200 nM, which approximates to the IC50 value of fluvoxamine on the 5-HT transporter in synaptosomes and is 50 times higher than the Kd value for the 5-HT reuptake site. In conclusion, no evidence was found for changes in 5-HT1A,B receptor function using 8-OH-DPAT and RU-24969 as probes after continuous treatment with fluvoxamine by means of osmotic minipumps.
Article
Changes in the extracellular concentration of 5-HT evoked by electrical stimulation of brain slices containing either dorsal raphe nucleus (DRN) or suprachiasmatic nucleus (SCN) from rats treated for 21 days with fluoxetine (5 mg/kg; i.p.) or water were monitored using fast cyclic voltammetry (FCV). Stimulated 5-HT overflow was enhanced significantly in both brain regions after 21 days treatment with fluoxetine but there was no change in the half time for re-uptake (t1/2). Concentration response curves for inhibition of electrically stimulated 5-HT overflow by 8-OH-DPAT (5-HT1a receptor agonist) or RU24969 (5-HT1b receptor agonist) in the DRN or SCN respectively were obtained in slices prepared from both groups of animals. There was a significant shift to the right in the dose-response curve for RU24969 in the SCN in fluoxetine treated animals but a shift to the left for the dose-response curve for 8-OH-DPAT in the DRN. These data suggest that down regulation of the 5-HT1b autoreceptors occurs in an axon terminal region (SCN) but that there is a sensitisation of 5-HT1a autoreceptor mechanisms controlling 5-HT overflow in the DRN.
Article
The physiological role of the serotonin transporter on serotonin neuronal membranes apparently is to inactivate serotonin that has been released into the synaptic cleft. Drugs that inhibit the uptake of serotonin increase the amount of serotonin in the synaptic cleft and enhance serotonergic neurotransmission. As an adaptive response to the increased amount of serotonin in the synaptic cleft, serotonin neurons decrease their firing and release of serotonin to limit the magnitude of the increase in extracellular serotonin concentration. The increase in extracellular serotonin in rat brain caused by inhibitors of the serotonin uptake carrier has been characterized by brain microdialysis coupled to liquid chromatography with electrochemical detection. These drugs cause rapid accumulation of extracellular serotonin in several brain regions, although the increase in frontal cortex may be smaller than in other nerve terminal regions or in the cell body-containing raphe region.
Article
Established antidepressants including tricyclic antidepressants (TCAs), tetracyclic antidepressants and monoamine oxidase inhibitors (MAOIs) affect a series of neurotransmitter functions. In the debate of clinical efficacy much attention has focused on the uptake of noradrenaline (NA) and serotonin (5-HT) as a means to increase neuronal activity. Most antidepressants, whether classic or new, inhibit the uptake of either one or the other or both transmitters. Besides that, all of the classical antidepressants potently inhibit a series of neurotransmitter receptors. A series of newer antidepressants preferentially increase 5-HT transmission by inhibiting 5-HT uptake. Selective serotonin reuptake inhibitors (SSRIs) are those which preferably inhibit 5-HT uptake compared with NA, and which at the same time have no or only slight effect on other uptake mechanisms, neurotransmitter receptors, enzymes, etc. Five SSRIs are currently marked, i.e. citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. They all fulfil the above-mentioned criteria. Citalopram is the most selective 5-HT-uptake inhibitor, whereas paroxetine is the most potent. By and large the rank order of selectivity is equal in in vitro studies, in biochemical in vivo studies and in behavioural studies. Selectivity and potency for 5-HT uptake do not coincide. The selectivity of SSRIs is also founded on the lack of inhibition of receptors for different neurotransmitters, e.g. acetylcholine, histamine, NA, 5-HT or dopamine (DA), as well as monoamine oxidase (MAO). Citalopram, fluoxetine and sertraline are metabolized to compounds possessing similar properties as the parent drugs, whereas this is not the case with the metabolites of fluvoxamine and paroxetine. Upon repeated administration SSRIs maintain the selective and potent inhibition of 5-HT uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effects of systemic administration of the serotonin (5-hydroxytryptamine) 5-HT1A receptor agonists flesinoxan and 8-hydroxy-2-(di-n-propylamino)tetralin on extracellular 5-HT were measured using microdialysis probes in both median raphe nucleus and dorsal hippocampus. Both 5-HT1A agonists dose-dependently decreased dialysate 5-HT levels from both brain regions. The effects of flesinoxan in the median raphe (0.3 mg/kg) and dorsal hippocampus (1.0 mg/kg) could be blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexane carboxamide trihydrochloride (WAY 100,635) at a dose of 0.05 mg/kg s.c. The antagonist itself had no effect at this dosage. Local perfusion of flesinoxan for 30 min through the dialysis probe into the median raphe region at concentrations of 20, 100, and 1,000 nM resulted in a significant decrease in dialysate 5-HT content from both regions. The effect of 100 nM flesinoxan could be blocked by coperfusion of 1,000 nM WAY 100,635. The data indicate that flesinoxan is a potent 5-HT1A receptor agonist and also support the notion that somatodendritic 5-HT1A autoreceptors regulate both terminal and somatodendritic 5-HT release.
Article
The administration of tryptophan (Trp)-free amino acid mixtures to depressed patients responding to serotonin [5-hydroxytryptamine (5-HT)] uptake inhibitors (SSRIs) worsens their clinical state. This procedure reduces Trp availability to brain and thus impairs 5-HT synthesis. We have examined the influence of Trp depletion on extracellular 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the rat brain using in vivo microdialysis. The treatment with the SSRI fluvoxamine significantly increased 5-HT content in dialysates from frontal cortex, as compared with control rats (10.2 +/- 2.7 vs. 3.1 +/- 0.4 fmol per fraction), whereas 5-HIAA was unaffected. Food deprivation for 20 h reduced dialysate 5-HT content to almost control values in fluvoxamine-treated rats (10.2 +/- 2.7 vs. 4.3 +/- 0.6 fmol per fraction) but did not alter dialysate 5-HIAA content (7.8 +/- 0.4 vs. 7.2 +/- 0.5 pmol per fraction). The administration of Trp-free amino acid mixtures to fluvoxamine-treated rats significantly attenuated the release of 5-HT in frontal cortex (approximately 50%) and, to a lesser extent, in the midbrain raphe nuclei. This effect was more marked in rats not deprived from food before the experiments (67% reduction of dialysate 5-HT content in frontal cortex) and was absent in control rats (treated with saline). In contrast, dialysate 5-HIAA was markedly affected by Trp depletion in all groups, including controls (65-75% reductions). These data show that the administration of an amino acid mixture with the same composition and dose (in milligrams per kilogram of body weight) as those inducing a severe mood impairment in depressed patients reduces 5-HT and 5-HIAA concentrations in brain dialysates. The reduction of 5-HT release, however, occurs only in animals previously treated with the antidepressant fluvoxamine for 2 weeks, which would be consistent with a marked reduction of 5-HT-mediated transmission in treated depressed patients but not in healthy controls.
Article
In major depression in humans and in animal models of depression, there is a defect in serotonergic neurotransmission that can be relieved by chronic antidepressant treatment. One possibility is that this pathologic state is caused by excessive presynaptic autoreceptor activity in serotonergic neurons, and that antidepressants down-regulate the number of these inhibitory receptors, allowing more normal serotonin release to occur. To evaluate this hypothesis, we measured the effects of the antidepressant fluoxetine on neuronal levels of 5-HT1B receptor mRNA, the putative serotonin terminal autoreceptor in rat brain, and on serotonin transporter mRNA, the direct site of fluoxetine binding. Fluoxetine reduced serotonin transporter mRNA briefly, but this was not sustained after 21 days of treatment. However, fluoxetine reduced dorsal raphe 5-HT1B mRNA levels in a time-dependent and washout-reversible manner. This reduction in 5-HT1B mRNA was specific to dorsal raphe nucleus and was not found in several postsynaptic (nonserotonergic) regions. These results suggest that chronic fluoxetine may increase serotonin release from axonal terminals by down-regulating the messenger RNA coding for presynaptic 5-HT1B autoreceptors while causing only transient effects on serotonin transporter mRNA.
Article
Alpha-ethyltryptamine (AET), a monoamine oxidase inhibitor and potent monoamine releasing agent, has been sold illicitly as a substitute for the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA), and is the first example of an indolealkylamine analog demonstrated to substitute in MDMA-trained animals. Previous studies have demonstrated that MDMA and AET have similar effects on unconditioned motor behavior in rats. Furthermore, the locomotor-activating effects of both MDMA and AET are blocked by pretreatment with fluoxetine, a selective serotonin (5-HT) uptake inhibitor, suggesting that the two compounds may share a presynaptic mechanism of action. This study examined the effects of AET using measures of startle plasticity, specifically prepulse inhibition (PPI), and habituation. PPI, a measure of sensorimotor gating, is reduced in rats treated with hallucinogens, 5-HT releasers, and dopamine agonists. In contrast, startle habituation is reduced in rats treated with hallucinogens and 5-HT releasers. AET (1.25, 2.5, 5, and 10 mg/kg) decreased PPI of acoustic startle and reduced the habituation of tactile startle. To determine whether AET produces these effects via pre- or postsynaptic actions, fluoxetine (10 mg/kg) was used as a pretreatment. By itself, fluoxetine did not disrupt PPI, but did reduce startle habituation. Fluoxetine pretreatment prevented the AET-induced disruption of PPI and reduced the AET-induced disruption of startle habituation. Combined with previous findings, these results confirm that AET produces behavioral effects that mimic those of other indirect 5-HT agonists and that the effects of AET on startle plasticity are due to the release of presynaptic 5-HT.
Article
A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against nonselective and noradrenergic reuptake inhibitors (mainly tricyclic antidepressants, TCAs) in depressed inpatients was carried out. Twenty-five double-blind studies provided data on relative efficacy which was determined by a summary variance-weighted mean effect size calculated from the difference in the reduction in mean Hamilton Depression Rating Scale (HDRS) scores for the two antidepressants in each study. Twenty-three studies provided data on dropouts and relative tolerability which was determined as the variance-weighted pooling of the relative risk (RR) of dropout for all reasons and for adverse effects from each study. TCAs were significantly more effective than SSRIs (effect size = -0.23, 95% CI -0.40 to -0.05, P = 0.011), although sensitivity analyses by analysing larger studies (> 100 patients) and those providing complete data reduced the advantage to TCAs to a trend (P < 0.10). When the TCAs were grouped into those with dual action on 5-hydroxytryptamine (HT) and noradrenaline reuptake (clomipramine and amitriptyline) and those with predominantly noradrenaline reuptake (imipramine, desipramine and maprotiline), only the dual action TCAs had greater efficacy than SSRIs (effect size = -0.30, 95% CI -0.54 to -0.05, P = 0.017). When TCAs were considered individually, only amitriptyline was significantly more effective than comparator SSRIs (effect size = -0.37, 95% CI -0.67 to -0.07, P = 0.015). More patients overall discontinued treatment on TCAs than on SSRIs (29.0% vs. 25.5%), although this did not reach statistical significance (RR = 0.88, 95% CI 0.75 to 1.03, P = 0.121). However, significantly more patients stopped treatment due to adverse effects on TCAs compared to SSRIs (14.2% vs. 9.1%, RR = 0.66, 95% CI 0.50 to 0.87, P = 0.003) with no difference in discontinuations due to treatment failure (10% vs. 11.6%, RR = 1.13, 95% CI 0.84 to 1.51, P = 0.42). This meta-analysis suggests that at least some TCAs may be more effective than SSRIs in depressed inpatients, with there being the strongest evidence for amitriptyline. A possible explanation is that this is related to a dual action in inhibiting both 5-HT and noradrenaline reuptake. In agreement with previous meta-analyses, TCAs appear less well tolerated than SSRIs, although the absolute risk difference for discontinuation due to adverse effects (4.9%, 95% CI -8.1 to -1.7%) is of uncertain clinical significance.
Article
The objective of this study was to characterize the lasting effects of fluoxetine on the locomotor behavior of rats using a computerized activity-monitoring system. Challenge dosages (8, 16, and 24 mg/kg i.p.) of fluoxetine 2 h into the dark phase resulted in dose-dependent suppression of locomotor activity for 4 h following injection. Escalating (10-30 mg/kg i.p.) semidaily fluoxetine administration for the next five days resulted in decreasing locomotor activity during the multiple-administration period relative to saline control. Circadian activity patterns at the conclusion of the regimen were unchanged in shape, but featured uniform decreases in locomotor activity at every hour which were more significant during the phase. Upon discontinuation, fluoxetine-treated rats showed a significant increase in activity during the first 4 h following the first "missed" dose which was not seen in subsequent washout. Ninety-six h after the final maintenance dose, the initial three dosages were readministered, and the locomotor activity suppression in response to the rechallenge dose of fluoxetine was significantly lessened compared to initial challenge. These findings suggest that tolerance and withdrawal were obtained.