Potentiation of the Antidepressant Action of Clomipramine by Tryptophan

Wålinder, Jan; Skott, Annika; Carlsson, Arvid; Nagy, Ádám; Roos, B. E.

doi:10.1001/archpsyc.1976.01770110112012

Cited by 129 publications

(19 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In patients, tryptophan augmentation of 5-HT reuptake therapy is supported by a limited number of clinical trials [47], [48]. These data are, however, not definitive [46], [50] and large follow-up clinical trials have not been reported.…”

Section: Discussionmentioning

confidence: 99%

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

et al. 2009

View full text Add to dashboard Cite

BackgroundSerotonin (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.Methodology/Principal FindingsCitalopram 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.Conclusions/SignificanceTaken 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The increase in number of TPH2+ neurons in the anhedonic condition (susceptible animals), was somewhat unexpected, given that serotonergic depletion is conventionally associated with depression based on studies that used SSRI treatment (Delgado, 2004;Abumaria et al, 2007), tryptophan treatment (Persson, 1967;Glassman and Platman, 1969;Wålinder et al, 2003) or 5-HT depletion (Shopsin et al, 1976;Delgado et al, 1994;Sachs et al, 2015). However, increased TPH2 immunoreactivity has been observed after exposure to stress (Poeggel et al, 2003) and in brains of depressed patients who committed suicide (Underwood et al, 1999;Boldrini et al, 2005), suggesting that this may be a homeostatic mechanism by the DR to compensate for serotonin depletion and deficient signaling in target areas.…”

Section: Discussionmentioning

confidence: 99%

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

Prakash

Stark

Keisler

et al. 2019

Preprint

View full text Add to dashboard Cite

critical feedback on the research and Dr.Byung Kook Lim for his valuable feedback and the use of his slide-scanning microscope. ABSTRACTChronic stress induces anhedonia in susceptible, but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in SIGNIFICANCE STATEMENTDepression and other mental disorders can be induced by chronic or traumatic stressors.However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.

show abstract

“…However, this strategy has the limitation that SSRI + moclobemide co-treatment occasionally triggers serious adverse events [29, 30]. In double-blind trials, adjunctive treatment with the 5-HT precursor tryptophan augments the efficacy of SERT inhibitors [31, 32]. However, this approach has the limitations that just a few percent of tryptophan is metabolized to 5-HT [45], and that tryptophan’s short T 1/2 of 3h [46] necessitates frequent dosing.…”

Section: Elevating 5-htext Beyond the Sert Inhibitor Effect Has Shownmentioning

confidence: 99%

Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale

Jacobsen

Krystal

Krishnan

et al. 2016

Trends in Pharmacological Sciences

104

View full text Add to dashboard Cite

Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HTExt). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HTExt beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HTExt beyond the SERT inhibitor effect in humans; but, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhance the pharmacological action, and transform 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here we review the clinical and preclinical evidence.

show abstract

Potentiation of the Antidepressant Action of Clomipramine by Tryptophan

Cited by 129 publications

References 20 publications

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale

Contact Info

Product

Resources

About