Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine

The neurobiological basis of panic disorder has not been clearly established, although a role for serotonin (5-HT) has been postulated. It is clear that drugs which increase 5-HT neurotransmission are effective in treating the condition but how they do so remains a point of debate. The aim of this study was to determine if lowering brain serotonin activity using the technique of tryptophan depletion provoked a short-term relapse of panic symptoms in patients with panic disorder who had responded to drug treatment. Fourteen patients with panic disorder who had responded to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received an infusion of flumazenil (used as a pharmacological challenge) and placebo on each day. The tryptophan depleted drink produced an 87% reduction in plasma tryptophan concentration. Flumazenil produced a panic attack (defined by changes in the panic inventory) in seven out of 14 patients when tryptophan depleted and one out of 14 on the control day (p < 0.02). Three patients also experienced temporary depressive symptoms when tryptophan depleted, with no mood changes being seen on the control days. We conclude that rapid lowering of brain serotonin function can allow the precipitation of panic symptoms in response to flumazenil in panic disorder patients who have responded to treatment with an SSRI. This implies that in panic disorder increased 5-HT availability is important in maintaining the response to SSRIs.     

The effect of 5-hydroxytryptophan on cholecystokinin-4-induced panic attacks in healthy volunteers

Previous studies suggest a modulatory role of serotonin (5-HT) in experimentally-induced panic attacks. In the current study, we investigated the acute effects of 5-HT precursor l-5-hydroxytryptophan (5-HTP) on the response to panicogenic challenge with cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Thirty-two subjects were randomized to receive either 200 mg of 5-HTP or placebo with the CCK-4 challenge following in 90 min in a double-blind, parallel-group design. The results showed a nonsignificant difference between the groups in panic rate (19% after 5-HTP and 44% after placebo, p = 0.13) with a trend for lower intensity of symptoms after 5-HTP (p = 0.08). Further analysis by gender revealed that females in the 5-HTP group had a significantly lower panic rate and intensity of cognitive symptoms whereas, in males, the effect of 5-HTP was limited to lowering the intensity of somatic panic symptoms. Thus, an increased availability of 5-HT may have a gender-dependent protective effect in CCK-4-induced panic.     

Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacks

Data from animal studies suggest a functional relationship between the cholecystokinin-ergic (CCK) and the serotonergic (5-HT) system. There is increasing evidence that the cholecystokinin-4 (CCK₄) challenge test could be a valid experimental model for panic attacks in man. The aim of the present study is twofold; 1) to validate this model further and 2) to shed more light on the putative CCK\5-HT interaction. To this end, we studied the effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on CCK₄-induced panic attacks. Twenty-six panic disorder (PD) patients received, before and after a double blind 8-week treatment period with fluvoxamine (n = 17) or placebo (n = 9), a single blind bolus injection with 50 μg CCK₄. Treatment with fluvoxamine (150 mg daily) significantly decreased the sensitivity of PD patients for CCK₄ while placebo was without effect. Of the patients who responded to treatment, 83% no longer experienced a panic attack when rechallenged with CCK₄, whereas in the non-responders group this was only 28%. In the fluvoxamine group the treatment response evaluated by the Hamilton Anxiety Scale (HAS) showed a statistically significant treatment effect. The results of this study strengthen the validity of the CCK₄ test as an experimental human model for panic attacks and yield evidence supporting the hypothesis that both CCK and serotonin are implicated in the regulation of anxiety. Received: 15 April 1996/Final version: 27 September 1996     

d-Fenfluramine in panic disorder: a dual role for 5-hydroxytryptamine

Rationale: 5-Hydroxytryptamine (5-HT) appears to modulate different forms of anxiety in different ways, but the importance of this in human anxiety disorders is unknown. Objectives: To investigate whether the 5-HT releasing agent d-fenfluramine (dFEN) has different effects on resting and panic anxiety in panic disorder. Methods: Thirteen drug-free patients with DSM-IIIR panic disorder were tested in a double-blind placebo-controlled crossover design. Carbon dioxide 7% (CO₂) was given as a panic challenge 270 min after administration of dFEN or placebo. Results: Compared to placebo, dFEN increased anxiety and arousal, maximal at 120 min, but tended to reduce CO₂-induced anxiety and panic attacks with a significant reduction in Panic Visual Analogue Scale ratings (P=0.040). Anxiety following CO₂, but not dFEN, administration resembled panic attacks (compared to Acute Panic Inventory symptom profile during patients’ usual attacks). Patients with more severe disorders exhibited enhanced behavioural responses and blunted prolactin responses to dFEN. Conclusions: dFEN caused anxiety similar to generalised anxiety in panic disorder patients but reduced anxiety following 7% CO₂ challenge, a laboratory analogue of naturally occurring panic attacks. These findings are consistent with a dual role for 5-HT in pathological anxiety. Patients with more severe symptoms differed in 5-HT function compared to more mildly affected individuals. Received: 4 August 1999 / Final version: 14 November 1999     

The effect of 6-week treatment with escitalopram on CCK-4 challenge: A placebo-controlled study in CCK-4-sensitive healthy volunteers

Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5±5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 μg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p=0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies.     

Gender differences in brain serotonin transporter availability in panic disorder

The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP (ND)) in male and female patients with PD. The SERT BP (ND) was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [11C]MADAM tracer. SERT BP (ND) were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP (ND) were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT(1A) receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.     

Phenylalanine kinetics are associated with tardive dyskinesia in men but not in women

Rationale: An association between tardive dyskinesia (TD) and severely impaired metabolism of the large neutral amino acid (LNAA), phenylalanine (Phe) was defined in a group of mentally retarded patients. Subsequently, an altered kinetics of Phe was associated with TD in men with schizophrenia based on plasma analyses subsequent to the ingestion of a protein meal. Methods: In the present study, a standardized oral challenge of pure Phe (100 mg/kg in 170 ml orange juice) was administered to psychiatric patients of both sexes (n = 312), with and without TD after an overnight fast. Plasma LNAA levels were assayed both fasting and 2 h subsequent to the ingestion of the challenge. The extent of the increase in plasma Phe levels 2 h following a standardized challenge is determined by the sum of the kinetic processes of plasma absorption, tissue distribution, metabolism and elimination. Results: The study hypothesis, that TD would be associated with significantly higher post-challenge plasma Phe indices of an absolute plasma Phe level and plasma Phe/LNAA ratio (a brain availability measure), was verified for the study men (n = 209), but not for the study women (n = 103). Conclusions: The demonstrated altered kinetics of Phe in men with TD indicates a greater availability of Phe to the brain in these men. We suggest that the disorder may be related to the effects of this greater availability. Such effects could be the direct neurotoxic effects of Phe and its metabolites and/or the modulating effects of these compounds on the synthesis of the monoamine neurotransmitters. The fact that TD (Yes/No) group differences in post-challenge plasma Phe indices were not seen for the study women suggests the possibility of a sex difference in the biology of TD that we propose may be reflective of the young age of the study sample. Received: 28 January 1998/Final version: 14 December 1998     

Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers.

Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4-induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 microg CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panic-symptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4-induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API- and PSS-scores. Moreover, there was a significant attenuation of CCK-induced elevation of ACTH and cortisol levels following vigabatrin treatment. In conclusion, our data show that GABA-transaminase inhibitors exert anxiolytic effects in CCK-4-induced panic in healthy volunteers and suggest that GABA transaminase inhibitors might be useful in ameliorating panic symptoms also in patients with PD.     

The ventilatory response to cholecystokinin tetrapeptide in healthy volunteers.

The cholecystokinin (CCK) system, which has been shown to interact with both the panicogenic and respiratory systems, provides an interesting mechanism to further evaluate the central chemoreceptor and its effect on panic attack sensitivity. Intravenous CCK, a naturally occurring neuropeptide in the brain, has been found to induce the emotional and somatic symptoms of panic in both Panic Disorder (PD) and Normal Control (NC) subjects in a dose-dependent and reproducible fashion. To induce these effects, lower doses of intravenous CCK are required in the PD patients, relative to the NC subjects potentially suggesting that endogenous alterations in the CCK system may be contributing to the development of PD. Intravenous administration of CCK-4 in association with panic also results in subjective dyspnea, that is, diminution in vital capacity without an effect on the respiratory resistance. CCK-4 also causes a significant increase in tidal volume and minute ventilation but has no effect on breathing frequency. These observations suggest that a CCK-B receptor agonist may be acting as a respiratory stimulant, exerting its effect on anxiety through a direct effect on respiration. This study represents an examination of the specific effects of CCK-4 on the central chemoreceptor response. The study used a modified rebreathing technique, which accurately measures the ventilatory response to carbon dioxide in terms of both threshold and sensitivity. This technique requires the subject to rebreathe from a bag containing a hyperoxic and hypercapnic gas mixture resulting in rapid equilibration between alveolar gas and arterial blood. Use of a hyperoxic gas allows for the preferential examination of the central chemoreflexes (sensitive to CO(2)) with little if any effect of the peripheral (oxygen sensitive) chemoreflexes. After significant training, 15 healthy control subjects were assigned via a double blind procedure to receive an intravenous injection of placebo or CCK-4, using a between-subjects design. A between-subjects comparison was undertaken for the injection run (run #3) between subjects receiving the CCK-4 injection and those receiving the placebo injection. As well, a within-subject comparison was undertaken to compare the results of the run following the injection (run #3) vs. the previous run when no injection took place (run #2). No significant differences were noted between subjects who received CCK-4 as compared with placebo for: basal or sub-threshold ventilation, threshold CO(2) resulting in a change in ventilation, or sensitivity of the central chemoreflex, regardless of whether a panic attack did or did not take place. In addition, within the group receiving the CCK-4 challenge, no significant differences were noted during run #3 (received the CCK-4 injection) and a prior run where no injection took place (run #2).We conclude that CCK-4 does not act to induce panic by altering the central (CO(2) sensitive) chemoreceptor.     

Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.

Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 microg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.     

The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder

Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO(2) panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO(2) panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.     

Escitalopram,the S-(+)-enantiomer of citalopram,is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities

Objective. The pharmacological profile of escitalopram, the S-(+)-enantiomer of citalopram, was studied and compared with citalopram and the R-(−)-enantiomer, R-citalopram. Methods. Inhibition of the serotonin transporter (5-HTT) was studied in COS-1 cells expressing the human 5-HTT (h-5-HTT) and in rat brain synaptosomes. In vitro selectivity was studied relative to noradrenaline transporter (NAT) and dopamine transporter (DAT) function in rat brain synaptosomes, and affinities for other binding sites were determined. In vivo 5-HT activity was measured as inhibition of neuronal firing rate in rat dorsal raphe nucleus (DRN) and enhancement of 5-hydroxytryptophan (5-HTP)-induced behaviour (mouse and rat). Furthermore, studies were conducted in models of antidepressant (mouse forced-swim test), anxiolytic [foot-shock-induced ultrasonic vocalization (USV) in adult rats and mouse black and white box] and anti-aggressive activity (socially isolated mice). Results. Escitalopram inhibited 5-HTT functions approximately 2 times more potently than citalopram and at least 40 times more potently than R-citalopram. Escitalopram showed insignificant activity at other monoamine transporters and 144 other binding sites. Escitalopram inhibited 5-HT neuronal firing in DRN and potentiated 5-HTP-induced behaviours more potently than citalopram; R-citalopram was inactive. Escitalopram and citalopram, but not R-citalopram, reduced forced-swimming-induced immobility and facilitated exploratory behaviour in the black and white box. Escitalopram and citalopram inhibited USV potently; R-citalopram was several times less potent. Escitalopram, citalopram and R-citalopram inhibited aggressive behaviour weakly. Escitalopram and citalopram had very potent anti-aggressive effects when co-administered with l-5-HTP. Conclusion. Escitalopram is a very selective 5-HT reuptake inhibitor. It is more potent than its racemate citalopram and is effective in animal models predictive of antidepressant and anxiolytic activities. Electronic Publication     

Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study

Rationale Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules. Objectives To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection. Methods We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly. Results The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers. Conclusions The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective “read out”. The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.     

Reboxetine and citalopram in panic disorder: a single-blind,cross-over,flexible-dose pilot study

Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder. The advent of selective serotonin (5-HT) reuptake inhibitors (SSRIs) (e.g. citalopram) and, more recently, selective noradrenergic (NA) reuptake inhibitors (NRIs) (e.g. reboxetine) has provided potentially important avenues of treatment for the disorder. To date, the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved. Nineteen patients with panic disorder were randomized in a single-blind, cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug. At week 18, seven of 13 patients (54%) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram (82%). Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy. However, citalopram demonstrated superior efficacy in treating depressive symptoms. One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram. Although SSRIs are viewed as a first-line treatment for panic disorder, these results suggest that a NA agent such as reboxetine may also have a role. These data also suggest an advantage for citalopram in treating comorbid depressive symptoms, although some patients may respond preferentially to an SSRI and other patients to an NRI.     

Plasma anti-serotonin and serotonin anti-idiotypic antibodies are elevated in panic disorder.

The psychoneuroimmunology of panic disorder is relatively unexplored. Alterations within brain stress systems that secondarily influence the immune system have been documented. A recent report indicated elevations of serotonin (5-HT) and ganglioside antibodies in patients with primary fibromyalgia, a condition with documented associations with panic disorder. In line with our interest in dysregulated 5-HT systems in panic disorder (PD), we wished to assess if antibodies directed at the 5-HT system were elevated in patients with PD in comparison to healthy volunteers. Sixty-three patients with panic disorder and 26 healthy volunteers were diagnosed by the SCID. Employing ELISA, we measured anti-5-HT and 5-HT anti-idiotypic antibodies (which are directed at 5-HT receptors). To include all subjects in one experiment, three different batches were run during the ELISA. Plasma serotonin anti-idiotypic antibodies: there was a significant group effect [patients > controls (p = .007)] and batch effect but no interaction. The mean effect size for the three batches was .76. Following Z-score transformation of each separate batch and then combining all scores, patients demonstrated significantly elevated levels of plasma serotonin anti-idiotypic antibodies. Neither sex nor age as covariates affected the significance of the results. There was a strong correlation between anti-serotonin antibody and serotonin anti-idiotypic antibody measures. Plasma anti-serotonin antibodies: there was a significant diagnosis effect [patients > controls (p = .037)]. Mean effect size for the three batches was .52. Upon Z-score transformation, there was a diagnosis effect with antibody elevations in patients. Covaried for sex and age, the result falls below significance to trend levels. The data raise the possibility that psychoimmune dysfunction, specifically related to the 5-HT system, may be present in PD. Potential interruption of 5-HT neurotransmission through autoimmune mechanisms may be of pathophysiologic significance in certain patients with panic disorder. It remains to be demonstrated if the peripheral autoimmunity is representative of CNS 5-HT neuronal alterations. Replication appears warranted.     

Altered neuroendocrine and behavioral responses to m-chlorophenylpiperazine in 3,4-methylenedioxymethamphetamine (MDMA) users

Rationale: (±) 3,4-Methylenedioxymethamphetamine (MDMA, ”Ecstasy”) is a popular drug of abuse and a brain serotonin neurotoxin in animals. Growing evidence indicates that humans are also susceptible to MDMA’s neurotoxic effects, although few functional consequences of MDMA-induced 5-HT damage have been identified. Objective: The present study sought to determine whether possible differences between MDMA users and control subjects could be unmasked by utilizing a pharmacological challenge with the mixed 5-HT agonist, meta-chlorophenylpiperazine (m-CPP). It was postulated that 5-HT neurotoxicity in MDMA users would be associated with altered 5-HT responsivity, exemplified by altered physiological and behavioral responses to m-CPP. Methods: Twenty-five MDMA users who had not taken MDMA for at least 3 weeks and 25 controls received intravenous placebo (normal saline) and m-CPP (0.08 mg/kg) in a fixed order, single blind design. Repeated measures of mood, physical symptoms, and blood samples for neuroendocrine analyses were collected during the 90 min after each infusion. Results: MDMA users reported more positive and fewer negative emotions and physical symptoms following m-CPP than controls, and were significantly less likely to report an m-CPP-induced panic attack. Male MDMA users had diminished cortisol and prolactin responses to m-CPP. Conclusions: The present data indicate that MDMA users have alterations in 5-HT neuronal function, possibly as a consequence of MDMA-induced brain serotonin neural injury. Received: 27 January 1999 / Final version: 12 May 1999     

Effect of a specific 5-HT uptake inhibitor,citalopram (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro

The uptake of ³H-5-HT in synaptosomes from rat brains was investigated. Addition of DA or NA had only a slight or no effect on the uptake. When the uptake into NA and DA neurons was inhibited by the addition of high concentrations of NA and DA, the uptake of ³H-5-HT was unchanged. This was also found after destruction of NA and DA neurons by 6-hydroxydopamine treatment. Furthermore, the uptake of ³H-5-HT was almost equal in different brain parts containing NA and DA in very different amounts. These observations show that the uptake measured with ³H-5-HT is specific for 5-HT neurons.The present study revealed that citalopram and chlorimipramine inhibited uptake competitively, and in this respect the two drugs were equipotent. Compared with a series of tricyclic thymoleptics, the two drugs were the most potent inhibitors of 5-HT uptake, about 20 to 35 times more active than imipramine and amitriptyline. The metabolites of citalopram were also rather potent. The results obtained in the present study correlate closely with those obtained using inhibition of ¹⁴C-5-HT uptake in blood platelets, or using the inhibition of H 75/12-induced 5-HT depletion in rat brain.When rats were treated orally with citalopram or chlorimipramine, the inhibition of ³H-5-HT uptake in synaptosomes derived from these rats was two times greater after citalopram than after chlorimipramine.     

Citalopram decreases tryptophan 2,3-dioxygenase activity and brain 5-HT turnover in swim stressed rats

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their effects by increasing synaptic concentrations of serotonin (5-HT).The forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Rationale of the present study was to investigate the acute effects of citalopram on hepatic tryptophan metabolism and disposition in rats exposed to FST.MethodsWe investigated the effects of acute citalopram (20 mg/kg, ip) administration on rat's behavioral responses in FST paradigm, hepatic tryptophan 2,3-dioxygenase (TDO) activity, serum corticosterone levels and brain regional 5-HT metabolism.ResultsCitalopram administered to swim-stressed rats showed a decrease in FST-induced increases in plasma corticosterone concentration and 5-HT turnover in hypothalamus, amygdala and hippocampus. The drug also decreases immobility and increases swimming during the FST. Citalopram administration to unstressed rats increases plasma corticosterone concentration but decreases 5-HT turnover in all three brain areas examined.ConclusionsOur findings support the hypothesis that acute citalopram administration increases tryptophan (by inhibiting TDO activity) availability for 5-HT synthesis and activates serotonergic neurotransmission in limbic brain areas in rats exposed to FST paradigm. The mechanism of action of citalopram in ameliorating social stress related depressive disorder in humans is discussed.     

Anxiogenic effects of Sumatriptan in panic disorder: a double-blind, placebo-controlled study.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with panic disorder (PD). Our goal was to further examine central serotonergic function in panic patients using autonomic and subjective responses to the postsynaptic serotonin 5-HT1D receptor agonist Sumatriptan. METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed autonomic and subjective responses to oral Sumatriptan (100 mg) and placebo in 15 patients with PD, free of medication. Subjective responses were measured using the Hamilton Anxiety Rating Scale (HAM-A), National Institute of Mental Health Anxiety Scale (NIMHA), a modified version of the Panic Symptom Inventory (PI), Hamilton Depression Rating Scale (HAM-D), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: PD patients exhibited significantly enhanced autonomic and subjective responses following challenge with Sumatriptan. We observed an increased pulse rate and augmentation of various parameters measured on different anxiety scales. A constant inclination of aggravation of the measured parameters was detected during the hour post challenge. CONCLUSION: Oral administration of Sumatriptan, a 5-HT1D agonist, has been associated with an anxiogenic effect in PD patients.     

Acute tryptophan depletion and self-injurious behavior in aggressive patients and healthy volunteers

Rationale  An association between serotonin (5-HT) activity and self-injurious (i.e., self-aggressive) behavior across the spectrum of lethality (from self-mutilation through completed suicide) is a well-replicated finding. Studies to date, however, have relied on nonexperimental designs to examine this relationship, limiting the causal inferences that can be drawn about the role of 5-HT in self-aggressive behavior. Objective  Examine the effect of experimentally altered 5-HT activity (via dietary tryptophan depletion) on self-aggressive behavior among adults with and without intermittent explosive disorder (IED). Individuals with a marked history of aggression, such as those with IED, are characterized by compromised 5-HT and heightened risk for self-aggression, making this a population of interest for examining the proposed relations. Materials and methods  IED patients (n = 16) and healthy controls (n = 16) received a tryptophan depletion and a placebo drink on separate days at least 1 week apart. Self-aggressive behavior was assessed on both study days using a well-validated laboratory-based behavioral assessment with self-aggression defined as the intensity of shock self-administered. Results  Tryptophan depletion facilitated selection of more intense shocks, on average, in both groups. Patients with IED were also more self-aggressive overall than healthy volunteers. No IED by drink condition interactions were found. Conclusion  Experimentally lowered 5-HT bioavailability enhances overall self-injurious behavior irrespective of aggression history.