Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients

The effects of pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK₄), were studied in 15 patients with panic disorder and 15 healthy controls. Three different intravenous dosages of pentagastrin (0.1, 0.3 and 0.6 µg/kg) and saline were investigated. Subjects were randomly allocated to two of the four treatment groups and tested on two separate occasions, 1 week apart, using an unbalanced double-blind incomplete block design. The mean panic rate with pentagastrin was 55% (12/22) for patients and 5% (1/22) for controls. None of the subjects panicked with saline. The frequency of panic attacks between the three pentagastrin doses in patients was not different. One control subject had a panic-like attack at the highest dose of pentagastrin. These findings concur with previous studies on the panicogenic effect of CCK₄ and pentagastrin and suggest a greater sensitivity for CCK receptor agonists in patients suffering from panic disorder than in healthy controls.     

The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients

The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK₄) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two different dosages of CI-988 (50 mg or 100 mg) or placebo 2 h prior to an IV bolus injection of CCK₄ (20 μg) on two separate occasions. The primary efficacy parameter was the total intensity score on the Panic Symptoms Scale (PSS). Secondary parameters were the number of panic symptoms, time to and occurrence of the first panic symptoms, duration of symptoms, intensity of apprehension and the percentage of patients who did not have a panic attack. The PSS failed to show a statistically significant treatment effect on any of these outcome measures. The average panic rate was 50%, 14.3% and 37.5% after placebo, 50 and 100 mg CI-988, respectively. The differences in panic rate were not statistically significant. The results of this study suggest that CI-988 in doses up to 100 mg is not effective in reducing symptoms of panic anxiety induced by CCK₄. Received: 13 May 1996/Final version: 27 September 1996     

Tryptophan depletion does not modify response to CCK-4 challenge in patients with panic disorder after treatment with citalopram

Rationale Data by [Bell et al. J Psychopharmacol (2002) 16:5–14] suggest that a decrease in 5-HT neurotransmission predisposes to panic attacks and that the antipanic effect of SSRIs depends upon the availability of 5-HT in the brain.Objectives Our aim was to assess the effect of acute tryptophan depletion (TD) on cholecystokinin-tetrapeptide (CCK-4)- induced symptoms in patients with panic disorder (PD) who had responded to a 10-week treatment with a selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram.Materials and methods A total of 18 patients (6 males and 12 females, mean age 34.5 years) received a tryptophan-free amino acid drink and a control drink, each followed by a CCK-4 challenge (25 μg), 1 week apart in a double-blind crossover design.Results The results showed no significant differences in response to the CCK-4 challenge between the TD and the control conditions. Panic rate after the CCK-4 challenge was 27.8% after depletion and 33.3% after control drink (χ ²=0.13, p=0.72). No significant effects of TD were observed in panic intensity scores, subjective anxiety, or cardiovascular indices.Conclusions This study demonstrates that an acute lowering of brain 5-HT availability with TD does not affect response to a CCK-4 challenge in PD patients successfully treated with citalopram. Thus, the reduction of CCK-4 sensitivity following SSRI-treatment in patients with PD may be related to mechanisms other than 5-HT availability in the brain, possibly to a reduction in brain cholecystokinin receptor sensitivity.     

Delayed increase in LDL cholesterol following pentagastrin-induced panic attacks

Objective Panic disorder (PD) has been associated with an increased risk for cardiovascular (CV) morbidity and mortality. There are inconsistent reports of increased low-density lipoprotein cholesterol (LDL-C) in patients with PD. Studies have reported a correlation between cholesterol levels and the intensity and frequency of panic attacks (PAs), suggesting that an elevation in cholesterol could be due to physiological and neurochemical changes that occur during and after a PA. The objective of our study was to show that the occurrence of a PA is associated with an increase in LDL-C. Materials and methods We used a double-blind, placebo-controlled crossover design with randomized injections of placebo and pentagastrin in 18 patients with PD (11 men, 7 women) and 33 healthy-control subjects (24 men, 9 women). Results Pentagastrin-induced PAs were associated with a statistically significant 10.4% delayed (24 h) increase in LDL-C levels in male subjects. Such an effect was not observed in female subjects. Conclusion LDL-C levels are directly affected by the occurrence of a PA in males. These findings, in association with previous reports of increased cholesterol levels in PD patients, suggest that a chronic increase in LDL-C as a result of frequent PAs may be one of the mechanisms that contributes, at least in male patients, to previously reported increased CV risk in patients with PD. The gender difference and the temporal association between PAs and increased LDL-C may explain the inconsistency in the findings of previous investigations of cholesterol levels in PD patients.     

Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder

Normal controls (NC) (n=15), patients with panic disorder (PD) (n=13) and patients with major depression (MD) (n=17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo. Blood samples were assayed for cortisol and MCPP levels every 30 min. The PD group had an augmented cortisol release when compared to the other two groups. Finally, a significant correlation was found across all subjects between clinical anxiety level and cortisol release on MCPP. These data support the hypothesis of 5HT receptor hypersensitivity in PD.     

The selective serotonin reuptake inhibitor fluvoxamine suppresses post-feeding hyperactivity induced by food restriction in rats

Previous studies demonstrated that rats allowed access to running wheel with food restriction schedules run excessively. This hyperactivity consisted of a pre-feeding activity (an increase in running activity before the feeding time, also termed food-anticipatory activity: FAA) and a post-feeding activity (an increase in running activity after the feeding time, succeeding activity: SA). Here we evaluated the effect of fluvoxamine, a selective serotonin reuptake inhibitor, on food restriction-induced hyperactivity in rats. Furthermore, the effect of fluvoxamine on each of the FAA and the SA was also investigated. Rats were individually housed in a running-wheel cage under food restriction for 3 h per day, and running activity was measured for 7 consecutive days. This restricted feeding significantly increased the running activity and decreased body weight. Simultaneous administration of fluvoxamine (50 mg/kg/day, p.o.) for 7 days suppressed the increase in running activity (P<0.05) with no modification of the decrease in body weight or food intake. Analysis of each activity revealed that fluvoxamine's efficacy was observed only in the SA (p<0.01). These results suggest that repeated treatment with fluvoxamine attenuates the hyperactivity, which is exclusively dependent on the substantial reduction in the SA.     

A serotonin hypothesis of panic disorder

Despite numerous animal studies indicating an important role of serotonin (5-HT) in anxiety, 5-HT's function in the regulation of human anxiety has hardly been studied. Recent clinical studies suggest an involvement of 5-HT systems in panic disorder. This paper will briefly review the pertinent data on 5-HT and panic disorder and propose a specific hypothesis on 5-HT abnormalities in that disorder.     

N-methyl-citalopram: A quaternary selective serotonin reuptake inhibitor

We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [³H]citalopram and uptake studies with [³H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10⁻⁷ M as well as [³H]ketanserin binding to rat brain membranes at 10⁻⁵ M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.     

Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers

The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 µg) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered.     

Allelic variation in the serotonin transporter promoter affects neuromodulatory effects of a selective serotonin transporter reuptake inhibitor (SSRI)

Rationale. Antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) has been shown to depend on functional polymorphisms within the promoter region of the serotonin transporter gene (5-HTTLPR). This gene gives rise to a biallelic polymorphism designated long (l) and short (s). Homozygosity for the long variant (ll-genotype) is associated with a two times more efficient 5-HT uptake compared to the s/l- or s/s-genotype. Paired pulse transcranial magnetic stimulation is a feasible tool in detecting changes of motor cortex excitability induced by SSRIs. Objective. Our study aimed to measure neuromodulatory effects of SSRIs on cortical excitability in healthy volunteers characterized by distinct genotypes of the 5-HTTLPR. Methods. Cortical excitability was determined in eight genetically defined subjects pre- and post-ingestion of 60 mg citalopram. Results. Subjects with the ll-genotype of the 5-HTTLPR showed a significant enhancement of a particular component of motor cortex excitability (intracortical inhibition) as compared to volunteers without the ll-genotype. Conclusion. Distinct neuromodulatory effects after intake of citalopram based on allelic variations of the 5-HTTLPR may explain variable response of patients treated with SSRIs. Electronic Publication     

Relief of serotonin selective reuptake inhibitor induced sexual dysfunction with low-dose mianserin in patients with traumatic brain injury

RATIONALE: Serotonin selective reuptake inhibitors (SSRI) are commonly used in the treatment of many psychiatric disorders. Although possessing a relatively mild side effect profile, these drugs can cause a number of difficulties, including sexual dysfunction. A variety of strategies have been reported in the management of SSRI-induced sexual dysfunction, including dose reduction, drug holidays, substitution of another antidepressant drug, and various augmentation strategies, including use of sildenafil citrate (Viagra), buspirone, and others.OBJECTIVES: We aimed to examine the effect of adding another medication, mianserin, a mainly postsynaptic serotonin 2A agonist, to ongoing SSRI treatment in order to alleviate sexual side effects caused by SSRIs.METHODS: The patients included in this study suffered from traumatic brain injury and from psychiatric complications that necessitated the use of SSRIs. Seventeen patients were included in this study, all were being treated with SSRIs, and all complained of sexual dysfunction. Mianserin was added to on-going treatment at low doses, 7.5-15 mg/day. Patients were followed for at least 3 months.RESULTS: Fifteen of the 17 patients (88%) included in this study reported improvement in sexual dysfunction following this intervention. Ten (59%) reported that sexual function achieved pretreatment level. Five (29%) reported "significant improvement," and two (12%) did not respond to this intervention and were given sildenafil citrate, with good results. Side effects were minimal and included dry mouth, drowsiness, headaches, and agitation.CONCLUSIONS: The use of low-dose mianserin as an add-on treatment to SSRIs appears to be an effective and well tolerated intervention for sexual dysfunction caused by SSRIs.     

Fluvoxamine, a selective serotonin reuptake inhibitor, suppresses tetrahydrobiopterin in the mouse hippocampus

In the present study, we investigated the effects of fluvoxamine, a selective serotonin reuptake inhibitor, on brain tetrahydrobiopterin (BH4) levels. We directly measured levels of BH4 by Tani and Ohno's direct method as well as the serotonin (5-HT) turnover ratio, i.e. 5-hydroxyindoleacetic acid (5-HIAA)/5-HT, after sub-acute s.c. injection of fluvoxamine in the hippocampus of mice. Our animal model incorporated two risk factors of depression, social isolation and acute environmental change. Male ddY mice (6W) were housed in isolation (1 per cage; 35 days), injected with fluvoxamine (20 or 40 mg/kg; days 29-35), and exposed to novelty stress (20 min; day 35). In the stress session, behavioral parameters, i.e. total distance and rearing behavior, were measured. Isolation housing increased both behaviors. Fluvoxamine attenuated rearing behavior, but did not influence total distance. Isolation housing increased BH4 levels. Novelty stress increased BH4 levels in group housing, although it did not change them in isolation housing. Fluvoxamine suppressed BH4 levels. In isolation housing, fluvoxamine increased 5-HT turnover ratios, while it decreased them in group housing. In conclusion, fluvoxamine, housing condition, and novelty stress regulated BH4 levels. Fluvoxamine may have changed behavior and 5-HT turnover by suppressing BH4 levels as well as by inhibiting 5-HT reuptake.     

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT₂ receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of -endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of -endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in K_m was observed after treatment with fluvoxamine, whereas V_max decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT₂ receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.     

Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2C receptor

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic anti-depressant (TCA) imipramine with the rat serotonin 5-HT_2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT_2C and 5-HT_2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT_2C receptor in the choroid plexus, with a K_i value for inhibition of [³H]mesulergine binding of 55.4 nM. The K_i values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT_2C receptor without exhibiting inverse agonist activity. [³H]Ketanserin (5-HT_2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT_2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT_2A and 5-HT_2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT_2C receptor.     

Effect of combined treatment with noradrenaline and serotonin reuptake inhibitors on conditioned freezing

To clarify the therapeutic interaction between serotonin and noradrenaline reuptake inhibition on fear, this study examined the acute and subchronic effects of combined treatment with the selective serotonin reuptake inhibitor citalopram and the selective noradrenaline reuptake inhibitor reboxetine on the expression of conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks). After fear conditioning was achieved with footshocks, the drugs were administered to rats and freezing behavior, as an index of fear, was observed in the shock chamber. Acute and subchronic treatment with citalopram was reproducibly anxiolytic against conditioned freezing. Acute reboxetine worsened conditioned freezing and reversed the acute anxiolytic effects of citalopram, but this anxiogenic effect of noradrenaline reuptake inhibition was not observed after subchronic treatment. These results suggest that adding noradrenaline reuptake inhibitors to serotonin reuptake inhibitors adversely affects fear, at least with acute treatment.     

Fluvoxamine,a selective serotonin reuptake inhibitor,suppresses tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice

Rationale Tetrahydrobiopterin (BH₄) is a coenzyme of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), rate-limiting enzymes of monoamine biosynthesis. According to the monoamine hypothesis of depression, antidepressants will restore the function of the brain monoaminergic system, and BH₄ concentration.Objective To investigate the effects of fluvoxamine on BH₄ levels and dopamine (DA) and serotonin (5-HT) turnover in the mesoprefrontal system, incorporating two risk factors of depression, social isolation and acute environmental change.Methods Male ddY mice (6W) were divided into two housing groups, i.e. group-housing (eight animals per cage; 35 days), and isolation-housing (one per cage; 35 days), SC injected with fluvoxamine (20 or 40 mg/kg; days 29–35), and exposed to 20-min novelty stress (day 35). The levels of BH₄, DA, homovanilic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the prefrontal cortex and midbrain.Results Under the group-housing condition, novelty stress significantly increased BH₄ levels in both regions, and the HVA/DA ratio in the midbrain, whereas it did not change any parameters in either region under the isolation-housing condition. In the prefrontal cortex, fluvoxamine significantly decreased the 5-HIAA/5-HT ratio under the group-housing condition, and BH₄ levels and the HVA/DA ratio under the isolation-housing condition. In the midbrain, fluvoxamine significantly decreased all parameters, except for an increasing in the 5-HIAA/5-HT ratio under the isolation-housing condition.Conclusion Isolation-housing suppressed the increase of BH₄ levels and DA turnover elicited by novelty stress. Fluvoxamine suppressed BH₄ levels, and DA and 5-HT turnover. Fluvoxamine may have altered DA turnover by suppressing BH₄ levels.