J Clin Psychiatry 1997;58 Suppl 5:50-4 Related Articles, Books, LinkOut

Role of serotonin drugs in the treatment of social phobia.

Tancer ME, Uhde TW.
Psychiatry Service, Detroit Veterans Affairs Medical Center, MI 48201, USA.

Social phobia is a common anxiety disorder that is underdiagnosed and undertreated. To date, three classes of serotonin drugs have been used to treat patients suffering from social phobia. These include the serotonin selective reuptake inhibitors (SSRIs), the partial 5-HT1A agonist buspirone, and the 5-HT3 antagonist ondansetron. Although none of the serotonin agents have yet been directly compared with the gold standard monoamine oxidase inhibitor phenelzine or the high potency triazolobenzo-diazepines alprazolam or clonazepam, the SSRIs, as a class, appear to be clinically useful agents. Further studies using larger sample sizes and double-blind methodology are needed to clarify the role of serotonin drugs in the treatment of social phobia.
 

Physical Symptoms Associated With Social Phobia - CME Reviews (Full article here)

Blushing

Blushing, or flushing -- as well as a fear of blushing -- has been noted to be a prevalent and psychologically debilitating condition.14 Charles Darwin was the pioneer who related blushing to social anxiety: "The thinking of others thinking of us . . . excites a blush. Most persons, while blushing intensely, have their mental powers confused. They lose their presence of mind and utter singularly inappropriate remarks."15

Goldstein16 reported that clonidine was successfully used to treat a patient with social phobia and blushing, when treatment with alprazolam, phenelzine, and propranolol failed. Clonidine has also been used to treat the vasomotor instability associated with menopause,17 with variable results, in a dosage range of 0.05-0.15 mg/day. Goldstein's patient with social phobia16 took 0.1 mg bid with continued benefit at 4-month follow-up. Limiting side effects can include orthostatic hypotension, sedation, depression, fatigue, and gastrointestinal upset.

16) Goldstein S. Treatment of social phobia with clonidine. Biol Psychiatry. 1987;22:369-372.
Nausea
Ondansetron, an antiemetic with anxiolytic properties, has been shown to be effective for treatment of social phobia in a double-blind, placebo-controlled study.30 Although Ondansetron might be ideal in social phobia-related nausea, its cost is prohibitive.
 
30) DeVaugh-Geiss J, Bell J. Multicenter trial of a 5-HT3 antagonist, ondansetron, in social phobia (poster). Presented at: Annual Meeting of the American College of Neuropsychopharmacology; December 1994; San Juan, Puerto Rico.
 
Anxiety 1996;2(4):199-202 Related Articles, Books, LinkOut

Ondansetron in the treatment of panic disorder.

Schneier FR, Garfinkel R, Kennedy B, Campeas R, Fallon B, Marshall R, O'Donnell L, Hogan T, Liebowitz MR.

Anxiety Disorders Clinic, New York State Psychiatric Institute, New York, NY 10032, USA.

PMID: 9160623 [PubMed - indexed for MEDLINE]

Anxiety Disorders Clinic
Michael R. Liebowitz, M.D., Director

4/2/2001 (http://www.nyspi.org/development/web/rs2.htm):

"A number of specific areas of study within the Anxiety Disorders CIinic have been quite active:

Panic Disorder During the past year, the Anxiety Disorders Clinic, as part of a full Phase-III development program, completed two multi-center, industry-supported, double-blind efficacy and safety trials of the 5HT3 antagonist ondansetron. To date, ondansetron is the most pharmacologically specific anti-panic agent to be developed. Positive results would provide us with a better understanding of the mechanisms of anti-panic drug action. Results of the studies are now being analyzed.

Anxiety Disorders Clinic (http://www.nyspi.org/development/web/pidpt%5Ft.htm):
The Anxiety Disorders Clinic has continued its work to advance an understanding of the diagnosis, etiology, and treatment of DSM-IV anxiety disorders. Efforts have been particularly concentrated on panic disorder and agoraphobia, social phobia, obsessive-
compulsive disorder (OCD), generalized anxiety, hypochondriasis, post-traumatic stress disorder, and new areas of research activity involving the neuropsychiatric sequelae of Lyme disease, mixed anxiety and depression, and cross-cultural studies. 
Panic Disorder An open trial of the 5HT3 antagonist ondansetron was completed in the earlier part of the year, under the direction of Dr. Michael Liebowitz. Results from this pilot were so favorable that a multi-center, industry supported, double-blind efficacy trial was initiated, which confirmed our findings. A full Phase-III development program is now under way in which we are participating. Ondansetron may work faster and be better tolerated than existing anti-panic medication treatments. A multi-center trial of sertraline in panic disorder has also begun in our clinic. "

Sertraline has been approved for anxiety disorders for years now so what happened to ondansetron?  Marketing decision perhaps as SSRIs reign through their product cycle.  It's unfortunate ondansetron commonly sells for $40/pill in the US (price based on lower volume sales of limited indications & the country's price regulations) as it has been reported effective for hard to treat conditions such as refractory anxiety disorders, withdrawal and pain syndromes, fibromyalgia, gastrointestinal motility disorders, Tourette's syndrome, pruritus, flushing disorders and erythemateous rosacea & ocular rosacea.

Like other SSAs (Selective Serotonin Antagonists), it has a much lower incidence of sexual side effects than SSRIs.

 

Wollina U.
The response of erythematous rosacea & ocular rosacea to ondansetron.
Br J Dermatol. 1999 Mar;140(3):561-2.
PMID: 10233299 [PubMed - indexed for MEDLINE]

The neurotransmitter substance P and neuropeptide vasoactive intestinal peptide have been shown to be elevated.

Some of these effects are related to an antagonism of ondansetron to substance P

 

 
CNS Drug Rev 2001 Summer;7(2):199-213 Related Articles, Books

Ondansetron: a selective 5-ht(3) receptor antagonist and its applications in cns-related disorders.

Ye JH, Ponnudurai R, Schaefer R.

Department of Anesthesiology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA. ye@umdnj.edu

Ondansetron is a selective 5-hydroxytryptamine(3) (5-HT(3)) receptor antagonist that has been introduced to clinical practice as an antiemetic for cancer treatment-induced and anesthesia-related nausea and vomiting. Its use under these circumstances is both prophylactic and therapeutic. It has a superior efficacy, safety and pharmacoeconomic profile compared with other groups of antiemetics, namely antidopaminergics, antihistamines and anticholinergics. However, its place in the management of anticipatory and delayed vomiting in cancer treatment and as a rescue antiemetic in surgical patients needs to be further explored. Furthermore, recent animal and human research also reflects its possible novel application in the treatment of other disease states, such as alcoholism, cocaine addiction, opioid withdrawal syndrome, anxiety disorders, gastrointestinal motility disorders, Tourette's syndrome and pruritus. This review revisits the widespread physiological and pathological effects of 5-HT and discusses both the basic science literature and the clinical developments responsible for the conventional and novel uses of ondansetron. In addition, new discoveries relating to the effects of ondansetron on other receptors/channels and their possible therapeutic applications are presented.

PMID: 11474424 [PubMed - in process]
 
Scand J Rheumatol Suppl 2000;113:37-45 Related Articles, Books

Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists.

Wolf H.

Dept. of Clinical Research, Novartis Pharma GmbH, Nuremberg, Germany.

5-HT3-receptor antagonists are potent and highly selective competitive inhibitors of the 5-HT3-receptor with negligible affinity for other receptors. They are rapidly absorbed and penetrate the blood-brain barrier easily. 5-HT3-receptor antagonists are metabolized by diverse subtypes of the cytochrome P450-system, metabolites are excreted mainly in urine. Half-lifes in healthy subjects vary from 3-4 hours (ondansetron, granisetron) to 7-10 hours (tropisetron, hydrodolasetron). 5-HT3-receptor antagonists do not modify any aspect of normal behaviour in animals or induce remarkable changes of physiological functions in healthy subjects. They are well tolerated over wide dose ranges, most common side effects in clinical use are headache and obstipation. Clinical efficacy was first established in chemotherapy-induced emesis. In this indication, 5-HT3-receptor antagonists set a new standard regarding efficacy and tolerability. Further established indications are radiotherapy-induced and post-operative emesis. Antiemetic efficacy results from a simultaneous action at peripheral and central 5-HT3-receptors. Other peripheral actions include reduction of secretion and diarrhea caused by increased intestinal serotonin content (e.g. in carcinoid syndrome), a limited antiarrhythmic activity and a reduction of experimentally induced pain. CNS effects comprise anxiolysis, attenuation of age-associated memory impairment, reduction of alcohol consumption in moderate alcohol abuse and an antipsychotic effect in patients with parkinson psychosis. In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favourable treatment results with 5-HT3-receptor antagonists in fibromyalgia. (another condition associated with increased levels of substance P).

Publication Types:
  • Review
  • Review, tutorial

PMID: 11028830 [PubMed - indexed for MEDLINE]
 
 
Naunyn Schmiedebergs Arch Pharmacol 1993 Jan;347(1):111-4 Related Articles, Books

Inhibition by 5-HT3 receptor antagonists of release of cholecystokinin-like immunoreactivity from the frontal cortex of freely moving rats.

Raiteri M, Paudice P, Vallebuona F.

Istituto di Farmacologia e Farmacognosia, Universita degli Studi di Genova, Italia.

Effects of the 5-HT3 receptor antagonists, ondansetron and tropisetron, on the release of cholecystokinin-like immunoreactivity (CCK-LI) in rat frontal cortex were investigated in conscious, unrestrained rats using intracerebral microdialysis. The release of CCK-LI was augmented by perfusion with 100 micrograms/ml veratrine and was fully Ca(2+)-dependent and tetrodotoxin-sensitive. Ondansetron and tropisetron, each at 0.1-1 mumol/l, decreased concentration-dependently the veratrine-evoked efflux of CCK-LI. The reduction of CCK-LI output was approximately 30% when the antagonists were infused at 0.1 mumol/l. The data suggest that 5-HT3 receptor antagonists prevent the release of CCK evoked by endogenous 5-hydroxytryptamine. These drugs may thus represent a novel therapeutic approach in disease states, like anxiety, in which an inappropriately high release of brain CCK or 5-hydroxytryptamine seems to be involved.

PMID: 8446179 [PubMed - indexed for MEDLINE]
 
Methods Find Exp Clin Pharmacol 1997 Mar;19(2):107-11 Related Articles, Books

Antianxiety profile of ondansetron, a selective 5-HT3 antagonist, in a novel animal model.

Roychoudhury M, Kulkarni SK.

Pharmacology Division, Panjab University, Chandigarh, India.

The profile of action of ondansetron was assessed in a novel animal model of anxiety. The mirrored chamber is a nonpunishing quantitative model of anxiety which measures approach-conflict behavior. Ondansetron in all the doses tested (0.01, 0.1 and 1 mg/kg i.p.) showed significant anxiolytic action as compared to naive mice, but it was less potent as compared to a well-known anxiolytic, diazepam (1 mg/kg). These results suggest that ondansetron has anxiolytic efficacy in nonconflict paradigms of anxiety, a response not mediated by the conventional neurotransmitter receptors. GABA-benzodiazepine as flumazenil (4 mg/kg), a benzodiazepine receptor antagonist, failed to reverse the behavioral parameters evoked by ondansetron.

PMID: 9151286 [PubMed - indexed for MEDLINE]
 
Clin Investig 1994 Oct;72(10):811-3 Related Articles, Books, LinkOut

Treatment of acute gouty arthritis with the 5-hydroxytryptamine antagonist ondansetron.

Schworer H, Ramadori G.

Abteilung Gastroenterologie und Endokrinologie, Medizinische Universitatsklinik, Gottingen, Germany.

We report on a 28-year-old man with hematemesis, renal dysfunction, and arterial hypertension who suffered from an acute gouty attack presenting as podagra. Because of the accompanying symptoms conventional treatment of the gouty attack with colchicine or nonsteroidal anti-inflammatory drugs was contraindicated. We treated the pain of acute arthritis with the specific 5-hydroxytryptamine subtype 3 receptor antagonist ondansetron. Within 30 min after intravenous injection of this drug a substantial degree of pain relief had occurred. Unwanted side effects due to treatment were not observed. It is suggested that the 5-hydroxytryptamine released during a gouty attack induces pain via activation of 5-hydroxytryptamine subtype 3 receptors on nociceptive afferent nerve fibers. 5-Hydroxytryptamine subtype 3 receptor antagonists may therefore be a novel class of drugs for the effective treatment of acute gouty attacks when conventional treatment is contraindicated.

PMID: 7865988 [PubMed - indexed for MEDLINE]

Anesth Analg 1997 Nov;85(5):1116-21 Related Articles, Books

Ondansetron exhibits the properties of a local anesthetic.

Ye JH, Mui WC, Ren J, Hunt TE, Wu WH, Zbuzek VK.

Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Newark 07103-2714, USA. ye@umdnj.edu

The purpose of this study was to determine whether ondansetron (OND) has local anesthetic effects. Using a patch-clamp technique, we showed that OND concentration dependently blocked Na channel currents in freshly isolated neurons of rat brains with a 50% inhibition concentration of 12 microM. The blockade started immediately when OND was applied to the cell body using a fast perfusion system, reached a plateau within 15 s, and recovered to the control level within 30 s after washout of the OND-containing solution. Because this is a known property of local anesthetics, we used the tail-flick technique to verify this effect in vivo in Sprague-Dawley rats (n = 46). OND was injected subcutaneously into the tail at the doses of 0.08, 0.16, and 0.2 mg. The tail-flick latency increased 2 min after OND injection, reaching the plateau within 5 min. This effect was dose-related, lasting from 10 to 25 min. These preliminary data indicate that OND, a selective 5-HT3 receptor antagonist, might serve as a prototype molecule for development of a novel series of local anesthetics. IMPLICATIONS: Ondansetron is a drug used to prevent vomiting, especially in cancer patients after chemotherapy. We found that it also causes numbness when injected under the skin. This new action may contribute to its role in "calming the stomach." We studied the effect of ondansetron on the isolated brain cells of live rats.

PMID: 9356111 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1999 Nov;24(9):1015-8 Related Articles, Books, LinkOut

Effects of peripheral stem cell or bone marrow reinfusion on peripheral serotonin metabolism.

Wymenga AN, van der Graaf WT, Kema IP, Smit Sibinga CT, Vries EG, Mulder NH.

Department of Medical Oncology, University Hospital Groningen, The Netherlands.

Reinfusion of autologous hematopoietic peripheral blood stem cells (PBSC) or bone marrow is often accompanied by flushing, dyspnea, abdominal cramping, nausea and diarrhea. These symptoms and the observation that they can be prevented by ondansetron, a selective 5-HT3 receptor antagonist, led to the assumption that these side-effects are due to infusion of free serotonin during the reinfusion of PBSC or bone marrow. Twenty-five patients with solid tumors received, after myeloblative chemotherapy, a total of 30 reinfusions of PBSC and/or bone marrow. In 17 patients, serotonin levels in the bags containing the PBSC were measured. In all patients, platelet serotonin levels were determined before and 1 h post-reinfusion. In addition, before and 24 h after reinfusion urine was collected for determination of 5-hydroxyindole acetic acid (5-HIAA) and serotonin concentrations. Mean (+/- s.d.) total serotonin concentration in the bags was 2404 +/- 1555 nmol/l. Mean total volume reinfused was 471 +/- 185 ml. After reinfusion, the mean (+/- s.d.) levels of serotonin in platelets in patients increased from 3.2 +/- 1.4 nm/10(9) at baseline to 3.8 +/- 2.0 nm/10(9) (P = 0.02). Neither 24 h urinary 5-HIAA nor serotonin levels were affected. These results indicate that reinfusion of PBSC or bone marrow is accompanied by substantial infusion of free serotonin, which might explain the observed side-effects and justify the use of 5-HT3 receptor antagonists as pre- medication for this procedure.

PMID: 10556962 [PubMed - indexed for MEDLINE]

C Fiber

The A-Delta Fiber pain pathway carries information away from damaged skin tissue at a rapid rate. This information reflects the sharp pain experienced almost immediately following damage to the skin.

The C Fiber pain pathway carries information away from damaged skin tissue at a slow pace. This information reflects the burning and aching sensation associated with prolonged pain following damage.

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