Posted by Ame Sans Vie on July 25, 2003, at 21:56:31
First, some abstracts concerning Klonopin (clonazepam) in the treatment of social phobia:
1. A COMPARISON OF THE EFFICACY OF CLONAZEPAM AND COGNITIVE-BEHAVIORAL GROUP THERAPY FOR THE TREATMENT OF SOCIAL PHOBIA
Michael W. Otto Ph.D., a, Mark H. Pollack M.D.a, Robert A. Gould Ph.D.a, John J. WorthingtonIII M.D.a, Eliza T. McArdle B.A.a, Jerrold F. Rosenbaum M.D.a and Richard G. Heimberg Ph.D.b
--There is a growing body of evidence that social phobia may be treated effectively by either pharmacologic or cognitive-behavioral interventions, but few studies have examined the relative benefits of these treatments. In this study, we examined the relative efficacy of pharmacotherapy with clonazepam and cognitive-behavioral group therapy (CBGT) for treating social phobia. In addition, we examined potential predictors of differential treatment response. Outpatients meeting Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria for social phobia were randomly assigned to treatment. Clinician-rated and patient-rated symptom severity was examined at baseline and after 4, 8, and 12 weeks of treatment. All clinician-rated assessments were completed by individuals blind to treatment condition. Patients in both conditions improved significantly, and differences between treatment conditions were absent, except for greater improvement on clonazepam on several measures at the 12-week assessment. Symptom severity was negatively associated with treatment success for both methods of treatment, and additional predictors––sex, comorbidity with other anxiety or mood disorders, fear of anxiety symptoms, and dysfunctional attitudes––failed to predict treatment outcome above and beyond severity measures. In summary, we found that patients randomized to clinical care with clonazepam or CBGT were equally likely to respond to acute treatment, and pretreatment measures of symptom severity provided no guidance for the selection of one treatment over another.
2. BENZODIAZEPINES AND ANTICONVULSANTS FOR SOCIAL PHOBIA (SOCIAL ANXIETY DISORDER)
--Both benzodiazepines and conventional anticonvulsants have been evaluated as treatments for social phobia (social anxiety disorder). Among the benzodiazepines, clonazepam is the best studied, although there is reason to expect that all benzodiazepine anxiolytics would be effective for this condition. Among the anticonvulsants, gabapentin and pregabalin, an analogue of gamma-aminobutyric acid (GABA), have been shown to be more effective than placebo in double-blind studies. Other than a small negative open study of valproic acid for social phobia, there is a paucity of information on whether other anticonvulsants might be useful for this condition.
3. PHARMACOTHERAPY OF SOCIAL ANXIETY DISORDER
Blanco C, Antia SX, Liebowitz MR.
--Over the last few years, a number of medications have demonstrated their efficacy in the acute treatment of social anxiety disorder. At present, selective serotonin reuptake inhibitors probably constitute the first line treatment, based on their safety, tolerability, and efficacy in the treatment of social anxiety disorder and common comorbid conditions. Data from single trials suggest that clonazepam, bromazepam, and gabapentin may have efficacy similar to the serotonin reuptake inhibitors, but further studies are needed to confirm these findings. The monoamine oxidase inhibitor phenelzine appears to be at least as efficacious as these other agents, but should be reserved for cases that fail to respond to these safer medications. Among the reversible inhibitors of monoamine oxidase A, brofaromine may also be an effective drug, while moclobemide appears to be less potent. Future research directions should include delineating ways to achieve remission (as opposed to response); developing strategies for augmenting partial responders and treating nonresponders to first line approaches; studying the long-term response to medication and prevention of relapse when medication is discontinued; clarifying ways to integrate psychosocial and pharmacological treatment approaches; developing predictors of which patients do best with which treatments; and the treatment of social anxiety disorder in children and adolescents.
4. A REVIEW OF 19 DOUBLE-BLIND PLACEBO-CONTROLLED STUDIES IN SOCIAL ANXIETY DISORDER (SOCIAL PHOBIA)
--Nineteen double-blind placebo-controlled studies on the treatment of Social Anxiety Disorder (Social Phobia) are reviewed. Initial trials yielded a high degree of efficacy for phenelzine, a large difference between drug and placebo and a low rate of placebo response. Controlled studies with RIMAs (moclobemide and brofaromine) yielded more moderate levels of efficacy and more pronounced placebo effects. Results of the Liebowitz Social Anxiety Scale (LSAS) permit a comparison of the outcomes of the different controlled trials. Overall, the reduction in the mean total score with various drugs is inferior to 50%, probably because the chronic nature of the disorder is not amenable to drastic changes in short-term trials. Results with the LSAS and other scales justify a ranking of the efficacy of the drugs: Classical MAOIs > SRIs > RIMAs. Two controlled studies with benzodiazepines (clonazepam and bromazepam) would position them together with the SRIs relative to efficacy but with problems associated with unwanted effects and dependence. Controlled studies with SRIs (paroxetine and fluvoxamine) demonstrated very significant differences from placebo. Paroxetine is the SRI most extensively studied in Social Anxiety Disorder with positive therapeutic results.
5. 2-YEAR FOLLOW-UP OF SOCIAL PHOBIA STATUS AFTER A BRIEF MEDICATION TRIAL
Sutherland SM, Tupler LA, Colket JT, Davidson JR.
--Although social phobia is thought to be a chronic disorder, little is known about its long-term course in patients who engage in brief treatment studies. We, therefore, conducted a follow-up study of social phobics who had participated in a brief, placebo-controlled treatment trial of clonazepam. Of the original 75 subjects, 56 were assessed through telephone interview and self-report questionnaires that evaluated current social phobia symptoms. Information was also gathered about treatment received in the 2-year interval since the initial pharmacotherapy trial. The group as a whole showed maintenance of the gains acquired during initial treatment. On a number of symptom scales, subjects initially treated with clonazepam exhibited significantly less severe scores compared with placebo subjects. This study provides evidence of long-term benefit for social phobics when treated with a brief medication trial.
6. SOCIAL PHOBIA: A PHARMACOLOGIC TREATMENT OVERVIEW
--Generalized and specific social phobias are common, chronic, and potentially debilitating conditions. In recent years, there have been major advances in the pharmacotherapy of social phobia; efficacy has become better established for a diverse group of medications. Controlled studies have shown substantial benefit from monamine oxidase inhibitors, both irreversible (phenelzine) and reversible (brofaromine and moclobemide). The serotonin selective reuptake inhibitor antidepressants have shown promise in case reports, uncontrolled studies, and double-blind trials (fluvoxamine and sertraline). The benzodiazepines have been extensively used to treat social phobia, although only recently has a controlled, double-blind study confirmed efficacy (clonazepam). The beta-adrenergic receptor blockers have been widely used on an as needed basis to treat specific social phobia (i.e., performance anxiety), although their value in generalized social phobia has not been convincing. Finally, pharmacologic approaches to social phobia must take into consideration the common coexistence of other psychiatric conditions.
7. MEDICATION THERAPY FOR SOCIAL PHOBIA
Marshall RD, Schneier FR, Fallon BA, Feerick J, Liebowitz MR.
--Social phobia, though the third most common psychiatric disorder in the United States, has received little systematic attention until recently. Chronic and disabling symptoms usually precede other disorders in individuals with comorbidity, including alcohol abuse. Though about 80% of individuals do not seek treatment, controlled trials have demonstrated efficacy for several medications, of which phenelzine (an irreversible monoamine oxidase inhibitor [MAOI]) is the best studied. The benzodiazepines, clonazepam and alprazolam, also hold promise. New reversible MAOIs such as moclobemide and brofaromine are under investigation; fluoxetine and other serotonin selective reuptake inhibitors need further controlled study. The benefits of group cognitive-behavioral therapy also appear substantial. Issues for future investigation include long-term outcome, differential therapeutics, diagnostic subtyping, and combination treatments.
8. TREATMENT OF SOCIAL PHOBIA WITH BENZODIAZEPINES
Davidson JR, Tupler LA, Potts NL.
--Although social phobia is a common and highly treatable anxiety disorder, the majority of social phobics do not receive treatment. Without intervention, it is unlikely that patients will attain significant relief from the symptoms and disability associated with the disease. The authors review the results of studies concerning the use of high-potency benzodiazepines in the treatment of social phobia. These studies, which include open trials as well as a double-blind, placebo-controlled evaluation of clonazepam, have demonstrated clinical efficacy and suggest a therapeutic role for this drug class in the treatment of social phobia. Developmental work with the Davidson Brief Social Phobia Scale is described, along with predictors of treatment outcome for clonazepam and placebo and relapse data upon discontinuation of both treatments. Finally, the authors discuss general issues concerning the relapse of patients upon drug discontinuation, the long-term use of benzodiazepines, and other important issues concerning the use of these agents for the treatment of social phobia.
9. TREATMENT OF SOCIAL PHOBIA WITH CLONAZEPAM AND PLACEBO
Davidson JR, Potts N, Richichi E, Krishnan R, Ford SM, Smith R, Wilson WH.
--Clonazepam and placebo were administered in a double-blind pilot study to 75 outpatients with social phobia. The mean maximum dose of clonazepam was 2.4 mg/day at endpoint (range, 0.5 to 3 mg). Treatment was continued for up to 10 weeks. The results of an intent-to-treat analysis indicated superior effects of clonazepam on most measures. Response rates for clonazepam and placebo were 78.3 and 20.0%. Drug effects were apparent on performance and generalized social anxiety, on fear and phobic avoidance, on interpersonal sensitivity, on fears of negative evaluation, and on disability measures. Significant differences were evident by week 1, 2, or 6, depending upon the rating scale used. Clonazepam was well tolerated in general, although unsteadiness and dizziness were more severe and persistent than was the case for placebo subjects.
10. LONG-TERM TREATMENT OF SOCIAL PHOBIA WITH CLONAZEPAM
Davidson JR, Ford SM, Smith RD, Potts NL.
--Twenty-six socially phobic outpatients were treated with clonazepam for the relief of symptoms. At evaluation, which took place after an average of 11.3 months of continuous treatment, 22 (84.6%) patients showed good improvement and 4 (14.4%) showed no improvement or were not recovered. The dose declined over time, from a peak mean of 2.1 mg/day to a mean of 0.94 mg/day at follow-up. Side effects are described, along with individual case descriptions that illustrate important aspects of the use of benzodiazepines for the treatment of social phobia.
11. CLONAZEPAM FOR THE TREATMENT OF SOCIAL PHOBIA
Reiter SR, Pollack MH, Rosenbaum JF, Cohen LS.
--Nine of 11 patients with social phobia of both the generalized and performance type responded to treatment with clonazepam in total daily doses ranging from 0.75 to 3 mg. Only 2 of these 9 had comorbid panic disorder; the benefit for social phobic symptoms appears independent of clonazepam's putative efficacy for panic disorder.
12. SOCIAL PHOBIA AND CLONAZEPAM
Ontiveros A, Fontaine R.
--Five patients meeting the DSM-III-R criteria for social phobia, without any other psychiatric diagnosis, were treated with clonazepam, a high potency benzodiazepine. All patients improved markedly within four weeks. By the end of the eighth week of treatment, a marked improvement of their symptoms was reported. The adverse effects were minimal at an average dose of 3 mg per day. The authors suggest that clonazepam is a safe and effective medication in the treatment of social phobia. Moreover, clonazepam is easier to use as compared to other drugs which are used (atenolol, phenelzine, alprazolam).
13. CLONAZEPAM IN THE TREATMENT OF SOCIAL PHOBIA: A PILOT STUDY
Munjack DJ, Baltazar PL, Bohn PB, Cabe DD, Appleton AA.
--Twenty-three patients who met DSM-III-R criteria for social phobia were randomly assigned either to a clonazepam treatment group or to a nontreatment control group in an 8-week pilot study. Clonazepam was found to have a significant effect on the treated patients, as demonstrated by scores on a variety of instruments measuring overall anxiety and phobic avoidance, and social phobic symptoms. Initial sedation, which was experienced by 70% of the treated subjects, was the most common side effect of clonazepam treatment and usually resolved spontaneously or with dose reduction. The preliminary findings of this pilot study are sufficiently promising to warrant further study of the efficacy of clonazepam in this condition.
A few studies about the use of Xanax (alprazolam) in treating social phobia, avoidant personality disorder, panic disorder and agoraphobia (all of which I have, which may help to explain why Xanax XR works so well for me):
1. ALPRAZOLAM TREATMENT OF AVOIDANT PERSONALITY TRAITS IN SOCIAL PHOBIC PATIENTS
Reich J, Noyes R Jr, Yates W.
--The authors examined the effect of alprazolam treatment on avoidant personality traits in 14 DSM-III-R social phobics. Six of the nine avoidant traits examined improved with treatment. However, all but one trait (avoiding social or occupational activities requiring interpersonal contact) returned to baseline levels posttreatment. Treatment response and intercorrelation of items indicated two traits that may represent a separate segment of avoidant personality: "No close friends or confidants outside of relatives and family members" and "Exaggerates the potential dangers or risks of everyday situations."
2. ALPRAZOLAM IN PANIC DISORDER AND AGORAPHOBIA: RESULTS FROM A MULTICENTER TRIAL. PATIENT ACCEPTANCE, SIDE EFFECTS, AND SAFETY
Noyes R Jr, DuPont RL Jr, Pecknold JC, Rifkin A, Rubin RT, Swinson RP, Ballenger JC, Burrows GD.
--In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.
3. A PILOT STUDY OF TREATMENT OF SOCIAL PHOBIA WITH ALPRAZOLAM
Reich J, Yates W.
--Fourteen patients with DSM-III social phobia were treated with alprazolam in an open study. Multiple measures of symptoms and disability showed significant improvement. The symptoms improved during the first and second weeks, and disability improved at 3 weeks and beyond. After medication withdrawal the symptom and disability measures were no longer significantly different from those at baseline.
4. ALPRAZOLAM IN THE TREATMENT OF SOCIAL PHOBIA
Lydiard RB, Laraia MT, Howell EF, Ballenger JC.
--Pharmacological treatment of social phobia has not been extensively studied. Recent reports suggest that social phobia may be treated with monoamine oxidase inhibitors, tricyclic antidepressants, beta-blockers, or clonidine. The authors describe four patients with social phobia who responded moderately to markedly well when treated with the triazolobenzodiazepine alprazolam. Patients with social phobia and patients with agoraphobia with panic attacks differ in the focus of anxiety, sensitivity to lactate infusion, and the pattern of symptoms during anxiety episodes. However, there is significant overlap in the clinical features of these two patient groups. The preliminary finding that several types of pharmacological agents that are effective in treating agoraphobia with panic attacks may also be effective in treating social phobia suggests that the two disorders may share some common pathophysiology.
5. BENZODIAZEPINES IN PANIC DISORDER AND AGORAPHOBIA
--Benzodiazepines, particularly alprazolam, are quickly becoming the drugs of first choice in the treatment of many cases of panic and agoraphobia. The reason for this choice is that these drugs are safer to use, quicker in onset of action, easier for the physician to prescribe and more pleasant for the patient to take than the alternatives. Although the treatment of panic disorder and agoraphobia has been best studied with the benzodiazepine alprazolam, it now appears likely that other benzodiazepines, for example diazepam, lorazepam and chlorazepam, may also be effective when correctly used. There is no reason at this point to believe that any of the benzodiazepines are unique in this regard. Future research will undoubtedly clarify this observation. In the meantime, it is hoped that some of the guidelines in this paper will help the practicing clinician in the management of his patient with this disabling and neglected disease.
Now some info regarding the use of tramadol in OCD and depression:
1. TRAMADOL INDUCES ANTIDEPRESSANT-TYPE EFFECTS IN MICE
Rojas-Corrales MO, Gibert-Rahola J, Mico JA
--Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibits preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.
2. EFFECTS OF CHRONIC TRAMADOL ON PRE- AND POST-SYNAPTIC MEASURES OF MONOAMINE FUNCTION
Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA.
--The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150-200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H]dihydroalprenolol and [3H]ketanserin binding was lower in the chronic tramadol group than controls (beta: 37+/-8 and 217+/-56 fmol/mg; 5-HT2A: 23+/-3 and 44+/-7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164+/-7%) than tramadol-treated rats (144+/-6%; p < 0.05). Chronic tramadol had no effect on dorsal raphe (DRN) or median raphe (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p = 0.055) in DRN. The selective 5-HT1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54+/-2 versus 32+/-6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre- and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology.
3. VENLAFAXINE-TRAMADOL SIMILARITIES
Markowitz JS, Patrick KS
--Venlafaxine [Effexor] and tramadol are relatively new compounds indicated for the treatment of depression and pain, respectively. These agents share a number of molecular and pharmacological features that may allow for broader and overlapping therapeutic indications for both drugs. Additionally, certain patient populations with coexisting depression and pain syndromes could potentially be treated with a single agent.
4. "NEW HOPE FOR 3 MILLION AMERICANS"
PR Newswire, July 9, 2002; NewsRx.com, Aug. 19, 2002
--UC has received a U.S. patent to use the painkiller tramadol to treat obsessive/compulsive disorder (OCD) and related disorders i.e. eating disorders, Tourette syndrome. "In some patients, tramadol can...decrease symptoms within 30 minutes to an hour," according to Dr. Nathan Shapira, former UC department of psychiatry resident. "Traditional drugs...have to be taken at least 8-12 weeks before any response is apparent." Approximately 3.3 million Americans suffer from OCD. In clinical trials with tramadol, Dr. Shapira, now assistant professor of psychiatry at the University of Florida, said, "All the patients we have studied have had anywhere from 25-65 percent relief from their symptoms."
5. THE MU OPIOID RECEPTOR GENE AS A CANDIDATE FOR THE STUDY OF OBSESSIVE COMPULSIVE DISORDER WITH AND WITHOUT TICS
1N. Urraca, 1B. Camarena, 1L. Gómez-Caudillo, 2M.C. Esmer, 1H. Nicolini
1Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco no.101, 2Instituto Nacional de Pediatría, Insurgentes Sur 3700
--Obsessive-Compulsive disorder (OCD) is a complex psychiatric disease characterized by recurring obsessions or compulsions that cause significant distress to the patient. The etiology of this disorder remains largely unknown, although a genetic component has been suggested based on family, twin, segregation analysis and association studies. Many candidate genes have been evaluated based on a possible serotoninergic and dopaminergic brain dysfunction. We postulate the mu opioid receptor gene as a candidate because some observations support a role of the opioid system in OCD. The opioid antagonist, naloxone, rapidly exacerbates OCD symptoms and the opioid agonist, tramadol, was reported to be effective in the treatment of some patients. We studied two single nucleotide polymorphisms (C17T and A11G) in 51 trios with OCD. Genotyping was analyzed transmission desequilibrium test (TDT). The allelic variant +17T of the C17T polymorphism had a low frequency (1%) in our population that did not allow for statistic analysis. However, for the allelic variant +G of the A118G polymorphism we were able to performed statistical comparisons. We looked for differences in clinical variables as gender (29 males and 22 females), comorbid depression (n=7), tics (n=17) and the type of obsessions and compulsions. Our results showed a trend toward significance (p=.065) for TDT in patients with comorbid tics. After subgrouping this sample, we ended up with decreased statistical power due to sample size. But, still it is an interesting finding that should be tested in a larger sample of OCD patients with tics.
Finally, here's some interesting info on morphine, since you also expressed an interest in it, and opioids in general:
1. THE COGNITIVE AND PSYCHOMOTOR EFFECTS OF MORPHINE IN HEALTHY SUBJECTS: A RANDOMIZED CONTROLLED TRIAL OF REPEATED (FOUR) ORAL DOSES OF DEXTROPROPOXYPHENE, MORPHINE, LORAZEPAM AND PLACEBO
O'Neill WM, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K
--Ten healthy subjects (four male) of mean age 31 years (range 25-40) took part in a randomized double-blind four-way crossover study to examine the cognitive and psychomotor effects of repeated oral doses of dextropropoxyphene and morphine. Four treatments were compared: dextropropoxyphene napsylate 100 mg, morphine sulphate 10 mg, lorazepam 0.5 mg and placebo. Four doses of each drug were given at 4-h intervals to each subject on four separate study days at least 1 week apart. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam impaired the speed of responding on all tasks in which speed was recorded (except digit vigilance) and increased subjective ratings of calmness. Morphine had one major effect, which was to increase the accuracy of responding on the choice reaction time task, at every assessment. Morphine produced some sporadic effects in other tests and an increase in subjective calmness. Dextropropoxyphene impaired performance on choice reaction time and picture recognition. These data show that oral morphine may enhance performance in some measures of cognitive function, whereas dextropropoxyphene (in usual therapeutic doses) seems more likely to cause impairment. Neither opioid has substantial effects on cognition and psychomotor function compared with lorazepam.
2. IMPLICATION OF ENDOGENOUS OPIOID SYSTEM IN THE LEARNED HELPLESSNESS MODEL OF DEPRESSION
Tejedor-Real P, Mico JA, Maldonado R,
Roques BP, Gibert-Rahola J
--The involvement of opioid system on the learned helplessness model of depression was investigated. Animals preexposed to inescapable shocks were treated with either Met-enkephalin, Leu-enkephalin, morphine, imipramine, naloxone, RB 38A (a mixed inhibitor of enkephalin degrading enzymes), or RB 38B (a selective inhibitor of neutral endopeptidase EC 188.8.131.52). Stimulation of opioid system by either opioid agonists or enkephalin catabolism inhibitors reversed the escape deficit induced by shock pretreatment. In contrast, administration of naloxone potentiated the effect of inescapable shocks. Imipramine reduced the number of escape failures in this test, and this effect was antagonized by naloxone. These results point to the involvement of the endogenous opioid system in this model of depression.
3. ANTIMANIC, ANTIDEPRESSANT, AND ANTIPANIC EFFECTS OF OPIATES: CLINICAL, NEUROANATOMICAL, AND BIOCHEMICAL EVIDENCE
Gold MS, Pottash AC, Sweeney D, Martin D, Extein I
--These clinical data may offer some support for the hypothesis that opiates have antidepressant, antimanic, and antipanic effects. This hypothesis should be studied directly by double-blind studies of the effects of exogenous and synthetic endogenous opioid peptides in patients with major depressive illness, panic and anxiety states, schizophrenia, and schizo-affective illness. These clinical data support our studies in nonhuman primates and man which suggest a common LC or NE hyperactivity may underly both drug withdrawal and spontaneous panic states. Whether endorphin deficiency or derangements account for the postulated NE hyperactivity needs additional study and we will discuss our preliminary work later. Failure of endorphins to terminate bursts in LC firing rate and NE release may be responsible for both of these types of panic states. In addicts, this mechanism could exist prior to opiate use, or abuse of potent exogenous endorphinomentic compound may cause an endorphin-abnormality. Both of these possibilities would be compensated by continuous opiate maintenance. Methadone maintenance is a complicated psychiatric, psychological, and social phenomenon. Further studies are necessary to evaluate the role of opiate maintenance in treating or suppressing the emergence of underlying psychopathology. Previous psychiatric hospitalization or treatment for a schizophrenic or affective illness may contraindicate absolutely the use of clonidine or other rapid detoxification methods. These data suggest the possibility of substituting a nonaddicting psychotropic medication for opiates in some patients who are self-medicators. The clinical data support other data suggesting the potential antipsychotic, antidepressant, and antianxiety/antipanic effects of the endogenous opioids, endorphins, and exogenous opioids, endorphins, and exogenous opiates. These and other data suggest potential utility for opioid agonists and endorphin testing in psychiatric treatment and diagnosis.
4. CURRENT AND HISTORICAL CONCEPTS OF OPIATE TREATMENT IN PSYCHIATRIC DISORDERS
Weber MM, Emrich HM
--In recent years psychiatric research has rediscovered the theoretical and clinical importance of opiates, especially for the understanding of depressive disorders. However, opiate treatment is not a new therapeutic concept in psychiatry. The use of opium for "melancholia" and "mania" may be traced to ancient classical medicine. After Paracelsus and Sydenham, the psychiatry of the German Romantic Era widely discussed therapeutic opium use with the Engelken family going on to develop a structured opium treatment of depression in the first half of the nineteenth century. Although the underlying scientific problems of psychiatric opium therapy were never solved, it gained an outstanding position as a practical treatment for over 100 years.
5. BUPRENORPHINE TREATMENT OF REFRACTORY DEPRESSION
Bodkin JA, Zornberg GL, Lukas SE, Cole JO
--Opiates were used to treat major depression until the mid-1950s. The advent of opioids with mixed agonist-antagonist or partial agonist activity, with reduced dependence and abuse liabilities, has made possible the reevaluation of opioids for this indication. This is of potential importance for the population of depressed patients who are unresponsive to or intolerant of conventional antidepressant agents. Ten subjects with treatment-refractory, unipolar, nonpsychotic, major depression were treated with the opioid partial agonist buprenorphine in an open-label study. Three subjects were unable to tolerate more than two doses because of side effects including malaise, nausea, and dysphoria. The remaining seven completed 4 to 6 weeks of treatment and as a group showed clinically striking improvement in both subjective and objective measures of depression. Much of this improvement was observed by the end of 1 week of treatment and persisted throughout the trial. Four subjects achieved complete remission of symptoms by the end of the trial (Hamilton Rating Scale for Depression scores < or = 6), two were moderately improved, and one deteriorated. These findings suggest a possible role for buprenorphine in treating refractory depression.
6. ORAL MORPHINE IN TREATMENT-RESISTANT OBSESSIVE-COMPULSIVE DISORDER (OCD)
Bettina Franz, M.D., Ph.D 1; E-mail: firstname.lastname@example.org
Kimberly D. Bullock, M.D 1
Michael A. Elliot, M.A. 1
Lorrin M. Koran, M.D. 1
Purpose: To test the hypothesis that once a week oral morphine will benefit patients with treatment-resistant OCD in a placebo controlled, double blind trial.
Background: About 30-40% of patients with OCD fail to show even moderate improvement despite good trials of multiple medications. Case reports and open label trials have documented response to oral morphine and tramadol HCl by treatment-resistant OCD patients.
Method: Patients were recruited from the OCD clinic at Stanford Medical Center. Inclusion criteria were OCD for > 3 years, having failed adequate trials of at least two selective serotonin reuptake inhibitors, and a Y-BOCS score > 21. Patients could continue current medications, which were required to be stable for 2 months before the trial. Exclusion criteria were history of narcotic-, benzodiazepine- or alcohol abuse, or a medical condition in which narcotics were contraindicated. Patients underwent a screening evaluation including the Y-BOCS. Patients were randomized double blind to either MS Contin 30 mg, lorazepam, 1 mg, or placebo. The medication was administered in the clinic. One week later, the Y-BOCS was repeated, side effects assessed, and a decision made to increase, decrease, or maintain the dosage of the medication for week 2. Assessments were repeated after week 2 of medication. The patient was then reassigned to one of the other two medications for the next two weeks, and the third medication for the last two weeks. In this way, all patients received a 2 week trial of oral morphine, lorazapam, and placebo in random order, in a double crossover, double blind design. Lorazepam was included to reduce the chances of the patient guessing when morphine was received since both can cause drowsiness.
Results: We report results for the first 8 patients. The mean Y-BOCS score at entry into the study was 28.3 +5.9. One week after taking a single dose of oral morphine, the mean Y-BOCS score was 21+ 6.1, at the highest dose taken, which was 37.5+8.0 mg. Three of the 8 patients had reduction in the Y-BOCS of >40%, and 1 patient had a decrease of nearly 30%. The average decrease in Y-BOCS scores was 26.2%+14.5. In none of the patients receiving morphine did the Y-BOCS scores increase. In contrast, 1 week after 1 dose of lorazepam (1.6+0.5 mg), the mean Y-BOCS score was 24.8+5.3. Two of the patients had a decrease of >25%, but 2 others had an increase in the Y-BOCS. The mean decrease in Y-BOCS was 11.3%+14.4. In the placebo group, the mean Y-BOCS was 25.3+4.9, which was a decrease of 10.1%+11.41. No placebo patient achieved a Y-BOCS decrease of >25% and 1 patient's Y-BOCS increased slightly on the placebo. The percent decrease achieved with morphine compared to placebo was statistically significant (p=0.006) compared to that achieved with lorazepam, which was not statistically different from placebo (p=0.71).
Conclusion: A single dose of oral morphine is well tolerated and can achieve improvement in the symptoms of OCD for one week as reflected in a decrease of over 40% in the Y-BOCS score.
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poster:Ame Sans Vie