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Thread: baclofen and psych problems

  1. #1

    baclofen and psych problems

    Has anyone had psych problems after going on baclofen. My adult son was fine until he was 25. Then he started on baclofen. A few months later he began having psych problems which were easily controlled with psych meds. The psych problem are now pretty severe. The baclofen doctor says there is no relationship. The psychiatrist says there is a relationship between baclofen and psych problems and particularly have to be careul with anti-depressents and anti-psychotic meds. Be interested as to the experiences of those on baclofen for a year or more.

  2. #2
    Baclofen can cause sedation and (rarely) problems with memory, and once you have been on it for a while, sudden withdrawal can cause hallucinations and severe nightmares, but I have seen no research or literature on its impact on personality disorders or other psychiatric disorders. We use it on a regular basis for our clients with depression, bipolar disorders and even schizophrenia. It is actually used in some types of drug and alcohol withdrawal treatment protocols.

    I would think that this is much more likely a coincidence that the psychiatric disorder worsened at the same time that baclofen was started or increased in dosage.

    I will also ask Dr.Young for his input on this question.

    (KLD)

  3. #3
    Thanks for your response. Its helpful in deciding whether or not my som will take oral baclofen. He decided to have the baclofen pump removed and not replaced because of difficuty in having the dosage adjusted. His pump manager was not readily available.

  4. #4
    Abrupt cessation of baclofen is as dangerous and potentially lethal as it is from benzodiazapines and alcohol. http://www.nbiadisorders.org/images/baclofen.pdf

    It's certainly a necessary medication but I think it is perceived as relatively harmless and safe. It's not. Perhaps valium in small doses would be helpful. At least ask the psych MD about it.

  5. #5
    Do a google search on 'baclofen psychiatric disturbances'
    http://doublecheckmd.com/EffectsDeta...12579&eid=1900
    Baclofenmay cause mental health and behavior problems.

    This drug may also cause the following symptoms that are related to mental health and behavior problems:

    Medical Source Information
    Yellow highlights indicate symptoms related to mental health and behavior problems.

    Psychiatric side effects have been reported including paranoia, mania, euphoria, depression, anxiety, psychosis, hallucinations, paresthesias, hysteria, and personality disorder.

  6. #6
    Baclofen has a long history of use and possible benefit for various neurological and psychiatric problems. I did a quick literature search of the subject and summarize what I found below:

    Psychiatric Effects of Baclofen

    Baclofen has been used to treat various drug addictions, including methamphetamine abuse [1-3], eating disorders [4], cocaine [5-9], opioid [10] and alcohol dependence [11-17], craving for tobacco or marijuana [18]. Baclofen is sometimes used to treat addictive drug withdrawal [19, 20] and drug-induced behavior behaviors [21-23], obsessive compulsive disorders [24], binge eating [25-27], impulsivity [28], and chronic post-traumatic stress disorders [29] but apparently is not effective for treating pathological gambling [30]. It has been used to treat resistant schizophrenia [15, 31-33] to reduce anxiety [34] but it is said to be ineffective for the treatment of depression [35] and may increase irritability, assaultiveness, and auditory hallucinations in schizophrenia [36].

    Baclofen is a GABA(B) agonist [37]. As such, it is one of the mainstay therapies for the treatment of spasticity associated with many neurological conditions, including of course spinal cord injury, multiple sclerosis [38], spastic paraplegia [39], Lesch-Nyhan syndrome [40], stiff-man’s syndrome [41], Tourette’s syndrome [42], severe tardive dystonia [43, 44], nocturnal leg spasticity [45], “painful leg and moving toes” syndrome [46], and Satoyoshi syndrome [47].

    Baclofen, however, can cause psychosis [48]. Withdrawal from baclofen use can cause delirium [49] and neuroleptic syndrome [50]. Baclofen is known to cause memory deficits in animals [51] and have occasionally even been reported to cause mania [52]. In people with spinal cord injury, higher doses of baclofen are associated with a sense of fatigue [53] but generally it does not cause major adverse psychological effects. Baclofen does increase growth hormone although the psychiatric effects of this increase are not well understood [54, 55]. At therapeutic doses, baclofen reduce spasticity [56]. Baclofen overdoses cause hypotonia, respiratory depression, and seizures [57].
    References Cited
    1. Brackins T, Brahm NC and Kissack JC (2011). Treatments for Methamphetamine Abuse: A Literature Review for the Clinician. Journal of pharmacy practice Pharmacy Practice, Harding University College of Pharmacy, Searcy, AR, USA. Methamphetamine (METH) use and dependence is a serious public health concern with implications across multiple areas from societal impact to burden on psychiatric and medical resources. An estimated 8% of admissions to substance abuse treatment programs are related to stimulants with METH/amphetamine abuse. To date, effective pharmacotherapy options to enhance abstinence have not been identified. The objective of this article is to critically review the literature of METH treatment options. Preclinical research and human research with compounds not yet available commercially in the United States will not be included. A literature review was conducted for research on pharmacological treatments for METH use and addiction. Trial information on the use of sertraline, bupropion, mirtazapine, modafinil, dextroamphetamine, ondansetron, risperidone, aripiprazole, baclofen, and gabapentin was reviewed. Aripiprazole trials appeared in the reviewed literature more frequently than the other medications. Based on the findings of this review, no single medication demonstrated consistent efficacy and each trial contained a variety of methodological limitations.
    2. Mizoguchi H and Yamada K (2011). Pharmacologic Treatment with GABA(B) Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice. Current neuropharmacology 9: 109-12. Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABA(B) receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABA(A) receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABA(B) receptors may constitute a putative new target in treating cognitive deficits in chronic METH users.
    3. Heinzerling KG, Shoptaw S, Peck JA, Yang X, Liu J, Roll J and Ling W (2006). Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug and alcohol dependence 85: 177-84. Integrated Substance Abuse Programs, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA. OBJECTIVE: To conduct a 16-week, randomized, placebo-controlled, double-blind trial of two GABAergic medications, baclofen (20 mg tid) and gabapentin (800 mg tid), for the treatment of methamphetamine dependence. METHODS: Adults with methamphetamine dependence were randomized to one of three conditions for 16 weeks: baclofen (n = 25), gabapentin (n = 26) or placebo (n = 37). All participants attended clinic thrice weekly to receive study medication and psychosocial counseling, complete study assessments, and provide urine samples. RESULTS: No statistically significant main effects for baclofen or gabapentin in reducing methamphetamine use were observed using a generalized estimating equation (GEE). A significant treatment effect was found in post hoc analyses for baclofen, but not gabapentin, relative to placebo among participants who reported taking a higher percentage of study medication (significant treatment group and medication adherence interaction in GEE model of methamphetamine use). CONCLUSIONS: While gabapentin does not appear to be effective in treating methamphetamine dependence, baclofen may have a small treatment effect relative to placebo. Future studies evaluating the effectiveness of baclofen and other GABAergic agents for treatment of methamphetamine may be warranted.
    4. Aigner M, Treasure J, Kaye W and Kasper S (2011). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 12: 400-43. Department of Psychiatry and Psychotherapy, Medical University Vienna (MUW), Vienna, Austria. martin.aigner@meduniwien.ac.at. OBJECTIVES: The treatment of eating disorders is a complex process that relies not only on the use of psychotropic drugs but should include also nutritional counselling, psychotherapy and the treatment of the medical complications, where they are present. In this review recommendations for the pharmacological treatment of eating disorders (anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED)) are presented, based on the available literature. METHODS: The guidelines for the pharmacological treatment of eating disorders are based on studies published between 1977 and 2010. A search of the literature included: anorexia nervosa bulimia nervosa, eating disorder and binge eating disorder. Many compounds have been studied in the therapy of eating disorders (AN: antidepressants (TCA, SSRIs), antipsychotics, antihistaminics, prokinetic agents, zinc, Lithium, naltrexone, human growth hormone, cannabis, clonidine and tube feeding; BN: antidepressants (TCA, SSRIs, RIMA, NRI, other AD), antiepileptics, odansetron, d-fenfluramine Lithium, naltrexone, methylphenidate and light therapy; BED: antidepressants (TCA, SSRIs, SNRIs, NRI), antiepileptics, baclofen, orlistat, d-fenfluramine, naltrexone). RESULTS: In AN 20 randomized controlled trials (RCT) could be identified. For zinc supplementation there is a grade B evidence for AN. For olanzapine there is a category grade B evidence for weight gain. For the other atypical antipsychotics there is grade C evidence. In BN 36 RCT could be identified. For tricyclic antidepressants a grade A evidence exists with a moderate-risk-benefit ratio. For fluoxetine a category grade A evidence exists with a good risk-benefit ratio. For topiramate a grade 2 recommendation can be made. In BED 26 RCT could be identified. For the SSRI sertraline and the antiepileptic topiramate a grade A evidence exists, with different recommendation grades. CONCLUSIONS: Additional research is needed for the improvement of the treatment of eating disorders. Especially for anorexia nervosa there is a need for further pharmacological treatment strategies.
    5. Holtz NA and Carroll ME (2011). Baclofen has opposite effects on escalation of cocaine self-administration: increased intake in rats selectively bred for high (HiS) saccharin intake and decreased intake in those selected for low (LoS) saccharin intake. Pharmacology, biochemistry, and behavior 100: 275-83. Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA. holt0324@umn.edu. Rats selectively bred for high saccharin intake (HiS) self-administer more cocaine, escalate their cocaine intake during long access, and reinstate cocaine seeking at higher levels than those bred for low saccharin intake (LoS). The present study was conducted to determine if baclofen, an agonist at the GABA(b) receptor, has differential effects on the escalation of i.v. cocaine intake and reinstatement of cocaine-seeking in HiS and LoS rats. HiS and LoS rats self-administered cocaine during a 2-h daily short-access (ShA) phase for 3 days and then long-access (LgA) sessions for 21 days followed by a second ShA phase. One group of HiS and LoS rats received i.p. injections of 2.5 mg/kg baclofen (HiS+B and LoS+B, respectively), and other groups of HiS and LoS rats received saline (HiS+Sal and LoS+Sal) before each daily session. In a second experiment, HiS and LoS rats self-administered i.v. cocaine during 2-h sessions for 14 days followed by a 21-day extinction period. Baclofen (2.5 mg/kg, i.p.) or saline was administered before saline- or cocaine-primed reinstatement sessions. The HiS+B group escalated their cocaine self-administration and had increased cocaine infusions in the post-LgA ShA phase. The LoS+B group self-administered less cocaine throughout the entire LgA period compared to the LoS+Sal or HiS groups. Baclofen attenuated reinstatement of cocaine seeking in both the HiS and LoS rats with no phenotype differences. Thus, baclofen had opposite effects on cocaine intake in HiS and LoS rats during escalation; but similar effects during reinstatement. These results suggest that treatment effects might vary with individual differences (HiS vs. LoS) and the phase of drug-motivated behavior that is modeled.
    6. Weerts EM, Froestl W, Kaminski BJ and Griffiths RR (2007). Attenuation of cocaine-seeking by GABA B receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons. Drug and alcohol dependence 89: 206-13. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University, Bayview Behavioral Biology Research Center, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA. eweerts@jhmi.edu. The current study evaluated the effects of drugs that increase GABA levels by activation of GABA(B) receptors (baclofen and CGP44532) or by inhibition of GABA reuptake (tiagabine) on the reinstatement of extinguished lever responding produced by priming doses of cocaine in baboons (i.e., cocaine-seeking). Cocaine self-injection was established and maintained under a fixed ratio (FR10) schedule of reinforcement during daily 2h sessions. Lever responding was extinguished by substituting vehicle (saline) for cocaine until the number of self-injections decreased to 10 or less per session for two consecutive sessions (defined as extinction). Once extinction occurred, priming doses of cocaine (0.1-3.2mg/kg, i.v.) were administered during extinction conditions. Administration of priming doses of cocaine significantly increased cocaine-seeking in a dose-dependent manner. Cocaine-seeking produced by priming doses of cocaine were attenuated by pretreatment with baclofen (N=5) or CGP44532 (N=5) but not tiagabine (N=3). The doses of baclofen (0.32 mg/kg), and CGP445532 (0.32 mg/kg) that reduced cocaine-seeking produced by cocaine priming doses did not reinstate cocaine-seeking and did not produce overt effects when administered alone. These data indicate that GABA(B) agonists may reduce relapse to cocaine taking.
    7. Haney M, Hart CL and Foltin RW (2006). Effects of baclofen on cocaine self-administration: opioid- and nonopioid-dependent volunteers. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 31: 1814-21. Department of Psychiatry, College of Physicians and Surgeons of Columbia University and the Division on Substance Abuse, New York State Psychiatric Institute, New York, NY 10032, USA. mh235@columbia.edu. Preclinical and clinical studies suggest that GABAB receptor agonists selectively decrease cocaine use. The behavioral mechanism for the interaction between baclofen and cocaine in humans is not known, nor have its effects been characterized in individuals dependent on both cocaine and methadone. The objective of this study is to determine how maintenance on baclofen influences smoked cocaine's reinforcing and subjective effects, mood and cocaine craving prior to and after the initiation of cocaine use in cocaine-dependent volunteers with and without concurrent opioid dependence. Nontreatment-seeking volunteers (10 nonopioid dependent; seven methadone maintained), residing on an in-patient research unit for 21 days, were maintained on each baclofen dose (0, 30, 60 mg po) for 7 days. A smoked cocaine dose-response curve (0, 12, 25, 50 mg) was determined twice: on days 3-4 and days 6-7 of each baclofen maintenance condition. Cocaine sessions began with a sample trial, when participants smoked the cocaine dose available that session, and five choice trials, when participants chose between smoking the available cocaine dose or receiving one 5 dollars merchandise voucher. The results show that in the nonmethadone group, baclofen (60 mg) decreased self-administration of a low cocaine dose (12 mg). In the methadone group, baclofen decreased craving for cocaine. In both groups, baclofen decreased cocaine's effects on heart rate. Baclofen did not alter cocaine's robust subjective effects (eg 'High,' 'Stimulated') for either group. The results from this laboratory study appear consistent with clinical evidence showing that baclofen decreases cocaine use in nonopioid-dependent patients seeking treatment for cocaine dependence. The distinct pattern of effects in methadone-maintained participants suggests baclofen may not be effective in opioid-dependent cocaine users.
    8. Kampman KM (2005). New medications for the treatment of cocaine dependence. Psychiatry 2: 44-8. Dr. Kampman is Associate Professor at the Department of Psychiatry, University of Pennsylvania School of Medicine; and the Medical Director, University of Pennsylvania Treatment Research Center, Philadelphia, Pennsylvania. Cocaine dependence continues to be a significant public health problem in the United States. Although some cocaine- dependent patients will respond well to drug counseling, for many, standard psychosocial treatment is inadequate. Therefore, the development of an effective medication for the treatment of cocaine dependence is a research priority. However, despite many years of research, no medication has emerged as consistently effective for the treatment of cocaine dependence. Progress in the understanding of the neurobiology of cocaine dependence has led to the discovery of several promising medications that have already shown encouraging results in controlled clinical trials. Among more severely addicted patients, propranolol may be helpful in promoting an initial period of stable abstinence. For the prevention of relapse, medications that block cocaine euphoria or reduce cocaine craving have shown promise. Potential relapse-prevention medications include GABAergic medications, such as baclofen, tiagabine, and topiramate, and the glutamatergic medication, modafinil. Surprisingly, an old treatment for alcohol dependence, disulfiram, may also have efficacy for cocaine relapse prevention. Finally, a vaccine capable of stimulating the production of cocaine specific antibodies has shown promise in preliminary studies for the prevention of relapse to cocaine use.
    9. Sofuoglu M and Kosten TR (2005). Novel approaches to the treatment of cocaine addiction. CNS drugs 19: 13-25. School of Medicine, Department of Psychiatry and VA Connecticut Healthcare System, Yale University, 950 Campbell Ave., Bldg 36/116A4, West Haven, CT 06516, USA. mehmet.sofuglu@yale.edu. Cocaine addiction continues to be an important public health problem with over 1.7 million users in the US alone. Although there are no approved pharmacotherapies for cocaine addiction, a number of medications have been tested with some promising results. In this review, we summarise some of the emerging targets for cocaine pharmacotherapy including dopaminergic and GABA medications, adrenoceptor antagonists, vasodilators and immunotherapies. The brain dopamine system plays a significant role in mediating the rewarding effects of cocaine. Among dopaminergic agents tested for cocaine pharmacotherapy, disulfiram has decreased cocaine use in a number of studies. Amantadine, another medication with dopaminergic effects, may also be effective in cocaine users with high withdrawal severity. GABA is the main inhibitory neurotransmitter in the brain, and accumulating evidence suggests that the GABA system modulates the dopaminergic system and cocaine effects. Two anticonvulsant medications with GABAergic effects, tiagabine and topiramate, have yielded positive findings in clinical trials. Baclofen, a GABA(B) receptor agonist, is also promising, especially in those with more severe cocaine use. Some of the physiological and behavioural effects of cocaine are mediated by activation of the adrenergic system. In cocaine users, propranolol, a beta-adrenoceptor antagonist, had promising effects in individuals with more severe cocaine withdrawal symptoms. Cerebral vasodilators are another potential target for cocaine pharmacotherapy. Cocaine users have reduced cerebral blood flow and cortical perfusion deficits. Treatment with the vasodilators amiloride or isradipine has reduced perfusion abnormalities found in cocaine users. The functional significance of these improvements needs to be further investigated. All these proposed pharmacotherapies for cocaine addiction act on neural pathways. In contrast, immunotherapies for cocaine addiction are based on the blockade of cocaine effects peripherally, and as a result, prevent or at least slow the entry of cocaine into the brain. A cocaine vaccine is another promising treatment for cocaine addiction. The efficacy of this vaccine for relapse prevention is under investigation. Many initial promising findings need to be replicated in larger, controlled clinical trials.
    10. Assadi SM, Radgoodarzi R and Ahmadi-Abhari SA (2003). Baclofen for maintenance treatment of opioid dependence: a randomized double-blind placebo-controlled clinical trial [ISRCTN32121581]. BMC psychiatry 3: 16. Psychiatric Research Center and Department of Psychiatry, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Avenue, Tehran 13337, Iran. assadism@sina.tums.ac.ir. BACKGROUND: Results of preclinical studies suggest that the GABA(B) receptor agonist baclofen may be useful in treatment of opioid dependence. This study was aimed at assessing the possible efficacy of baclofen for maintenance treatment of opioid dependence. METHODS: A total of 40 opioid-dependent patients were detoxified and randomly assigned to receive baclofen (60 mg/day) or placebo in a 12-week, double blind, parallel-group trial. Primary outcome measure was retention in treatment. Secondary outcome measures included opioids and alcohol use according to urinalysis and self-report ratings, intensity of opioid craving assessed with a visual analogue scale, opioid withdrawal symptoms as measured by the Short Opiate Withdrawal Scale and depression scores on the Hamilton inventory. RESULTS: Treatment retention was significantly higher in the baclofen group. Baclofen also showed a significant superiority over placebo in terms of opiate withdrawal syndrome and depressive symptoms. Non-significant, but generally favorable responses were seen in the baclofen group with other outcome measures including intensity of opioid craving and self-reported opioid and alcohol use. However, no significant difference was seen in the rates of opioid-positive urine tests. Additionally, the drug side effects of the two groups were not significantly different. CONCLUSION: The results support further study of baclofen in the maintenance treatment of opioid dependence.
    11. Dore GM, Lo K, Juckes L, Bezyan S and Latt N (2011). Clinical experience with baclofen in the management of alcohol-dependent patients with psychiatric comorbidity: a selected case series. Alcohol and alcoholism 46: 714-20. Northern Sydney Drug and Alcohol Service, Herbert St Clinic, RNS Hospital, St Leonards, Sydney, NSW 2065, Australia. gdore@nsccahs.health.nsw.gov.au. AIMS: To illustrate the potential indications for, and adverse effects of, baclofen pharmacotherapy for alcohol dependence in patients with co-existing psychiatric illness. METHODS: Audit of the files of alcohol-dependent patients treated for comorbid non-psychotic psychiatric illness in a specialist detoxification unit with integrated outpatient treatment. Files were selected of patients who had been offered treatment with baclofen because other alcohol pharmacotherapies had previously been unsuccessful in preventing relapse or were contraindicated. RESULTS: Of the 21 selected patients, 13 attended for outpatient treatment, with follow-up periods ranging from 4 days to 27 months, and the outcomes could be rated. Prescribed baclofen doses ranged from 30 to 275 mg daily. Common side effects at lower doses included tiredness and sedation; one patient on 120 mg/day developed reversible severe back pain, and a patient taking up to 275 mg/day developed somnolence, dizziness and incontinence. Seven patients maintained significant periods of abstinence, and one patient reduced daily consumption to non-problematic levels. Two patients consumed an overdose of other central nervous system (CNS) depressants, while taking baclofen in the first week of treatment, were briefly unwell, were given emergency monitoring, but made a full recovery. CONCLUSION: While more than half the patients reported significant reduction in alcohol use, it is not possible to draw definite conclusions about the effectiveness of baclofen, given that it was combined with other psychiatric and alcohol treatments, and because there was no control or comparison group. We recommend caution when offering baclofen to patients with a history of recurrent overdosing or a history of other substance misuse. When prescribing in conjunction with other medications with CNS depressant action, close monitoring is recommended at initiation and during dose escalation.
    12. Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L and Flannery BA (2010). Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcoholism, clinical and experimental research 34: 1849-57. Department of Psychiatry, University of North Carolina at Chapel Hill, CB#7160, Chapel Hill, NC 27599-7160, USA. jc_garbutt@med.unc.edu. BACKGROUND: Recent clinical trials and case-reports indicate that baclofen, a GABA(B) agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals in 2 placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. METHODS: The study was a double-blind, placebo-controlled, randomized study comparing 30 mg/d of baclofen to placebo over 12 weeks of treatment and utilizing 8 sessions of BRENDA, a low-intensity psychosocial intervention. One hundred and twenty-one subjects were screened to yield 80 randomized subjects (44 men) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined. RESULTS: Seventy-six percent of subjects completed the study. No difference by drug condition was seen in percentage of heavy drinking days where on-average rates were 25.5% (+/-23.6%) for placebo and 25.9% (+/-23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in percentage of days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)= 5.39, p=0.02). Baclofen was well tolerated with only 2 individuals stopping baclofen because of adverse events. There were no serious adverse events. CONCLUSIONS: Baclofen, a GABA(B) agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response.
    13. Soyka M and Rosner S (2010). Emerging drugs to treat alcoholism. Expert opinion on emerging drugs 15: 695-711. Psychiatric Hospital, University of Munich, Nussbaumstr. 7 80336 Munich, Germany. Michael.Soyka@med.uni-muenchen.de. IMPORTANCE OF THE FIELD: Alcoholism is a widespread disorder with substantial mortality and negative treatment outcomes. To date, few medications have been found to reduce relapse rates or drinking in alcohol-dependent patients. AREAS COVERED IN THIS REVIEW: This review focuses on drugs that have been clinically tested for the treatment of alcohol dependence in clinical trials, pilot trials or which are considered to have a clinical perspective. For this purpose, a detailed Medline search was conducted on this issue. Although the neurochemical basis of alcoholism and the neuronal circuitry mediating its psychotropic effects have been explored in great detail in recent years, few drugs have emerged for the treatment of alcohol dependence, also because pharmaceutical companies have only a limited interest in this area of research. Acamprosate and the opioid antagonist naltrexone have been found to be effective, although data are mixed. A depot formula of naltrexone and the alternate opioid antagonist nalmefene have been studied in clinical trials and will presumably be introduced in the markets soon. Other emerging drugs are topiramate, novel acetaldehyde dehydrogenase (ALDH) inhibitors, baclofen, a combination therapy of gababentin and flumazenil and drugs targeting the cortitropin-releasing factor/neuropeptide Y mediated stress axis. WHAT THE READER WILL GAIN: Insights on the neurochemical basis of alcohol dependence and possible targets of medications. TAKE HOME MESSAGE: Acamprosate, naltrexone and the ALDH inhibitor disulfiram are proven medications for the treatment of alcohol dependence with modest efficacy. Novel alternate medications, a depot formulation of the opioid antagonist naltrexone and another oral opioid antagonist, nalmefene, are available now with good evidence for clinical efficacy. Novel ALDH inhibitors, antiepileptic drugs such as topiramate and drugs targeting the stress axis are currently among the most promising emerging drugs.
    14. Johnson BA (2010). Medication treatment of different types of alcoholism. The American journal of psychiatry 167: 630-9. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, 22908-0623, USA. bankolejohnson@virginia.edu <bankolejohnson@virginia.edu>. Alcoholism remains a serious cause of morbidity and mortality despite progress through neurobiological research in identifying new pharmacological strategies for its treatment. Drugs that affect neural pathways that modulate the activity of the cortico-mesolimbic dopamine system have been shown to alter drinking behavior, presumably because this dopaminergic system is closely associated with rewarding behavior. Ondansetron, naltrexone, topiramate, and baclofen are examples. Subtyping alcoholism in adults into an early-onset type, with chronic symptoms and a strong biological predisposition to the disease, and a late-onset type, typically brought on by psychosocial triggers and associated with mood symptoms, may help in the selection of optimal therapy. Emerging adults with binge drinking patterns also might be aided by selective treatments. Although preliminary work on the pharmacogenetics of alcoholism and its treatment has been promising, the assignment to treatment still depends on clinical assessment. Brief behavioral interventions that encourage the patient to set goals for a reduction in heavy drinking or abstinence also are part of optimal therapy.
    15. Daskalakis ZJ and George TP (2009). Clozapine, GABA(B), and the treatment of resistant schizophrenia. Clinical pharmacology and therapeutics 86: 442-6. Department of Psychiatry, Schizophrenia Program, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada. Jeff_Daskalakis@camh.net.
    16. Johnson BA, Swift RM, Addolorato G, Ciraulo DA and Myrick H (2005). Safety and efficacy of GABAergic medications for treating alcoholism. Alcoholism, clinical and experimental research 29: 248-54. Department of Psychiatric Medicine, The University of Virginia, Charlottesville, Virginia 22908-0623, USA. bankolejohnson@virginia.edu. This article highlights the proceedings of a symposium presented at the 27th Annual Scientific Meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, June 29, 2004. The organizers and co-chairs were Bankole A. Johnson, MD, PhD, and Robert M. Swift, MD, PhD. The presentations included (1) Introduction, by Bankole A. Johnson; (2) Safety, Tolerability, and Efficacy of gamma-Hydroxybutyric Acid and Baclofen in the Treatment of Alcohol Addiction, by Giovanni Addolorato; (3) Safety of Gabapentin in Treating Alcoholism, by Hugh Myrick; (4) New Data on the Safety and Effectiveness of Topiramate in the Treatment of Alcohol Dependence, by Bankole A. Johnson; (5) Evaluating the Risk of Benzodiazepine Prescription to Alcohol-Dependent Individuals, by Domenic A. Ciraulo; and (6) Safety and Efficacy of GABAergic Agents in Treating Alcoholics: Discussion, by Robert M. Swift.
    17. Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, Agabio R, Colombo G, Gessa GL and Gasbarrini G (2002). Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol and alcoholism 37: 504-8. Institute of Internal Medicine and Institute of Psychiatry, Catholic University of Rome, Rome, Italy. AIMS: The gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, has recently been shown to reduce alcohol intake in alcohol-preferring rats and alcohol consumption and craving for alcohol in an open study in humans. The present study was aimed at providing a first evaluation of the efficacy of baclofen in inducing and maintaining abstinence and reducing craving for alcohol in alcohol-dependent patients in a double-blind placebo-controlled design. METHODS: A total of 39 alcohol-dependent patients were consecutively enrolled in the study. After 12-24 h of abstinence from alcohol, patients were randomly divided into two groups. Twenty patients were treated with baclofen and 19 with placebo. Drug and placebo were orally administered for 30 consecutive days. Baclofen was administered at the dose of 15 mg/day for the first 3 days and 30 mg/day for the subsequent 27 days, divided into three daily doses. Patients were monitored as out-patients on a weekly basis. At each visit alcohol intake, abstinence from alcohol, alcohol craving and changes in affective disorders were evaluated. RESULTS: A higher percentage of subjects totally abstinent from alcohol and a higher number of cumulative abstinence days throughout the study period were found in the baclofen, compared to the placebo, group. A decrease in the obsessive and compulsive components of craving was found in the baclofen compared to the placebo group; likewise, alcohol intake was reduced in the baclofen group. A decrease in state anxiety was found in the baclofen compared to the placebo group. No significant difference was found between the two groups in terms of current depressive symptoms. Baclofen proved to be easily manageable and no patient discontinued treatment due to the presence of side-effects. No patient was affected by craving for the drug and/or drug abuse. CONCLUSIONS: Baclofen proved to be effective in inducing abstinence from alcohol and reducing alcohol craving and consumption in alcoholics. With the limits posed by the small number of subjects involved, the results of this preliminary double-blind study suggest that baclofen may represent a potentially useful drug in the treatment of alcohol-dependent patients and thus merits further investigations.
    18. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Cooper ZD and Foltin RW (2010). Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse. Psychopharmacology 211: 233-44. Department of Psychiatry, Division on Substance Abuse, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA. mh235@columbia.edu. RATIONALE: Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. OBJECTIVES: We investigated the effects of baclofen (study 1) and mirtazapine (study 2) in a human laboratory model of marijuana intoxication, withdrawal, and relapse. METHODS: In study 1, daily marijuana smokers (n = 10), averaging 9.4 (+/-3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. In study 2, daily marijuana smokers (n = 11), averaging 11.9 (+/-5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (study 1: 3.3% THC; study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. RESULTS: In study 1, during active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. In study 2, mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. CONCLUSIONS: Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence.
    19. Ahmadi-Abhari SA, Akhondzadeh S, Assadi SM, Shabestari OL, Farzanehgan ZM and Kamlipour A (2001). Baclofen versus clonidine in the treatment of opiates withdrawal, side-effects aspect: a double-blind randomized controlled trial. Journal of clinical pharmacy and therapeutics 26: 67-71. Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Avenue, Tehran 13334, Iran. OBJECTIVE: Baclofen is known for the alleviation of signs and symptoms of spasticity. Reports from our previous study have suggested that it may be at least as effective as clonidine in the management of physical symptoms of opiate withdrawal syndromes and superior to clonidine in the management of mental symptoms. We now report on a randomized double-blind comparison of baclofen vs. clonidine in view of side-effects profile. METHODS: A total of 62 opiates addicts were randomly assigned to treatment with baclofen or clonidine during a 14-day, double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. Maximum daily doses were 40 mg for baclofen and 0.8 mg for clonidine. This trial medication was given three times per day in divided doses. The severity of side-effects was measured in days 0, 1, 2, 3, 4, 7 and 14. RESULTS: There was no significant difference between two treat7ments in terms of retention in treatment (dropout) and overall side-effect. Nevertheless, significantly more problems relating to hypotension were encountered with subjects on clonidine. CONCLUSION: We conclude that, the low incidence of hypotension with baclofen suggests that the drug may be suitable for outpatient ambulatory treatment of withdrawal from opiates.
    20. Akhondzadeh S, Ahmadi-Abhari SA, Assadi SM, Shabestari OL, Kashani AR and Farzanehgan ZM (2000). Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. Journal of clinical pharmacy and therapeutics 25: 347-53. Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Avenue, Tehran, Iran. s.akhond@neda.net. BACKGROUND: A variety of detoxification methods have been utilized for the treatment of opiate withdrawal syndrome, of which alpha-adrenergic agonists have attracted considerable attention over the last two decades. However, accumulating evidence in rats shows the efficacy of the GABAB receptor agonist, baclofen, in reducing alcohol intake and self-administration of cocaine. OBJECTIVE: To examine the ability of baclofen, in the management of opiate withdrawal. METHOD: A total of 62 opiate addicts randomly assigned to treatment with baclofen or clonidine during a 14-day, double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. Maximum daily doses were 40 mg for baclofen and 0.8 mg for clonidine given three times a day in divided doses. The severity of the opiate withdrawal syndrome was measured on days 0, 1, 2, 3, 4, 7 and 14 using the Short Opiate Withdrawal Scale (SOWS). RESULTS: Baclofen and clonidine were equally effective in treating the physical symptoms of withdrawal syndromes. However, baclofen showed a significant superiority over clonidine in the management of mental symptoms. CONCLUSION: These results suggest that baclofen might be a novel therapeutic agent for opiate withdrawal syndrome. However, a larger study to confirm our results is warranted.
    21. Franklin TR, Wang Z, Sciortino N, Harper D, Li Y, Hakun J, Kildea S, Kampman K, Ehrman R, Detre JA, O'Brien CP and Childress AR (2011). Modulation of resting brain cerebral blood flow by the GABA B agonist, baclofen: a longitudinal perfusion fMRI study. Drug and alcohol dependence 117: 176-83. Department of Psychiatry, University of Pennsylvania, Center for Studies of Addiction and VA Medical Center, Philadelphia, PA, USA. franklin t@mail.trc.upenn.edu. BACKGROUND: Preclinical studies confirm that the GABA B agonist, baclofen blocks dopamine release in the reward-responsive ventral striatum (VS) and medial prefrontal cortex, and consequently, blocks drug motivated behavior. Its mechanism in humans is unknown. Here, we used continuous arterial spin labeled (CASL) perfusion fMRI to examine baclofen's effects on blood flow in the human brain. METHODS: Twenty-one subjects (all smokers, 12 females) were randomized to receive either baclofen (80 mg/day; N=10) or placebo (N=11). A five minute quantitative perfusion fMRI resting baseline (RB) scan was acquired at two time points; prior to the dosing regimen (Time 1) and on the last day of 21 days of drug administration (Time 2). SPM2 was employed to compare changes in RB from Time 1 to 2. RESULTS: Baclofen diminished cerebral blood flow (CBF) in the VS and mOFC and increased it in the lateral OFC, a region involved in suppressing previously rewarded behavior. CBF in bilateral insula was also blunted by baclofen (T values ranged from -11.29 to 15.3 at p=0.001, 20 contiguous voxels). CBF at Time 2 was unchanged in placebo subjects. There were no differences between groups in side effects or cigarettes smoked per day (at either time point). CONCLUSIONS: Baclofen's modulatory actions on regions involved in motivated behavior in humans are reflected in the resting state and provide insight into the underlying mechanism behind its potential to block drug-motivated behavior, in preclinical studies, and its putative effectiveness as an anti-craving/anti-relapse agent in humans.
    22. Brebner K, Childress AR and Roberts DC (2002). A potential role for GABA(B) agonists in the treatment of psychostimulant addiction. Alcohol and alcoholism 37: 478-84. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. AIMS: Here we briefly review the preclinical and clinical evidence that gamma-aminobutyric acid (GABA(B)) agonists may be useful in the treatment of cocaine addiction. An extensive series of studies in rats has demonstrated that baclofen and other GABA(B) agonists reduce cocaine self-administration in an apparently specific manner. METHODS: A number of schedules of reinforcement, including fixed-ratio, progressive-ratio and discrete trials procedures, have been used to model various aspects of cocaine reinforcement and addiction. RESULTS: The results show that systemic pretreatment with baclofen can reduce cocaine intake at doses that do not affect responding for other positive reinforcers, such as food. Direct intracerebral injections of baclofen into the ventral tegmental area also produce a specific reduction in cocaine self-administration, suggesting that an inhibition of dopaminergic neurons may be responsible for the effect. Recent clinical evidence and case reports indicate some therapeutic value for baclofen in controlling cocaine intake and craving, although the evidence from controlled clinical trials has been less than convincing. Perhaps the most intriguing data come from human imaging studies, wherein cocaine addicts report increased cocaine craving and activation of orbital-frontal cortex, anterior cingulate and amygdala when shown videotapes of drug paraphernalia and other addicts taking cocaine. The craving is reduced and the limbic activation is eliminated in cocaine-dependent patients who had been taking baclofen (10-20 mg twice daily) for 7-10 days. CONCLUSIONS: Systematic clinical studies of GABA(B) agonists are needed to determine the extent to which these drugs might serve as tools to promote abstinence in cocaine users seeking treatment for their addiction. Several areas must still be addressed, including potential side-effects that may limit compliance and whether GABA(B) agonists interfere with other, non-drug-related behaviours.
    23. Cousins MS, Roberts DC and de Wit H (2002). GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings. Drug and alcohol dependence 65: 209-20. Department of Psychiatry, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA. hdew@midway.uchicago.edu. A growing preclinical and clinical literature suggests that GABA(B) receptor agonists promote abstinence and reduce the use of cocaine, heroin, alcohol and nicotine. The purpose of this paper is to critically review these data. GABA(B) receptor agonists, such as baclofen, appear to reduce the reinforcing effects of abused drugs in animal models under multiple experimental procedures. This occurs at doses that have little effect on responding for other positive reinforcers such as food or water. We review evidence that these potential therapeutic effects may be mediated by modulation of mesolimbic dopamine neurons. This review also examines the preliminary clinical data from studies of the efficacy of baclofen for treatment of cocaine, alcohol, and nicotine dependence. We suggest that these preliminary data provide a rationale for conducting more systematic studies of the effects of GABA(B) receptor agonists as treatment for drug abuse. This line of research may also improve our understanding of the neurochemical mechanisms underlying the drug dependence process.
    24. Fontenelle LF, Oostermeijer S, Harrison BJ, Pantelis C and Yucel M (2011). Obsessive-compulsive disorder, impulse control disorders and drug addiction: common features and potential treatments. Drugs 71: 827-40. Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Melbourne, Australia. lfontenelle@gmail.com. The basic concepts underlying compulsive, impulsive and addictive behaviours overlap, which may help explain why laymen use these expressions interchangeably. Although there has been a large research effort to better characterize and disentangle these behaviours, clinicians and scientists are still unable to clearly differentiate them. Accordingly, obsessive-compulsive disorder (OCD), impulse control disorders (ICD) and substance-related disorders (SUD) overlap on different levels, including phenomenology, co-morbidity, neurocircuitry, neurocognition, neurochemistry and family history. In this review we summarize these issues with particular emphasis on the role of the opioid system in the pathophysiology and treatment of OCD, ICD and SUD. We postulate that with progression and chronicity of OCD, the proportion of the OCD-related behaviours (e.g. checking, washing, ordering and hoarding, among others) that are driven by impulsive 'rash' processes increase as involvement of more ventral striatal circuits becomes prominent. In contrast, as SUD and ICD progress, the proportion of the SUD- and ICD-related behaviours that are driven by compulsive 'habitual' processes increase as involvement of more dorsal striatal circuits become prominent. We are not arguing that, with time, ICD becomes OCD or vice versa. Instead, we are proposing that these disorders may acquire qualities of the other with time. In other words, while patients with ICD/SUD may develop 'compulsive impulsions', patients with OCD may exhibit 'impulsive compulsions'. There are many potential implications of our model. Theoretically, OCD patients exhibiting impulsive or addictive features could be managed with drugs that address the quality of the underlying drives and the involvement of neural systems. For example, agents for the reduction or prevention of relapse of addiction (e.g. heavy drinking), which modulate the cortico-mesolimbic dopamine system through the opioid (e.g. buprenorphine and naltrexone), glutamate (e.g. topiramate), serotonin (e.g. ondansetron) or gamma-aminobutyric acid (e.g. baclofen and topiramate) systems, may prove to show some benefit in certain forms of OCD. Based on the available evidence, we suggest that the treatment of patients with these disorders must account for alterations in the underlying motivations and neurobiology of the condition. We provide an initial guide to the specific treatments that future clinical trials might consider in patients with OCD. For example, it might be wise to test naltrexone in patients with co-morbid SUD and ICD, topiramate in patients with co-morbid ICD and eating disorders, and baclofen in patients with co-morbid Tourette's syndrome. These trials could also include scales aimed at assessing underlying impulsivity (e.g. Barratt Impulsiveness Scale) to check whether this construct might predict response to drugs acting on the reward system.
    25. Broft AI, Spanos A, Corwin RL, Mayer L, Steinglass J, Devlin MJ, Attia E and Walsh BT (2007). Baclofen for binge eating: an open-label trial. The International journal of eating disorders 40: 687-91. Department of Psychiatry, Columbia University, New York, New York, USA. aib8@columbia.edu. OBJECTIVE: Baclofen is a GABA-B agonist that may be useful in the treatment of substance use disorders, and also reduces 'binge-like' eating in rodents. We hypothesized that baclofen might be effective in reducing binge eating episodes in binge eating disorder (BED) and bulimia nervosa (BN). METHOD: Seven women with BED (n = 4) or BN (n = 3) took baclofen (60 mg/day) for 10 weeks. RESULTS: Six out of seven patients completed the full 10-week trial. Five out of seven participants (3 BED; 2 BN) demonstrated 50% or greater reduction of frequency of binge eating from beginning to end of the study. Three out of seven participants (2 BED; 1 BN) were free of binge eating at study end. Four out of seven participants elected to continue baclofen at study end. Baclofen was well tolerated by the participants. CONCLUSION: In this open-label trial, baclofen was associated with decreased binge eating frequency in patients with BED and BN.
    26. Foltin RW (2005). Baclofen decreases feeding in non-human primates. Pharmacology, biochemistry, and behavior 82: 608-14. Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, NY 10032, USA. rwf2@columbia.edu. This study examined how the GABA(b) agonist baclofen (0.5-5.6 mg/kg, p.o.), reported to increase food intake in rodents, affected the appetitive and consummatory aspects of feeding of non-human primates. Baboons had access to food 24 h each day, but they had to complete a two-phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Responding during the appetitive phase resulted in presentations of food-related stimuli only. Baclofen increased the latency to the first meal and decreased both appetitive and consummatory behavior. At the largest dose, baclofen induced emesis, indicating that the effects were due to malaise rather than a specific motivational action. In contrast, the positive control diazepam (GABA(a) agonist, 1.0-2.0 mg/kg, i.m.) decreased the latency to the first meal and increased both appetitive (P < 0.07) and consummatory behavior. Although the baclofen-induced decrease in appetitive behavior replicates data obtained in rodents, the baclofen-induced decreases in consummatory behavior do not. The findings suggest that the effects of large doses of baclofen in non-human primates may, in part, be due to non-specific behavioral disruptions.
    27. Weerts EM, Froestl W and Griffiths RR (2005). Effects of GABAergic modulators on food and cocaine self-administration in baboons. Drug and alcohol dependence 80: 369-76. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University, Behavioral Biology Research Center, 5510 Nathan Shock Dr./Suite 3000, Baltimore, MD 21224-6823, USA. eweerts@jhmi.edu. Drugs that indirectly alter dopaminergic systems may alter the reinforcing effects of cocaine. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has extensive neural connections in mesolimbic regions that appear to modulate dopamine. The current study evaluated the effects of GABA(B) receptor agonists baclofen and CGP44532, the benzodiazepine agonist alprazolam, and the GABA reuptake inhibitor tiagabine on lever responding maintained by low dose cocaine injections (0.032 mg/kg) or by food pellet (1 g) delivery in baboons. The benzodiazepine antagonist flumazenil was tested as a negative control. Cocaine or food was available under a fixed ratio (FR 10) schedule of reinforcement during daily 2-h sessions. During baseline conditions, cocaine and pellets maintained similar numbers of reinforcers per session. Baclofen, CGP44532 and tiagabine dose-dependently reduced the number of cocaine injections, where as the benzodiazepine antagonist flumazenil did not. Baclofen, CGP44532 and tiagabine also produced dose-related decreases in food-maintained behavior. In contrast, the benzodiazepine agonist alprazolam, which positively modulates GABA(A) receptors via the benzodiazepine site, produced decreases in cocaine self-injection, but not food-maintained behavior. Thus, the effects of alprazolam were specific for cocaine-maintained behavior, where as the effects of baclofen and CGP44532 were not.
    28. Lee R, Chong B and Coccaro E (2011). Growth hormone responses to GABAB receptor challenge with baclofen and impulsivity in healthy control and personality disorder subjects. Psychopharmacology 215: 41-8. Department of Psychiatry, The University of Chicago, Chicago, IL, USA. rlee@yoda.bsd.uchicago.edu. BACKGROUND: The role of abnormal GABAergic neural transmission in impulsive aggression is not well understood. We have previously shown that central levels of GABA are positively correlated with impulsivity in adult humans with and without personality disorder. An important regulator of GABAergic function is the GABA(B) receptor, a presynaptic autoreceptor and heteroreceptor. GABA(B) receptor sensitivity may be tested by measuring the growth hormone response to the receptor-agonist baclofen. The purpose of this investigation is to test the hypothesis that dimensional measures of impulsivity and impulsive aggression are negatively correlated with growth hormone response. METHODS: Twenty healthy volunteers (without Axis I or II disorder) and 20 personality-disordered subjects (meeting DSM-IV general criteria for personality disorder) underwent challenge with 20 mg baclofen administered orally, followed by a time series of blood samples for measure of growth hormone response analyzed by repeated measures ANOVA. RESULTS: An expected significant effect for drug and drug x time interaction verified that baclofen caused a surge in growth hormone level. There was no effect of group (healthy volunteer or personality disorder) or interaction with group on the time series or peak growth hormone response. As hypothesized, peak growth hormone response was negatively correlated with impulsivity as measured by the Barratt Impulsivity Scale (BIS-11; r = -0.39, n = 37, p < 0.02). The relationship remained significant when examining the healthy volunteer and personality disorder groups separately, indicating that the relationship with impulsivity was not merely due to the presence or absence of personality disorder. The relationship with impulsive aggression was only at a trend level of significance. CONCLUSION: The magnitude of growth hormone response to baclofen, an index of GABA(B) receptor function, was negatively correlated with a dimensional measure impulsivity, but not related to the categorical diagnosis of personality disorder. Further work is necessary to understand how GABAergic dysfunction may play a role in impulsive aggression.
    29. Drake RG, Davis LL, Cates ME, Jewell ME, Ambrose SM and Lowe JS (2003). Baclofen treatment for chronic posttraumatic stress disorder. The Annals of pharmacotherapy 37: 1177-81. Clinical Pharmacy, Bryce Hospital, Tuscaloosa, AL, USA. OBJECTIVE: Previous studies have shown the efficacy of gamma-aminobutyric acid B (GABA(B)) receptor agonists in treating anxiety in patients with panic disorder and in treating depression and anxiety in alcoholic patients. We hypothesized that baclofen, a GABA(B) agonist, would be an effective treatment in the symptomatic management of veterans with chronic posttraumatic stress disorder (PTSD). METHODS: Fourteen male veterans with chronic, combat-related PTSD were enrolled in an open-label, 8-week, monotherapy trial of baclofen titrated to a maximum of 80 mg/d in 3 divided doses. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS), and secondary outcome measures included the Hamilton Rating Scale for Anxiety, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning Scale, and the Clinical Global Impressions. RESULTS: In the 11 patients who completed the 8-week trial, the mean total CAPS score decreased significantly from baseline (from 82.9 +/- 16.1 to 63.5 +/- 21.2). The avoidance and hyperarousal subscales showed significant decreases (from 36.2 +/- 6.2 to 26.5 +/- 9.6 and from 31.9 +/- 6.5 to 22.1 +/- 7.1, respectively), whereas the re-experiencing subscale remained unchanged. Significant improvements were also noted on all secondary outcome measures. Treatment response was noted within the first 4 weeks of treatment and was maintained throughout the trial. Baclofen therapy was well tolerated, as only 1 patient dropped out due to adverse effects. CONCLUSIONS: Baclofen therapy was effective in treating both the PTSD symptoms and accompanying depression and anxiety in patients with chronic PTSD due to combat. Larger, double-blind, placebo-controlled studies are needed to confirm the efficacy of baclofen in the treatment of PTSD.
    30. Dannon PN, Rosenberg O, Schoenfeld N and Kotler M (2011). Acamprosate and Baclofen were Not Effective in the Treatment of Pathological Gambling: Preliminary Blind Rater Comparison Study. Frontiers in psychiatry / Frontiers Research Foundation 2: 33. Beer Yaakov Mental Health Center affiliated to Tel Aviv University Beer Yaakov, Israel. Objectives: Pathological gambling (PG) is a highly prevalent and disabling impulse control disorder. A range of psychopharmacological options are available for the treatment of PG, including selective serotonin reuptake inhibitors, opioid receptor antagonists, anti-addiction drugs, and mood stabilizers. In our preliminary study, we examined the efficacy of two anti-addiction drugs, baclofen and acamprosate, in the treatment of PG. Materials and Methods: Seventeen male gamblers were randomly divided into two groups. Each group received one of the two drugs without being blind to treatment. All patients underwent a comprehensive psychiatric diagnostic evaluation and completed a series of semi-structured interviews. During the 6-months of study, monthly evaluations were carried out to assess improvement and relapses. Relapse was defined as recurrent gambling behavior. Results: None of the 17 patients reached the 6-months abstinence. One patient receiving baclofen sustained abstinence for 4 months. Fourteen patients succeeded in sustaining abstinence for 1-3 months. Two patients stopped attending monthly evaluations. Conclusion: Baclofen and acamprosate did not prove efficient in treating pathological gamblers.
    31. Schopf J and Hucker H (1977). Baclofen in the treatment of schizophrenia: a pilot study. Pharmakopsychiatrie, Neuro-Psychopharmakologie 10: 89-91. 10 chronic schizophrenics were treated with baclofen for 30 days in addition to the neuroleptic maintenance medication. The psychopathological findings were documented in intervals of 5 days using a global rating and the BPRS scale. 3 patients showed a definite slight improvement of their clinical condition, 2 patients showed a questionable improvement, whereas 5 patients did not change. The statistical analysis of the BPRS scale revealed a significant improvement of one higher order factor. Our pilot study suggests that baclofen may have positive effects on some schizophrenics.
    32. Bigelow LB, Nasrallah H, Carman J, Gillin JC and Wyatt RJ (1977). Baclofen treatment in chronic schizophrenia: a clinical trial. The American journal of psychiatry 134: 318-20.
    33. Gulmann NC, Bahr B, Andersen B and Eliassen HM (1976). A double-blind trial of baclofen against placebo in the treatment of schizophrenia. Acta psychiatrica Scandinavica 54: 287-93. Twenty male chronic schizophrenic patients participated in a double-blond between-patient study of the GABA-like drug baclofen to evaluate the antipsychotic effect of baclofen. No difference was found between the 10 patients who received baclofen and 10 who received placebo with regard to the number of days before a worsening of their psychiatric condition necessitated treatment with chlorpromazine, the total score for psychotic symptoms before and after treatment for 10 weeks, or the total consumption of chlorpromazine. Discontinuation of baclofen did not exacerbate the psychotic symptoms. Baclofen was superior to placebo in the treatment of anxiety, which is of particular interest in view of the recent theories on the mechanism of action of benzodiazepines. The relationship between the gabergic system and the dopaminergic system with regard to the substantia nigra and the corpus striatum is discussed as well as the suggestion based on animal experiments that baclofen has an antipsychotic effect.
    34. Hinderer SR (1990). The supraspinal anxiolytic effect of baclofen for spasticity reduction. American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 69: 254-8. Department of Rehabilitation Medicine, University of Washington, Seattle. Recent studies in the psychiatric literature indicate that baclofen has an anxiolytic action in certain psychopathologic conditions. Clinical observation has shown that manifestations of spasticity are increased in anxious individuals, implicating a supraspinal site of mediation for these responses. The purposes of this study were to determine if baclofen reduced anxiety in individuals with traumatic spinal cord lesions and whether that reduction was correlated with decreased spasticity from the baclofen. Five adult males with traumatic spinal cord injury were randomly assigned to the study protocol. A double-blind, repeated measures, multiple base-line, single-case research design was employed. The independent variable was dose of medication with the three levels being placebo, 40 mg/day of baclofen and 80 mg/day of baclofen, in four evenly divided doses. The dependent variable was the score obtained on the Beck Inventory-A anxiety scale (BIA). The subjects were administered the BIA twice per week for a nine-week period of time, during which they received the doses of medication as described. Quantitative measurements of spasticity were also taken at each session. Visual inspection analysis of the data showed that two subjects had no measurable anxiety of the BIA throughout the study. Three subjects had measurable anxiety on the BIA during the base-line/placebo phase. They showed a decreased level of their BIA scores with 40 mg/day of baclofen, and a further level reduction with 80 mg/day of baclofen. The reduction in BIA scores was statistically significant using the standard deviation band test in one of these subjects. These data indicate that BIA probably has an anxiolytic effect for individuals status post-traumatic spinal cord injury.(ABSTRACT TRUNCATED AT 250 WORDS).
    35. Post RM, Ketter TA, Joffe RT and Kramlinger KL (1991). Lack of beneficial effects of l-baclofen in affective disorder. International clinical psychopharmacology 6: 197-207. Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892. GABAB mechanisms have been implicated in the antinociceptive, but not anticonvulsant effects of carbamazepine. A variety of antidepressants have been reported to upregulate GABAB receptors after chronic administration. The GABAB agonist l-baclofen was studied in depressed patients based on two separate rationales. l-Baclofen, in doses ranging from 10-55 mg/day, was administered to five patients with primary affective disorder. No patient showed a positive clinical response, while three patients showed a pattern of increasing depression or cycling during treatment and improvement during withdrawal. These preliminary data suggest that GABAB agonism is unlikely to produce antidepressant effects and may be unrelated to the mechanism of carbamazepine's antidepressant action. These data, taken with a reinterpretation of other findings that antidepressant modalities upregulate GABAB receptors in brain following chronic administration, suggest that GABAB antagonism rather than agonism may be a fruitful clinical strategy to explore in depression.
    36. Wolf ME, Keener S, Mathis P and Mosnaim AD (1983). Phenylethylamine-like properties of baclofen. Neuropsychobiology 9: 219-22. Baclofen therapy resulted in improvement of dyskinesias only in patients with trunkal tardive dyskinesia. However, the appearance of undesirable side effects did not warrant continuation of treatment with this drug. Baclofen did not have any therapeutic effect in schizophrenia and moreover a trend towards a worsening of the psychiatric conditions with irritability, assaultiveness and prominent auditory hallucinations was observed. The effects of baclofen on tardive dyskinesia and schizophrenia can be explained in terms of its phenylethylamine-like properties.
    37. Bowery NG (2006). GABAB receptor: a site of therapeutic benefit. Current opinion in pharmacology 6: 37-43. GlaxoSmithKline, Verona Biology, Psychiatry Centre of Excellence for Drug Discovery - Psychiatry, Via A Fleming 4, 37135 Verona, Italy. Norman.2.Bowery@GSK.com. Although the presence of functional GABAB receptors in mammalian brain has been known for more than 20 years, there is still only one therapeutic agent in use, baclofen, which mediates its effects directly via this receptor. However, activation of this receptor can produce numerous effects that might be amenable to drug development. Evidence from preclinical studies also suggests that antagonism of the GABAB receptor produces beneficial clinical effects.
    38. Yeh EA (2011). Current therapeutic options in pediatric multiple sclerosis. Current treatment options in neurology 13: 544-59. Department of Neurology, Division of Child Neurology, Pediatric MS Center of the JNI, SUNY Buffalo, Women and Children's Hospital of Buffalo, 219 Bryant St., Buffalo, NY, 14222, USA, yehann1@gmail.com. OPINION STATEMENT: Therapies for relapsing-remitting pediatric multiple sclerosis (MS) are aimed at preventing relapses (disease modifying therapies), treating acute attacks, and managing disabling cognitive and physical symptoms. Initial disease modifying therapy to prevent relapses should use one of four first-line injectable therapies that are approved for adult relapsing-remitting MS: interferon beta 1a IM, interferon beta 1a SC, interferon beta 1b SC, or glatiramer acetate. If breakthrough disease occurs or the medication is poorly tolerated, the next step should be to try one of the other first-line therapies. If the first-line therapies have been exhausted, second-line therapies such as natalizumab, cyclophosphamide, or mitoxantrone may be considered. One must use caution when choosing these potent therapies, as secondary effects may include serious infection or malignancy. Phase III studies in adult MS have been published on two oral agents, fingolimod and cladribine, and fingolimod has received FDA approval for use in relapsing-remitting MS in adults. These drugs have not been evaluated in the pediatric MS population, nor have any of three other oral agents now in phase III development: laquinimod, BG-12, and teriflunomide. Acute relapses can be treated with pulse methylprednisolone at a dosage of 20 to 30 mg/kg per day (maximum 1 g per day) for 3 to 5 days. If this is ineffective, intravenous immunoglobulin (2 g/kg divided over 2-5 days) or plasmapheresis may be considered. Neuropsychological, physical therapy, and occupational therapy screening should be performed on patients with pediatric MS. Interventions focusing on visual motor integration may be particularly useful in this group Spasticity may be treated with symptomatic therapies, but one must be aware of potential adverse effects of agents such as baclofen and diazepam. Headache, fatigue, anxiety, and depression are frequently seen, and patients may need a psychiatry consultation and counseling.
    39. Stevanin G, Durr A and Brice A (1993). Spastic Paraplegia Type 11. In: GeneReviews (ed. Pagon RA, Bird TD, Dolan CR and Stephens K). pp. Seattle (WA). Spastic paraplegia type 11 (SPG11) is characterized by progressive spasticity, weakness of the lower limbs, and mild mental retardation with learning difficulties in childhood and/or progressive cognitive decline. Less frequent findings are cerebellar ocular signs (nystagmus, saccadic pursuit), pes cavus, and scoliosis. Some affected individuals develop pseudobulbar involvement with dysarthria and dysphagia; upper-limb spasticity; bladder dysfunction; and axonal, motor, or sensorimotor peripheral neuropathy. Onset occurs mainly during infancy or adolescence (range: age 1-31 years). Most affected individuals become wheelchair-bound one or two decades after disease onset. Diagnosis is based on (1) clinical findings; (2) a characteristic MRI pattern including thinning of the corpus callosum (TCC) and in most cases periventricular white matter alterations on MRI; and, because the combination of TCC with white matter changes is not specific to SPG11, (3) molecular genetic testing of SPG11. physiotherapy to stretch spastic muscles; anti-spastic drugs such as baclofen; botulin toxin and intrathecal baclofen for severe and disabling spasticity when oral drugs are ineffective. Urodynamic evaluation when bladder dysfunction is evident; anticholinergic drugs for urinary urgency. Treatment of psychiatric manifestations by standard protocols. Prevention of secondary complications: Treatment of sphincter disturbances to prevent urinary tract infection secondary to bladder dysfunction. Surveillance: Evaluation every six months to adjust physiotherapy and medications. SPG11 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible when the disease-causing mutations in a family are known.
    40. Nyhan WL, O'Neill JP, Jinnah HA and Harris JC (1993). Lesch-Nyhan Syndrome. In: GeneReviews (ed. Pagon RA, Bird TD, Dolan CR and Stephens K). pp. Seattle (WA). Lesch-Nyhan syndrome is characterized by motor dysfunction that resembles cerebral palsy, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenting features, hypotonia and developmental delay, are evident by age three to six months. Affected children are delayed in sitting and most never walk. Within the first few years, extrapyramidal involvement (e.g., dystonia, choreoathetosis, opisthotonos) and pyramidal involvement (e.g., spasticity, hyperreflexia, extensor plantar reflexes) become evident. Cognitive impairment and behavioral disturbances emerge between ages two and three years. Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs) is a hallmark of the disease. Overproduction of uric acid may lead to deposition of uric acid crystals or calculi in the kidneys, ureters, or bladder. Gouty arthritis may occur later in the disease. Related disorders with less severe manifestations include hyperuricemia with neurologic dysfunction but no self-injurious behavior and hyperuricemia alone, sometimes with acute renal failure. A urinary urate-to-creatinine ratio greater than 2.0, indicating uric acid overproduction (hyperuricemia), is a characteristic for children younger than age ten years who have Lesch-Nyhan syndrome. However, neither hyperuricuria nor hyperuricemia (serum uric acid concentration >8 mg/dL) is sensitive or specific enough for diagnosis. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity less than 1.5% of normal in cells from any tissue (e.g., blood, cultured fibroblasts, lymphoblasts) is diagnostic. Sequence analysis of HPRT1, the only gene known to be associated with Lesch-Nyhan syndrome, is available on a clinical basis. overproduction of uric acid with allopurinol reduces the risk of nephrolithiasis, gouty arthritis, and tophi but has no effect on behavioral and neurologic symptoms; treatment of renal stones may require lithotripsy or surgery; baclofen or benzodiazepines for spasticity; physical, behavioral, psychiatric, protective equipment to reduce complications from self-injury and other deleterious behaviors. Surveillance: monitoring for early signs of self-injury; medical history, plasma uric acid concentration, urinary oxypurine excretion to monitor for signs of renal stones. Agents/circumstances to avoid: probenecid and other uricosuric drugs designed to reduce the serum concentration of uric acid; periods of relative dehydration, which may increase risk for renal stones. Testing of relatives at risk: Prenatal testing or testing of at-risk males immediately after birth enables prompt initiation of allopurinol therapy; establishing the carrier status of at-risk female relatives through genetic testing may allow for early treatment that reduces their risk of gout in later years. Lesch-Nyhan syndrome is inherited in an X-linked manner. The father of an affected male will neither have the disease nor be a carrier of the mutant allele. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers. Thus, with each pregnancy, a carrier female has a 25% chance of having an affected male, a 25% chance of having a carrier female, and a 50% chance of having an unaffected male or female. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.
    41. Murinson BB and Vincent A (2001). Stiff-person syndrome: autoimmunity and the central nervous system. CNS spectrums 6: 427-33. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21289, USA. BethMurinson@hotmail.com. Stiff-person syndrome (SPS) is a rare disease of severe progressive muscle stiffness in the spine and lower extremities with superimposed muscle spasms triggered by external stimuli. Patients with SPS are often referred for psychiatric evaluation and the psychiatrist may be the first to diagnosis SPS. Psychosocial stressors often precede the first manifestations of the disease; depression, anxiety, and alcohol abuse are comorbid illnesses. The identification of an association with antibodies to glutamic acid decarboxylase (GAD) was invaluable for definitively establishing a pathological basis for the disease; antibodies to amphiphysin and gephyrin are also found in cases of SPS but at much lower frequencies. Whether the antibodies inhibit GAD activity in vivo, target GAD-expressing neurons for immune-mediated destruction, are part of a wider immune process, or are merely a marker for destruction of GAD-expressing neurons by an independent neurodegenerative process is not yet clear. Both electromyography and the detection of GAD antibodies are useful in establishing a diagnosis of SPS. Treatment of SPS includes the use of immunomodulating therapies (plasmapheresis and intravenous immunoglobulins) and symptomatic treatment with benzodiazepines and baclofen. The use of tricyclic antidepressants and rapid withdrawal from therapy should be avoided.
    42. Kossoff EH and Singer HS (2001). Tourette syndrome: clinical characteristics and current management strategies. Paediatric drugs 3: 355-63. Department of Paediatrics, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA. ekossoff@jhmi.com. Tourette Syndrome (TS) is a disorder comprised of involuntary motor and phonic tics often associated with psychiatric conditions. The etiology for TS is unclear, with both genetic and immunological theories being studied to date. When pharmacotherapy is considered by the patient and physician to be required, owing to either functional impairment from tics or comorbid psychiatric illness, dopamine receptor antagonists are commonly used. Our first-line agents for tic suppression include clonidine, guanfacine, clonazepam and baclofen. Should these agents be ineffective, we would recommend pimozide, fluphenazine, risperidone or haloperidol. The potential benefit of other agents, such as olanzapine, ziprasidone, pergolide and botulinum toxin, is encouraging. Despite many years of concern, we have found little exacerbation of tics with stimulant medications for attention deficit hyperactivity disorder, but clearly clonidine and guanfacine can ameliorate both comorbid conditions. Obsessive compulsive disorder, when associated with TS, may be treated with either a selective serotonin reuptake inhibitor in association with a dopamine receptor antagonist or risperidone alone. New therapies for all aspects of TS and its comorbid conditions are in active clinical trials.
    43. Dressler D, Oeljeschlager RO and Ruther E (1997). Severe tardive dystonia: treatment with continuous intrathecal baclofen administration. Movement disorders : official journal of the Movement Disorder Society 12: 585-7. Department of Psychiatry, Georg-August-University, Gottingen, Germany. Treatment of tardive dystonia with oral baclofen produces ambivalent and overall disappointing results. However, because only a small proportion of the baclofen penetrates into the central nervous system when administered orally, we tested whether it is possible to increase the efficacy of treatment by continuous intrathecal infusion of baclofen (CITB) in a patient with severe tardive axial dystonia unresponsive to conventional therapy. A dose of 100 micrograms/day improved muscle tone, head control, posture, and walking distance; electromyography showed a marked decrease of dystonic muscle activity with fully preserved voluntary muscle activity, and the patient reported substantial reduction of pain. Apart from some minor discomfort at the site of operation, no side effects were noted. Further studies should be encouraged to evaluate the usefulness of CITB for other patients with severe and otherwise untreatable tardive dystonia.
    44. Yadalam KG, Korn ML and Simpson GM (1990). Tardive dystonia: four case histories. The Journal of clinical psychiatry 51: 17-20. Department of Psychiatry, Medical College of Pennsylvania, Eastern Pennsylvania Psychiatric Institute, Philadelphia 19129. Tardive dystonia is an uncommon, disabling side effect of antipsychotic medication that is generally believed to be resistant to treatment. On the basis of a literature review and their experience, the authors propose treatment strategies and report the results of treatment in four patients.
    45. Kravitz HM, Corcos DM, Hansen G, Penn RD, Cartwright RD and Gianino J (1992). Intrathecal baclofen. Effects on nocturnal leg muscle spasticity. American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 71: 48-52. Department of Psychiatry, Rush-Presbyterian-Saint Luke's Medical Center, College of Kinesiology, University of Illinois, Chicago 60680. Electromyographic activity was recorded from tibialis anterior during nocturnal polysomnography in six patients with severe spasticity of spinal origin. The patients had a baclofen reservoir system implanted subcutaneously into their lumbar subarachnoid space and were studied for two nights in a double-blind, placebo controlled, crossover design. Tibialis anterior electromyographic activity per hour of sleep was reduced on the night of baclofen infusion. In particular, less electromyographic activity occurred after arousal from sleep.
    46. Sandyk R (1990). Neuroleptic-induced "painful legs and moving toes" syndrome: successful treatment with clonazepam and baclofen. Italian journal of neurological sciences 11: 573-6. Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461. The syndrome of "painful legs and moving toes" is characterised by spontaneous causalgic pain in the lower extremities associated with peculiar involuntary movements of the toes and feet. It has been observed after a variety of lesions affecting the posterior nerve roots, the spinal ganglia and the peripheral nerves. The pathophysiology of the syndrome is unknown. I report a patient who developed the syndrome during treatment for schizophrenia with the antipsychotic agent molindone hydrochloride. The patient's response to the combination of clonazepam and baclofen suggests that the pathophysiology of the "painful legs and moving toes" may be linked to impairment of spinal serotonergic and GABA functions.
    47. Satoyoshi E (1990). [Satoyoshi's syndrome: a syndrome of progressive muscle spasm, alopecia, and diarrhea]. Nihon rinsho. Japanese journal of clinical medicine 48: 1540-6. National Center of Neurology and Psychiatry.
    48. Chawla JM and Sagar R (2006). Baclofen-induced psychosis. The Annals of pharmacotherapy 40: 2071-3. Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India. OBJECTIVE: To report a case of psychosis induced by therapeutic doses of baclofen. CASE SUMMARY: A 32-year-old Hindu man was prescribed oral baclofen 10 mg twice daily for relief of muscular spasms secondary to tetanus. After 4 weeks of baclofen use, he presented to the psychiatry emergency facility with a 4 day history of third-person auditory hallucinations and persecutory and referential delusions without underlying mood symptoms. These symptoms resolved within 1 week of discontinuing baclofen. Rechallenge with baclofen resulted in reemergence of psychotic symptoms, which disappeared after discontinuing baclofen. DISCUSSION: Reemergence of psychotic symptoms after rechallenge with baclofen suggests baclofen-induced psychosis. Use of the Naranjo probability scale indicates a probable association of baclofen with this patient's psychosis. The absence of underlying mood disorder makes this case different from previously reported ones. CONCLUSIONS: Baclofen may be associated with the occurrence of psychosis. Clinicians should consider baclofen-induced psychosis as a differential diagnosis in patients presenting with psychosis during treatment with this drug.
    49. Leo RJ and Baer D (2005). Delirium associated with baclofen withdrawal: a review of common presentations and management strategies. Psychosomatics 46: 503-7. Department of Psychiatry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Erie County Medical Center, 462 Grider Street Buffalo, NY 14215, USA. rleomd@aol.com. The authors reviewed 23 published cases of psychiatric symptoms in association with baclofen withdrawal. Delirium, and not other functional psychiatric conditions, arose secondarily from abrupt baclofen cessation. Vulnerability to baclofen-withdrawal delirium appeared to be greater in individuals who received chronic baclofen therapy. Baclofen-withdrawal delirium can be difficult to distinguish from delirium of other etiologies, and unrecognized and inadequately treated baclofen-withdrawal delirium is associated with significant morbidity and mortality. Complete resolution of delirium symptoms was possible with reinstatement of baclofen. The clinical management of patients experiencing baclofen-withdrawal delirium includes supportive interventions to reduce complications of delirium until symptoms resolve.
    50. Turner MR and Gainsborough N (2001). Neuroleptic malignant-like syndrome after abrupt withdrawal of baclofen. Journal of psychopharmacology 15: 61-3. Academic Neurosciences Centre, Institute of Psychiatry, London, UK. m.turner@iop.kcl.ac.uk. We present the case of a 36-year-old man who presented with a clinically neuroleptic malignant-like syndrome involving disorientation, signs of autonomic dysfunction, rigidity and raised total creatine kinase level, but in the absence of any neuroleptic medication. He had, however, abruptly stopped taking his long-term baclofen in the days prior to presentation. He improved markedly after the reintroduction of baclofen, and we postulate that his clinical syndrome resulted from the sudden withdrawal of this drug. We concur with the concept that neuroleptic malignant syndrome represents a spectrum of disorders, and add it to the list of possible sequelae after abrupt withdrawal of baclofen.
    51. Levin ED, Weber E and Icenogle L (2004). Baclofen interactions with nicotine in rats: effects on memory. Pharmacology, biochemistry, and behavior 79: 343-8. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. edlevin@duke.edu. Nicotine has been shown in numerous previous studies to significantly improve memory on the radial-arm maze, yet the critical mechanisms underlying this effect are not fully characterized. Nicotine stimulates the release of a number of neurotransmitters important for memory function including (gamma-aminobutyric acid) GABA. The importance of nicotinic-GABA interactions regarding memory is currently unknown. The purpose of the current study was to determine the interactive effects of nicotine and the GABA agonist baclofen on working memory function as measured by choice accuracy in the radial-arm maze. Female Sprague-Dawley rats trained to asymptotic performance levels on a win-shift eight-arm radial maze task were used for assessment of nicotine-baclofen interactions. Low doses of baclofen improved memory performance while higher doses impaired it. Nicotine, as seen before, improved memory performance. Nicotine also significantly reversed the higher dose baclofen-induced deficit. These data show the importance of both nicotinic and GABA systems in working memory function and the interactions between these two transmitter receptor systems. This not only provides information concerning the neural bases of cognitive performance, it also lends insight into new combination treatments for memory impairment.
    52. Peet M and Peters S (1995). Drug-induced mania. Drug safety : an international journal of medical toxicology and drug experience 12: 146-53. University Department of Psychiatry, Northern General Hospital, Sheffield, England. Mania can occur by chance association during drug treatment, particularly in patients predisposed to mood disorder. Single case reports are unreliable, and evidence must be sought from large series of treated patients, particularly those with a matched control group. Drugs with a definite propensity to cause manic symptoms include levodopa, corticosteroids and anabolic-androgenic steroids. Antidepressants of the tricyclic and monoamine oxidase inhibitor classes can induce mania in patients with pre-existing bipolar affective disorder. Drugs which are probably capable of inducing mania, but for which the evidence is less scientifically secure, include other dopaminergic anti-Parkinsonian drugs, thyroxine, iproniazid and isoniazid, sympathomimetic drugs, chloroquine, baclofen, alprazolam, captopril, amphetamine and phencyclidine. Other drugs may induce mania rarely and idiosyncratically. Management involves discontinuation or dosage reduction of the suspected drug, if this is medically possible, and treatment of manic symptoms with antipsychotic drugs or lithium.
    53. Jamous A, Kennedy P, Psychol C and Grey N (1994). Psychological and emotional effects of the use of oral baclofen: a preliminary study. Paraplegia 32: 349-53. National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, Bucks, UK. Spasticity is a common problem following spinal cord injury. The drug of choice to control spasms is baclofen. There would appear to be no reported studies which have evaluated the psychological and emotional effect of this drug. This preliminary study investigated a number of such effects, including depression, anxiety and general mood state. First, we examined 10 subjects before and during the administration of baclofen. They were then compared to a control group of 12 subjects. A second cohort of 12 subjects taking baclofen were compared to a control group of nine subjects at a specific time after injury. Results indicated that whilst some significant differences were found, suggesting an increase in fatigue with use of baclofen, no major adverse psychological effects were noted. The implications of these results were discussed and suggestions for further research were highlighted.
    54. O'Flynn K and Dinan TG (1993). Baclofen-induced growth hormone release in major depression: relationship to dexamethasone suppression test result. The American journal of psychiatry 150: 1728-30. Department of Psychiatry, Trinity College Medical School, Dublin. Fifteen patients with DSM-III-R major depression and 15 matched comparison subjects underwent baclofen-induced growth hormone (GH) release and the dexamethasone suppression test (DST). The GH responses of the patients were significantly blunted, especially those of the patients who were DST nonsuppressors. These findings may indicate lower than normal responsivity of type B gamma-aminobutyric acid (GABA-B) receptors in depression and a relationship between GABA-B receptor abnormality and dysfunction of the hypothalamic-pituitary-adrenal axis.
    55. Marchesi C, Chiodera P, De Ferri A, De Risio C, Dasso L, Menozzi P, Volpi R and Coiro V (1991). Reduction of GH response to the GABA-B agonist baclofen in patients with major depression. Psychoneuroendocrinology 16: 475-9. Institute of Clinical Psychiatry, University of Parma, Italy. In order to establish whether alterations in the GABAergic control of GH secretion occur in male patients with major depression, the GH response to the GABAergic-B agonist baclofen (10 mg PO at 0830h) or to placebo was tested in 9 depressed men and in 10 age- and weight-matched male normal controls. The basal concentrations of GH were significantly lower in the depressed patients (0.87 +/- 0.69 ng/ml) than in the normal controls (1.57 +/- 0.33 ng/ml) (p = 0.011) and were not modified by the administration of placebo. The administration of baclofen induced a striking, significant increase in GH concentrations in the normal controls (mean peak at 90 min = 6.4 +/- 1.5 ng/ml). In contrast, a slight, nonsignificant GH increase occurred in the depressed patients after baclofen (mean peak at 90 min = 1.57 +/- 1.45 ng/ml). The GH response was significantly lower in the depressed than in the control subjects (p less than 0.001). These data indicate the presence of reduced GABAergic control of GH secretion in male depressed patients.
    56. Milanov IG (1992). Mechanisms of baclofen action on spasticity. Acta neurologica Scandinavica 85: 305-10. Institute of Neurology, Psychiatry & Neurosurgery, IIIrd Neurological Clinic, Sofia, Bulgaria. This investigation estimated the mechanisms of baclofen action on spasticity using a battery of electromyographic methods. Thirty patients with old post-stroke spastic hemiparesis took part in the investigation. They were treated with baclofen-mean daily dose 54.3 alpha 11.6 mg for a mean of 26.3 alpha 4.9 days. A questionnaire for assessment of subjective improvement after treatment used a 5-point scale. For standardization of the neurological examination 5-point scales were used to assess muscle tone, muscle force and tendon reflexes. A battery of electromyographic methods was used to analyse different mechanisms of spasticity: for alpha motoneurone activity--the F wave parameters; for gamma motoneurone activity--the T/H reflex amplitude ratio; for presynaptic inhibition--the ratio of H reflex amplitudes before and after vibration on the achilles tendon (Hvibr./Hmax); for common interneurone activity--the flexor reflex parameters. Our results revealed that baclofen reduces spastically increased muscle tone and Babinski sign. It has no influence on muscle force, tendon reflexes and ankle clonus. Baclofen acts by normalizing the altered interneurone activity and decreasing of alpha motoneurone activity. When spasticity has altered interneurone activity and increased motoneurone activity, it is better to treat with baclofen.
    57. May CR (1983). Baclofen overdose. Annals of emergency medicine 12: 171-3. Reported is a case of baclofen overdose in a 23-year-old woman. The patient manifested typical symptoms of baclofen overdose, including hypotonia, respiratory depression, and seizures. She was treated successfully with positive pressure ventilation, sedation, and intravenous antibiotics, and was discharged from the hospital on the 14th day following admission with no residual neurological signs, to be followed up in medical and psychiatric outpatient clinics. As baclofen becomes increasingly popular in the treatment of muscle spasm in certain neurological disorders, its availability for misuse increases.

  7. #7
    This is very helpful and I appreciate the time you took to respond to this. It is interesting to me that the baclofen doctors we dealt with are not open to the possibility of a relationship between baclofen and psych problems. My sons psychiatrist however sees a connection. My son would confirm that the drug is great for releiving spascity, but now believes that the drug has cbeen a big contributor to the periodic mental problems he encountered. Maybe the problem is just limited to a few who take the drug. But I am going to ask the question as to whether or not other on baclofen are also taking anti-depressents or anti-psychotioc meds.

  8. #8
    My son is now being weaned from baclofen...when they started weaning him, he was at around 350. As they reduce the dosage, he becomes depressed for a day or two. then is is OK. The amazing thing is that his strength has returned an he is able to rehab.

  9. #9
    Just an update. My son's pump is now down at 25. And he is alos completly off psych meds. He was taking anti-depressants, anti-psychotic meds, and sleeping pills before. Irrespective of occasion, down periods, his overall mood is the best we've seen in years.

  10. #10
    Yesterday the baclofen was removed from my son's pump (he is having the pump taken out at the end of the month). Initially when they turned down the pump, he would be depressed for a few days. Then he was ok. But recently he has been having bouts of severe depression even though, before yesterday, the last adjustment was a month ago. We understand this to be a side-effect of baclofen withdrawal. Hope he gets through this soon. Anyone withdraw from baclofen and how bad was the withdrawal?

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