- Email: [email protected]
P.6.c.008 Neural responses to rewards and punishments in patients with opiate dependence on methadone treatment: fNEMO study
S402
P.6.c. Addiction − Drugs (clinical)
that individual variation of TH gene may affect the prognosis of multiple substance abuse. Our sample size is, however, not large enough to eliminate the possibility of a type I error, our findings must be confirmed by replicate studies with larger samples.
as well as schizophrenia. In particular, these findings highlight the importance of competition between drug-related and other alternative rewards in addiction [3] and raise questions about the efficacy of reward-based contingency treatment in high risk contexts associated with previous drug use.
P.6.c.007 Associative blocking to reward-predicting cues is attenuated in ketamine users but can be modulated by images associated with drug use
References
T. Freeman1 ° , C.J.A. Morgan1 , F. Pepper1 , O.D. Howes2 , J.M. Stone2 , H.V. Curran1 1 University College London, Clinical Psychopharmacology Unit, London, United Kingdom; 2 Imperial College London, Division of Experimental Medicine/ MRC Clinical Sciences Centre, London, United Kingdom Blocking is a selective learning process demonstrating that the relationship between a cue and an outcome depends on the extent to which that outcome elicits prediction error or surprise [1]. Blocking is attenuated in schizophrenia, can be modulated by cue salience, and is accompanied by changes in selective attention. Repeated exposure to ketamine can model aspects of schizophrenia, and frequent users show a bias in selective attention to images of the drug. This study aimed to establish whether (i) ketamine users show a reduction in blocking to reward-predicting cues and (ii) this effect can be modulated by the use of images associated with drug use. Since drug images can also overshadow neutral cues that are equally predictive of reward during tobacco deprivation [2] we investigated drug cue induced overshadowing. Ketamine users (n = 18) and polydrug controls (n = 16) were assessed on the Drug Cue Reward Prediction Error Task (DCRPET; [2]) which assesses the effects of neutral and drug related cues on reward-based associative learning processes. Following pavlovian conditioning between cues and outcomes, accuracy and importance ratings to individual cues were used to index blocking and the ability of drug cues to modulate this effect as well as cause overshadowing. Delusions, schizotypy, depression and ketamine dependence were also recorded. The ketamine using group had used the drug for 10.39 (±3.58) years, and estimated that they were currently using 9.27 (±8.40) grams over 4.67 (±1.88) days per week, on average showing moderate to high dependence. This group also showed elevated delusional, schizotypal and depressive symptoms compared to controls. No group differences emerged during pavlovian conditioning to outcomes, but ketamine users showed a reduction in blocking as evidenced by higher accuracy to blocked cues compared to controls (t32 = 2.308, p = 0.032). Drug-related cues were most resistant to blocking in this group, with ketamine users scoring higher than controls on accuracy to these cues (t32 = 2.563, p = 0.015), and also rating them as more important for earning money (t32 = 3.296, p = 0.002). Both groups showed overshadowing of neutral cues by drug cues (F1,32 = 4.541, p = 0.041), and compared to controls, ketamine users gave both overshadowing cues higher importance ratings (F1,32 = 6.161, p = 0.018). This study showed a reduction in blocking amongst a group of ketamine users with elevated delusions, schizotypy, and depression. These findings are the first to link glutamatergic disruption with a failure to show selective learning through blocking. Drug cues were the most resistant to blocking in ketamine users and were also rated as more important for earning money, suggesting that blocking may contribute to aspects of addictive behaviour
[1] Kamin, LJ (1969). Selective association and conditioning. In Fundamental Issues in Associative Learning (Ed.) NJ Mackintosh, WK Honig, 42−64. Halifax: Dalhousie University Press. [2] Freeman TP, Morgan CJA, Beesley T, Curran HV (2012). Drug cue induced overshadowing: selective disruption of natural reward processing by cigarette cues amongst abstinent but not satiated smokers. Psychological Medicine 42: 161–171. [3] Goldstein RZ, Volkow ND (2012). Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nature Reviews Neuroscience 12, 652–669.
P.6.c.008 Neural responses to rewards and punishments in patients with opiate dependence on methadone treatment: fNEMO study V. Gradin1 ° , S. Gray1 , J. MacFarlane2 , G. Waiter3 , D. Balfour1 , K. Matthews1 , A. Baldacchino1 , D. Steele1 1 University of Dundee, Department of Psychiatry, Dundee Scotland, United Kingdom; 2 University of Dundee, Medical Physics, Dundee Scotland, United Kingdom; 3 University of Aberdeen, Medical Physics, Aberdeen Scotland, United Kingdom Substance dependence are common disorders spanning a range of severity from intermittent and mild to chronic and devastating. A core manifestation of the syndrome is a compulsion to seek and to use specific drugs, often to the neglect of non-drug related goals and despite negative consequences [1]. One hypothesis is that repeated use of addictive drugs ‘hijacks’ the normal cognitiveneural systems for learning about rewards and punishments, such that drug-related stimuli become overvalued and non-drug stimuli become undervalued. This is supported by evidence that most drugs of addiction exert common actions on the mesolimbic dopamine system which is critical for reward processing. Here we use functional Magnetic Resonance Imaging (fMRI) and a behavioral task to investigate the neural reward and aversive systems in patients with opiate dependence on methadone treatment. To date, 16 healthy controls and 22 patients (11 scanned after and 11 scanned before daily methadone intake) matched by age and gender have been scanned. During fMRI, participants played an instrumental reward and aversive learning task [2]. In this task there are three types of trial: reward, neutral and loss. On reward trials participants learn by trial and error to select most often the high-reward stimulus in comparison to a low-reward stimulus. Similarly on loss trials participants learn to select a high loss-avoidance stimulus vs. a low loss-avoidance stimulus. After scanning, participants are given a gift-voucher for the amount of points accumulated during the task. Behavioral analysis indicates that both controls and patients were capable of learning to select most often the high reward and high loss-avoidance stimuli with no significant differences between groups. For the image analysis we compared neural responses to favorable (reward success + loss avoidance success) vs. unfavorable outcomes (reward non-success + loss avoidance non-success). For this contrast, both controls and patients activated the ventral striatum bilaterally, consistent with the ventral striatum
P.6.c. Addiction − Drugs (clinical) being a core brain region for processing reward information. Importantly, significant between group differences were found in the bilateral ventral striatum (p < 0.05 whole brain corrected) with controls showing stronger responses to favorable vs. unfavorable outcomes than patients. This between group difference for the striatum was driven by a combination of two factors: (a) patients exhibiting diminished neural responses to reward success and (b) patients not showing differentiated neural responses for loss avoidance success vs. non-success. These findings indicate abnormal neural processing of rewards and punishments in patients with addiction. As neural responses to reinforcers in the ventral striatum are thought to relate to dopamine activity, our results imply abnormal functioning of the dopamine system in addicted patients. Diminished patient neural reward responsiveness is consistent with the hypothesis of patients under valuing natural rewards. Impairment in distinguishing at a neural level between receiving or not a negative outcome suggests difficulty in learning from punishments. This is consistent with addicted patients continuing to pursue seeking drugs despite negative consequences. These findings highlight the neural substrates of putative abnormalities in the reward and aversive neural systems in patients with opioid dependence on methadone treatment. References [1] Diekhof, E.K., Falkai, P., Gruber, O., 2008. Functional neuroimaging of reward processing and decision-making: A review of aberrant motivational and affective processing in addiction and mood disorders. Brain Research Reviews 164–184. [2] Pessiglionne, M., Seymour, B., Flandin, G., Dolan, R.J., Frith, C.D., 2006. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442(7106) 1042–1045.
P.6.c.009 Anabolic androgenic steroids in psychiatric practice R. Rodrigues1 ° , S. Ramos1 , N. Almeida1 of psychiatry, Guimar˜aes, Portugal
1 CHAA,
Department
Anabolic androgenic steroids (AAS), synthetic derivatives of testosterone, are being increasingly used in modern society by athletes and non-athletes to enhance performance and improve physical appearance. They generally use the combination of multiple AAS drugs in oral and intramuscular preparations, out of their medical indications and 10 to 100 times greater than their therapeutic doses. The use of AAS is spreading through Europe. In recent years the recreational use of these drugs has increased significantly in young people and in some professions such as security officers and nightclub bouncers. In the Internet era, it is very easy to obtain these substances. They are easily obtained in gyms, fitness centers and in pharmacies, without prescription, due to lack of inspection and absence of criminal liability. In Portugal AAS are Controlled Drugs, class C, and it is illegal to obtain them without prescription, a violation that can be penalized with fine from 5000 to 50,000 euros. There is a huge gap on data referring to this matter. In 1998 the Portuguese Nacional Council Doping tried to study our reality applying a Korkia and Stimpson questionnaire in gyms with the cooperation of the National Federation of Physical Culture, but from the 700 questionnaires distributed only 91 were valid. The results clearly show that the problem exists. AAS misuse has multiple adverse medical effects, usually reversible with cessation. Many studies have found evidence that AAs may lead to important psychiatric collateral effects, such as
S403
mood and anxiety disorders, psychosis and personality disorders (higher prevalence of cluster B personality traits). The authors present and comment four cases attended during 2011. All males, two with anxiety, insomnia, marked impulsivity, and with legal problems due to aggressive behavior. One referenced by the Reproductive Medicine presenting abnormalities of sperm count, using regularly AAS, refusing to stop using them, ending in divorce and abandoning treatment. A 24 years old man working as a nightclub bouncer, who presented with loss of inhibition and lack of judgment, mood swings, suspiciousness, being violent and hostile to is family. He was recently admitted to psychiatry word due to psychotic break, also in drug use (cannabinoids). The most frequent psychiatric symptoms described in AAS users are body misperception, anxiety, impulsivity, irritability, increase aggressive responding, headache, insomnia, mood oscillations particularly manic symptoms, sexual dysfunction and difficulties in reproduction. Psychosis is rare and may be related to high-dose testosterone. The most commonly use in Portugal are Deca Durabolin, Proviron, Testoviron and Sustenon. We refer to how they affect the brain, the real effect and side-effects. It is important to alert psychiatrists in the recognition and management of patients who show physical evidence of AAS misuse and these syndromes. If we are facing a new addictive disorder is still controversial, but there is evidence for dependence and withdrawal syndrome. AAS use is many times de gateway to other addictions, a public health risk. References [1] Rashid, H., Ormerod, S., Day, E., 2007. Anabolic androgenic steroids: what the psychiatrist needs to know. Advances in Psychiatric Treatment 13, 203–211. [2] Brower, KJ., 2002. Anabolic steroids abuse and dependence. Curr Psychiatry Rep 4(5): 377–387. [3] Pope, HG Jr., Kouri, EM., Hudson JI., 2000. Effects of supraphysiologic doses of testosterone on moood and aggression in normal men: A randomized controlled trial. Arch Gen Psychiatry 57(2): 133–140.
P.6.c.010 Differences in cannabinoid-induced changes in cognitive performance in light stimulant and cannabis users versus heavy cannabis users N. Levy-Cooperman1 ° , S.J. Harrison1 , N.L. Chen1 , B. Chakraborty1 1 INC Research, Research Consulting, Toronto, Canada Purpose: The effect of acute cannabinoid drug use has been shown to produce minimal effects on complex cognitive task performance [1,2]. This may be related to tolerance to the cognitive impairing effects of cannabis in regular/heavy users of cannabis versus light or na¨ıve users. The current analysis investigated cognitive performance in two groups of subjects, polydrug users with a history of light stimulant and cannabis (LCS) use and heavy cannabis users (HC). Heavy cannabinoid use was defined as use of smoked marijuana, hashish, or oral THC, at least once/week for 3 months prior to screening and, on at least one occasion, four times in a given week in the prior 3 months. Light cannabinoid use was defined as using smoked marijuana, hashish, or THC, on at least 10 occasions in the past 5 years and minimum once in 3 months prior to screening. These subjects also had experience with stimulants on at least 10 occasions in the past 5 years and at least once in the past 3 months.
P.6.c. Addiction − Drugs (clinical)
that individual variation of TH gene may affect the prognosis of multiple substance abuse. Our sample size is, however, not large enough to eliminate the possibility of a type I error, our findings must be confirmed by replicate studies with larger samples.
as well as schizophrenia. In particular, these findings highlight the importance of competition between drug-related and other alternative rewards in addiction [3] and raise questions about the efficacy of reward-based contingency treatment in high risk contexts associated with previous drug use.
P.6.c.007 Associative blocking to reward-predicting cues is attenuated in ketamine users but can be modulated by images associated with drug use
References
T. Freeman1 ° , C.J.A. Morgan1 , F. Pepper1 , O.D. Howes2 , J.M. Stone2 , H.V. Curran1 1 University College London, Clinical Psychopharmacology Unit, London, United Kingdom; 2 Imperial College London, Division of Experimental Medicine/ MRC Clinical Sciences Centre, London, United Kingdom Blocking is a selective learning process demonstrating that the relationship between a cue and an outcome depends on the extent to which that outcome elicits prediction error or surprise [1]. Blocking is attenuated in schizophrenia, can be modulated by cue salience, and is accompanied by changes in selective attention. Repeated exposure to ketamine can model aspects of schizophrenia, and frequent users show a bias in selective attention to images of the drug. This study aimed to establish whether (i) ketamine users show a reduction in blocking to reward-predicting cues and (ii) this effect can be modulated by the use of images associated with drug use. Since drug images can also overshadow neutral cues that are equally predictive of reward during tobacco deprivation [2] we investigated drug cue induced overshadowing. Ketamine users (n = 18) and polydrug controls (n = 16) were assessed on the Drug Cue Reward Prediction Error Task (DCRPET; [2]) which assesses the effects of neutral and drug related cues on reward-based associative learning processes. Following pavlovian conditioning between cues and outcomes, accuracy and importance ratings to individual cues were used to index blocking and the ability of drug cues to modulate this effect as well as cause overshadowing. Delusions, schizotypy, depression and ketamine dependence were also recorded. The ketamine using group had used the drug for 10.39 (±3.58) years, and estimated that they were currently using 9.27 (±8.40) grams over 4.67 (±1.88) days per week, on average showing moderate to high dependence. This group also showed elevated delusional, schizotypal and depressive symptoms compared to controls. No group differences emerged during pavlovian conditioning to outcomes, but ketamine users showed a reduction in blocking as evidenced by higher accuracy to blocked cues compared to controls (t32 = 2.308, p = 0.032). Drug-related cues were most resistant to blocking in this group, with ketamine users scoring higher than controls on accuracy to these cues (t32 = 2.563, p = 0.015), and also rating them as more important for earning money (t32 = 3.296, p = 0.002). Both groups showed overshadowing of neutral cues by drug cues (F1,32 = 4.541, p = 0.041), and compared to controls, ketamine users gave both overshadowing cues higher importance ratings (F1,32 = 6.161, p = 0.018). This study showed a reduction in blocking amongst a group of ketamine users with elevated delusions, schizotypy, and depression. These findings are the first to link glutamatergic disruption with a failure to show selective learning through blocking. Drug cues were the most resistant to blocking in ketamine users and were also rated as more important for earning money, suggesting that blocking may contribute to aspects of addictive behaviour
[1] Kamin, LJ (1969). Selective association and conditioning. In Fundamental Issues in Associative Learning (Ed.) NJ Mackintosh, WK Honig, 42−64. Halifax: Dalhousie University Press. [2] Freeman TP, Morgan CJA, Beesley T, Curran HV (2012). Drug cue induced overshadowing: selective disruption of natural reward processing by cigarette cues amongst abstinent but not satiated smokers. Psychological Medicine 42: 161–171. [3] Goldstein RZ, Volkow ND (2012). Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nature Reviews Neuroscience 12, 652–669.
P.6.c.008 Neural responses to rewards and punishments in patients with opiate dependence on methadone treatment: fNEMO study V. Gradin1 ° , S. Gray1 , J. MacFarlane2 , G. Waiter3 , D. Balfour1 , K. Matthews1 , A. Baldacchino1 , D. Steele1 1 University of Dundee, Department of Psychiatry, Dundee Scotland, United Kingdom; 2 University of Dundee, Medical Physics, Dundee Scotland, United Kingdom; 3 University of Aberdeen, Medical Physics, Aberdeen Scotland, United Kingdom Substance dependence are common disorders spanning a range of severity from intermittent and mild to chronic and devastating. A core manifestation of the syndrome is a compulsion to seek and to use specific drugs, often to the neglect of non-drug related goals and despite negative consequences [1]. One hypothesis is that repeated use of addictive drugs ‘hijacks’ the normal cognitiveneural systems for learning about rewards and punishments, such that drug-related stimuli become overvalued and non-drug stimuli become undervalued. This is supported by evidence that most drugs of addiction exert common actions on the mesolimbic dopamine system which is critical for reward processing. Here we use functional Magnetic Resonance Imaging (fMRI) and a behavioral task to investigate the neural reward and aversive systems in patients with opiate dependence on methadone treatment. To date, 16 healthy controls and 22 patients (11 scanned after and 11 scanned before daily methadone intake) matched by age and gender have been scanned. During fMRI, participants played an instrumental reward and aversive learning task [2]. In this task there are three types of trial: reward, neutral and loss. On reward trials participants learn by trial and error to select most often the high-reward stimulus in comparison to a low-reward stimulus. Similarly on loss trials participants learn to select a high loss-avoidance stimulus vs. a low loss-avoidance stimulus. After scanning, participants are given a gift-voucher for the amount of points accumulated during the task. Behavioral analysis indicates that both controls and patients were capable of learning to select most often the high reward and high loss-avoidance stimuli with no significant differences between groups. For the image analysis we compared neural responses to favorable (reward success + loss avoidance success) vs. unfavorable outcomes (reward non-success + loss avoidance non-success). For this contrast, both controls and patients activated the ventral striatum bilaterally, consistent with the ventral striatum
P.6.c. Addiction − Drugs (clinical) being a core brain region for processing reward information. Importantly, significant between group differences were found in the bilateral ventral striatum (p < 0.05 whole brain corrected) with controls showing stronger responses to favorable vs. unfavorable outcomes than patients. This between group difference for the striatum was driven by a combination of two factors: (a) patients exhibiting diminished neural responses to reward success and (b) patients not showing differentiated neural responses for loss avoidance success vs. non-success. These findings indicate abnormal neural processing of rewards and punishments in patients with addiction. As neural responses to reinforcers in the ventral striatum are thought to relate to dopamine activity, our results imply abnormal functioning of the dopamine system in addicted patients. Diminished patient neural reward responsiveness is consistent with the hypothesis of patients under valuing natural rewards. Impairment in distinguishing at a neural level between receiving or not a negative outcome suggests difficulty in learning from punishments. This is consistent with addicted patients continuing to pursue seeking drugs despite negative consequences. These findings highlight the neural substrates of putative abnormalities in the reward and aversive neural systems in patients with opioid dependence on methadone treatment. References [1] Diekhof, E.K., Falkai, P., Gruber, O., 2008. Functional neuroimaging of reward processing and decision-making: A review of aberrant motivational and affective processing in addiction and mood disorders. Brain Research Reviews 164–184. [2] Pessiglionne, M., Seymour, B., Flandin, G., Dolan, R.J., Frith, C.D., 2006. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442(7106) 1042–1045.
P.6.c.009 Anabolic androgenic steroids in psychiatric practice R. Rodrigues1 ° , S. Ramos1 , N. Almeida1 of psychiatry, Guimar˜aes, Portugal
1 CHAA,
Department
Anabolic androgenic steroids (AAS), synthetic derivatives of testosterone, are being increasingly used in modern society by athletes and non-athletes to enhance performance and improve physical appearance. They generally use the combination of multiple AAS drugs in oral and intramuscular preparations, out of their medical indications and 10 to 100 times greater than their therapeutic doses. The use of AAS is spreading through Europe. In recent years the recreational use of these drugs has increased significantly in young people and in some professions such as security officers and nightclub bouncers. In the Internet era, it is very easy to obtain these substances. They are easily obtained in gyms, fitness centers and in pharmacies, without prescription, due to lack of inspection and absence of criminal liability. In Portugal AAS are Controlled Drugs, class C, and it is illegal to obtain them without prescription, a violation that can be penalized with fine from 5000 to 50,000 euros. There is a huge gap on data referring to this matter. In 1998 the Portuguese Nacional Council Doping tried to study our reality applying a Korkia and Stimpson questionnaire in gyms with the cooperation of the National Federation of Physical Culture, but from the 700 questionnaires distributed only 91 were valid. The results clearly show that the problem exists. AAS misuse has multiple adverse medical effects, usually reversible with cessation. Many studies have found evidence that AAs may lead to important psychiatric collateral effects, such as
S403
mood and anxiety disorders, psychosis and personality disorders (higher prevalence of cluster B personality traits). The authors present and comment four cases attended during 2011. All males, two with anxiety, insomnia, marked impulsivity, and with legal problems due to aggressive behavior. One referenced by the Reproductive Medicine presenting abnormalities of sperm count, using regularly AAS, refusing to stop using them, ending in divorce and abandoning treatment. A 24 years old man working as a nightclub bouncer, who presented with loss of inhibition and lack of judgment, mood swings, suspiciousness, being violent and hostile to is family. He was recently admitted to psychiatry word due to psychotic break, also in drug use (cannabinoids). The most frequent psychiatric symptoms described in AAS users are body misperception, anxiety, impulsivity, irritability, increase aggressive responding, headache, insomnia, mood oscillations particularly manic symptoms, sexual dysfunction and difficulties in reproduction. Psychosis is rare and may be related to high-dose testosterone. The most commonly use in Portugal are Deca Durabolin, Proviron, Testoviron and Sustenon. We refer to how they affect the brain, the real effect and side-effects. It is important to alert psychiatrists in the recognition and management of patients who show physical evidence of AAS misuse and these syndromes. If we are facing a new addictive disorder is still controversial, but there is evidence for dependence and withdrawal syndrome. AAS use is many times de gateway to other addictions, a public health risk. References [1] Rashid, H., Ormerod, S., Day, E., 2007. Anabolic androgenic steroids: what the psychiatrist needs to know. Advances in Psychiatric Treatment 13, 203–211. [2] Brower, KJ., 2002. Anabolic steroids abuse and dependence. Curr Psychiatry Rep 4(5): 377–387. [3] Pope, HG Jr., Kouri, EM., Hudson JI., 2000. Effects of supraphysiologic doses of testosterone on moood and aggression in normal men: A randomized controlled trial. Arch Gen Psychiatry 57(2): 133–140.
P.6.c.010 Differences in cannabinoid-induced changes in cognitive performance in light stimulant and cannabis users versus heavy cannabis users N. Levy-Cooperman1 ° , S.J. Harrison1 , N.L. Chen1 , B. Chakraborty1 1 INC Research, Research Consulting, Toronto, Canada Purpose: The effect of acute cannabinoid drug use has been shown to produce minimal effects on complex cognitive task performance [1,2]. This may be related to tolerance to the cognitive impairing effects of cannabis in regular/heavy users of cannabis versus light or na¨ıve users. The current analysis investigated cognitive performance in two groups of subjects, polydrug users with a history of light stimulant and cannabis (LCS) use and heavy cannabis users (HC). Heavy cannabinoid use was defined as use of smoked marijuana, hashish, or oral THC, at least once/week for 3 months prior to screening and, on at least one occasion, four times in a given week in the prior 3 months. Light cannabinoid use was defined as using smoked marijuana, hashish, or THC, on at least 10 occasions in the past 5 years and minimum once in 3 months prior to screening. These subjects also had experience with stimulants on at least 10 occasions in the past 5 years and at least once in the past 3 months.