Contemplating neurosurgery for refractory OCD. Theperspective of the referring psychiatrist

S-75 Neurosurgery for Mental Disorders in the Decade of the Brain: Current Ethical, Clinical and Scientific Issues but not naive controls, respond to cocaine-related stimuli with self-reports of cocaine craving and activation of cortical areas thought to participate in episodic memory. Thus, metabolic mapping studies in human volunteers have provided information on the acute effects of drugs of abuse and on persistent abnormalities in brain metabolism in drug abusers. The studies provide insight that is needed in order to rationally design medication targeted at specific behavioral features of addictive disorders.

18-74-31 Quantitating Benzodiazepine and Opiate Receptor Sensitivity in Addicts J. Potokar, N. Coupland, S. Wilson, J. Bailey, F. Law, DJ. Nutt. Psychopharmacology Unit, University of Bristol, UK A major difficulty in quantitating benzodiazepine and opiate receptor sensitivity has been the lack of reliability of measures used, such as symptom reports and psychometric tests, both of which may be influenced by motivational factors. We have been using the technique of saccadic eye movement (SEM) analysis to measure the central effects of different drugs. SEMs are involuntary rapid conjugate gaze changes, enabling the eye to centre a target of interest onto the fovea. An infusion of the short TI/2 benzodiazepine, midazolam in volunteers, causes eye movement slowing that is highly correlated with midazolam dose and plasma concentration [I]. We have been extending this paradigm to patients on chronic benzodiazepine therapy; preliminary results show attenuation of SEM velocity which may be a hard measure of the tolerance that occurs with chronic benzodiazepine use. Since opiates also influence SEMs (the superior colliculus, a major relay station for SEMs, contains opiate receptors), we have been measuring them in studies of methadonelbuprenorphine transfer in addicts and find an increase in velocity to parallel self ratings of withdrawal. Traditional measures of opiate function include pupilometry, CRT and CFF. SEMs have several advantages. They are not significantly effected by emotional state, cognitions and accommodation. They have high test/retest reliability are sensitive and therefore a useful tool for probing central opiate function. [II Ball et al (1991) Psychopharmacology 105: 361-367

18-74-5 1 Gamma-Hydroxybutyric Acid: A "Methadone" for Alcoholism? G. Colombo, G.L. Gessa. Departmentof Neuroscience, University of

Cagliari, Italy Gamma-hydroxybutyric acid (GHB) is a normal constituent of the mammalian brain. The existence in brain of specific receptor sites, uptake system, synthesis, metabolizing enzymes and release mechanisms supports the idea that GHB might function as a neurotransmitter in the CNS. Experimental and clinical evidence, summarized here, indicates that GHB is not only an efficacious drug for alcoholism, but may represent an important tool to unravel the elusive mechanism of action of ethanol in brain. The administration of GHB inhibits voluntary alcohol intake in genetically selected alcohol-preferring sP [I] and P [2] rats. Similarly, in alcoholic patients, GHB has been shown to readily suppress alcohol withdrawal symptomatology and to reduce craving for alcohol, alcohol consumption and relapse [3-6]. Experimental evidence indicates that GHB mimics alcohol in different central actions [7]. More recently, drug discrimination studies have shown a symmetrical generalization between alcohol and GHB, in that GHB substitutes for alcohol in its discriminative stimulus effects and vice versa [8]. Moreover, the selective GHE receptor antagonist, NCS-382, has been shown to block not only, as expected, the discriminative stimulus effects of GHB [9], but also those of alcohol (Colombo et al, in preparation). These results suggest that GHB and alcohol elicit the same internal cues by an action on GHB receptors. The latter might represent a target for a novel approach to alcoholism. [I] Fadda F et al, Psychopharmacology 96(Suppl) (1998) 107. [2] June HLet aI, Alcohol. Clin. Exp. Res. 19(5uppl) (1995) 14A. [3] Gallimberti Let al, The Lancet ii (1989) 787-789. [4] Gallimberti Let aI, Alcohol. Clin. Exp. Res. 16(1992) 673-676. [5] Nimmerrichter AAet ai, Alcohol. Clin. Exp. Res. 19(5uppl) (1995) 18A. [6] Di BelloMGet al, Alcologia 7 (1995) 9-16. [7] DianaM et al Brain Res. 566 (1991) 208-211. [8] Colombo G et al, PhysioI. Behav. 57 (1995) 105-111. [9J Colombo G et al, Physio!. Behav. 58 (1995) 587-590.

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18-74-41 Stimulant-Opiate Interactions in Humans M.W. Fischman, R.W. Foltin. Department of Psychiatry, Columbia

University, New York, NY, USA Cocaine-heroin combinations Cspeedball') are popular with drug abusers. Laboratory data collected with humans suggest that combinations of single doses of intravenous cocaine with an opiate (morphine or buprenorphine, a partial opiate agonist) result in a profile of effects representative of both of them, suggesting that stimulant-opiate combinations can have high abuse liability. Interestingly, research with non-humans showed that cocaine self-administration is attenuated under buprenorphine maintenance, and laboratory data collected with human non-opiate dependent cocaine users indicate that buprenorphine treatment is associated with a decrease in self-administration of 16 and 32 mg/70 kg doses of cocaine, although not with decreases in cocaine "craving" scores. Since those data suggested that buprenorphine might be efficacious in the treatment of opiate dependent cocaine abusers, the effects of buprenorphine maintenance (8 mg sublingual plus oral placebo) and methadone maintenance (60 mg oral plus sublingual placebo) on cocaine self-administration were compared. All subjects were tested under both maintenance conditions. The transition from methadone to buprenorphine engendered moderate withdrawal symptoms which were not controlled by c1onidine, but responded well to several days of oxazepam and chloral hydrate. In general , the subjective and physiological effects of cocaine were similar regardless of the maintenance medication. Choice to self-administer cocaine was differentially affected by the two medications, with fewer 16 and 32 mg170 kg doses self-administered under buprenorphine maintenance. In addition, methadone and buprenorphine maintenance appeared to differentially affect drug craving scores, although the effect was not consistent. Thus, under some conditions, buprenorphine may be more useful than methadone for treating opiate/cocaine abusers. Support: DA-03818 and DA-06234 (NIDA) and MOI-RR-00645 (NIH)

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I8-75-1 I Neurosurgery for Mental Disorders in the Decade of the Brain. Purpose andIntroduction

P. Mindus (Chair), P. Sachdev (Co-chair).

Purpose: To offer an update on psychiatry's most strikingly braincentered and controversial treatment modality; Neurosurgery for Mental Disorders (NMD). Introduction: Although both unfounded and well-founded criticism has been able to knock it down, "psychosurgery" has not been knocked out. With the recognition that some cases with affective, obsessional, or anxiety disorders prove refractory even to extensive and intensive treatment efforts and remain extremely disabled, interest in NMD has reawakened, and a limited number of operations are carried out today. However, a recent survey among specialists clearly demonstrated a need for an update on NMD. Program: Panelists will discuss aspects of decision making, neuroanatomy, brain imaging, current techniques, contemporary indications and contraindications, expected clinical outcome in different patient populations, and risk-benefit and ethical issues.

I

8-75-2 1 Contemplating Neurosurgery for Refractory OCD. ThePerspective of the Referring Psychiatrist

J. Zohar, Y. Sasson, 1. Hendler, M. Lustig. Division of Psychiatry; Chaim Sheba Medical Center, Tel-Hashomer, Israel Obsessive compulsive disorder (OCD) is the second most prevalent psy-

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chiatric disorder after depression. OCD prevalence is extremely consistent around the globe and is about 2% in the general population. In the last 15 years. with the development of treatment with specific behavior therapy and serotonic reuptake blockers. there has been remarkable progress in our ability to administer effective treatment for patients who suffer from OCD . However. about 10 to 20 percent of patients are refractory to all pharmacological. behavioral and family intervention. If a patient fails to respond to an adequate trial of clomipramine and specific serotonin reuptake inhibitors (SSRIs), including augmentation with fenfluramine, lithium. busiparone. trazedone and dopamine blockers, or to an adequate and extensive behavioral approach, or to appropriate family therapy, then neurosurgery should be considered. This is especially true for patients who are non-responders and those whose quality of life, due to impairment caused by the disorder, is extremely poor.

18-75-31 The Functional Neuroanatomy of Prefrontal Cortex: Implications for Psychosurgery L.B. Geffen. PsychiatryDepartment, University of Queensland,

Brisbane. Australia Prefrontal cortex (PFC) is the largest and least understood area of association cortex. PFC has reciprocal connections to all other associat ion cortices, as well as exclusive reciprocal connections to all limbic cortices and brain stem aminergic nuclei. PFC has major inputs from thalamus and outputs to basal ganglia but no direct connections to primary sensory or motor cortices or their subcortical relays. The unique supramodal connectivity of PFC enables it to participate in cognitive networks that subserve the integration and control of conscious. goal directed behaviour. In particular, PFC is a site of central executive control of working memory. Working memory neuronal networks briefly maintain and update information (past and present) relevant for planning intentions and actions. A primary aim of neurosurgery is to irreversibly disrupt some of these network connections. More selective and reversible methods of modifying PFC functions (such as transmagnetic stimulation and receptor specific drugs), coupled with advances in functional brain imaging, are likely to replace current psychosurgical procedures. To assess the potential effects of disruption of PFC connections on working memory in humans, we have developed behavioural and electrophysiological measures of PFC function using a visuospatial delayed response task (DRT).

I8-75-41 Contemporary Indications and Interventions for Psychiatric Neurosurgery: An Overview P. Sachdev. School of Psychiatry, University of New Soutn Wales,

Sydney: AUSTralia There is a seeming international consensus that NPD has a small but important place in the management of severe psychiatric disorders. Its current usc is primarily for the treatment of intractable. disabling and long-standing obsessive-compul sive disorder (OCD) and major depression. Less we ll agreed indications are similarly intractable and severe generalised anxiety disorder and bipolar disorder. Its only place in the treatment of schizophrenia is when there is an associated severe and intractable affective component. Its use in primary disorders of impulse control, psychosexual disorders and eating disorders is not recommended. NPD is not performed on children, adolescents and the very old. All centres engaged in NPD accept that it is a treatment of last resort with all other treatments having been tried adequately and failed. There is no consensus on the duration of illness necessary before NPD is used, but most centres would need at least a duration of two years for depression and five years for OCD . The presence of repeated suicide attempts and intense subjective distress may influence the decision for surgery. All modem NPD is stereotactic, and one or more of the following brain regions are generally targeted bilaterally: the white matter in the orbitomedial frontal regions, the anterior limb of the internal capsule, and the cingulum. The method s (cryogenic, thermal, cobalt radiation), number and size of lesions vary widely from centre to centre. The safety of modern stereotactic NPD is well established, and it is witnessing a resurgence of interest within the new neurobiology.

I8-75-51 Obsessive-Compulsive Functional Neuroimaging Implications for Disorder Neurosurgery L. Baxter. S. Saxena, A. Brody, J. Schwartz, R. Ackermann . UA B Birmingham, AL USA; UCLA Los Angeles, CA, USA Human functional neuroimaging studies of obsessive-compulsive disorder (OCD) using PET and fMRI, as well as animal studies using PET and autoradiography, implicate a specific corticollimbic --+ basal ganglia --+ cerebellar --+ basal ganglia --+ thalamic --+ corticollimbic circuit in the mediation of OCD symptoms, and their response both to serotonin reuptake inhibitor medications and to behavioral decondition ing treatment methods. From these studies we have put forth a theory that an imbalance of neural tone through the impulse-facilitating "direct basal ganglia pathway", vs. that through an "indirect basal ganglia pathway" that facilitates behavioral reservation, may be critical for the expression of obsessions and compulsive behavior. Further, since recent studies suggest that paralimbic orbital frontal cortex seems to drive neural tone selectively through the direct basal ganglia pathway. while dorsal prefrontal cortex seems to drive indirect system tone, neuro-surgeries that decrease the latter, while not affecting the former, seem most promising. Thus, these functional neuroimaging data may be of help in designing more efficient procedures for refactory OCD.

I 8-75-6 1

The Clinical Outcome of Neurosurgical Treatment in Obsessive-Compulsive Disorder: A Review P. Hay. Department of Psychiatry. University ofAdelaide, South AUSTralia Aims: To evaluate the evidence for the neurosurgical treatment of patients with obsessive-compulsive disorder, and to evaluate the impact of potential adverse effects. Methods: A MEDLINE database search. and handsearch of reference lists of publications found in MEDLINE were done. All identified reports of outcome, including single case reports. were included in this review. Results and conclusions: The evaluation of outcome is problematic due to deficits in study methods. However the best evidence indicates that there is a therapeutic effect for some patients, and this effect is clinically meaningful. Outcome may be related to the site of the lesion, with anterior cingulate lesions most and cingulate only lesions least likely to be beneficial. There is less consistent evidence for the size of the lesion being important. Side-effects must be considered. Although small, there is a risk of personality change due to compl ications of neurosurgery. For some patients thus may be a positive change of reduced obsessionality, and for some an adverse change of the "frontal lobe type". Most studies have not evaluated the neuropsychological outcome following surgery. There is not enough evidence to be conclusive, and it is difficult to assess cognitive impairments independent of illness effects.

I8-75-7 1Whatif i do? What if I Don't? Risk-Benefit and Ethical Issues of Neurosurgical Treatment for Mental Disorders P. Mindus, Psychiatry. Karolinska Hospital, Stockholm

Candidates for neurosurgical treatment for mental disorders (NMD) have chronic, incapacitating, complicated cases refractory to extensive and intensive treatment efforts, and are rare. The likely future course of their disorder is a malignant one, with increased risk of complication s or even suicide. Weighing these risks against those of NMD is a difficult task, the more so since the data on risk-benefit issues are sparce, often unknown even to specialists, and NMD itself an emotive issue. Modern , restricted, stereotactic operations carry little surgical risks (the incidence of e.g. postoperative epilepsy is approx. 1%), and no death has been reported in more recent series. Prospective studies indicate that cognitive dysfunction may occur but may be transient (e.g. perseverative responses were more common at I year after capsulotorny, but not at 8 years), and that although negative personality changes may occur in occasional patients. this is generally not to be expected. With regard to benefit, there are no controlled studies. However, remarkably consistent results have been reported accross studies with non-blind. intra-individual, prospecti ve