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Subjective Effects of AMPT-Induced Dopamine Depletion In Subjective Effects of AMPT-induced Dopamine Depletion in Schizophrenia: Correlation between Dysphoric Responses and Striatal D2 Binding Ratios on SPECT Imaging Lakshmi Voruganti, M.D., M.Sc., Piotr Slomka, Ph.D., Pamela Zabel, M.Sc., Giuseppe Costa, B.Sc., Aaron So, B.Sc., Adel Mattar, M.D. and A. George Awad, M.D., Ph.D. Approximately one third of schizophrenic patients treated dysphoric responses, clearly distinguishing a dysphoric with neuroleptic drugs experience unpleasant subjective group from non-dysphoric responders. Severity of dysphoric responses, that are collectively known as neuroleptic responses, measured by standardized rating scales, dysphoria. Experimental research in animals indicates that correlated inversely with changes in D2 receptor binding drug induced dopaminergic blockade in mesolimbic circuits, ratios (r ϭ ϩ0.82, p Ͻ .01). These results support the especially the nucleus accumbens, leads to impaired notion that striatal dopaminergic activity is not uniformly pleasure responsivity and dysphoria. The present study elevated in all schizophrenic patients, and the sub-group of tested this putative mechanism in drug-free schizophrenic individuals with lower baseline dopamine function are at an patients (n ϭ 12), through inducing dysphoric responses increased risk for dysphoric responses during antipsychotic with alphamethyl paratyrosine (AMPT) and therapy with dopaminergic blocking drugs. simultaneously quantifying their baseline striatal dopmine [Neuropsychopharmacology 25:642–650, 2001] 123 (D2) function with IBZM-SPECT imaging. Results © 2001 American College of Neuropsychopharmacology. showed a wide variability in the occurrence and severity of Published by Elsevier Science Inc. KEY WORDS: Dysphoria; Dopamine; Schizophrenia; been focused on studying its role in psychotic disorders Antipsychotic drugs and the effects of antipsychotic drugs (Palermo-Neto 1997). This preoccupation has, to some extent, over- Dopamine carries a distinction of being the most widely shadowed the fact that dopamine plays a wide variety studied neurotransmitter, and much of the research has of physiological functions within the brain as well as the rest of the body (Le Moal 1995). One such example From the Institute of Medical Science, University of Toronto, Tor- is the role of dopamine in the regulation of affect; the onto, Ontario, Canada (LV, AGA); Department of Psychiatry (LV, GC), and Department of Nuclear Medicine (PS, PZ, AS, AM), Uni- relationship between altered dopaminergic function versity of Western Ontario, London, Ontario, Canada. and disturbed mood states has been sporadically stud- Address correspondence to: L. Voruganti, M.D., Schizophrenia ied in clinical settings as well as the laboratory (Big- Treatment and Research (STAR) Program, 850 Highbury Avenue, London, ON N6A 4H1, Canada, Tel.: 519-455-5110 x 2533; Fax: 519- nami 1991; Emerich and Sanberg 1991; Fibiger and Phil- 455-2677; e-mail: [email protected] lips 1986; Sachdev 1995). Received December 6, 2000; revised March 22, 2001; accepted In disease states, lowered dopaminergic activity has April 10, 2001. Online publication: 4/12/01 at www.acnp.org/citations/Npp been associated with depressive symptoms and lack of 0412011031. motivation (e.g., Parkinson’s disease and negative syn- NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 5 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00263-9 NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 5 Dopamine and Dysphoria 643 drome of schizophrenia) (Bermanzohn and Siris 1995; SUBJECTS Markou et al. 1998), while increased dopamine trans- mission has been linked to euphoria, irritability, hyper- The study participants (n ϭ 12) received a letter of infor- arousal and overactivity (e.g., mania and positive mation and provided informed consent, as required by symptoms of schizophrenia) (Gerner et al. 1976; Swerd- the institutional review board of the University of Western low and Koob 1987; Diehl and Gershon 1992). How- Ontario. The sample consisted of subjects who were previ- ever, some of the more convincing examples of the ef- ously treated with neuroleptic drugs, but went off their fects of altered dopaminergic function have been medications (for periods ranging from four weeks to a derived from studying the subjective effects of drugs, year) and returned to the clinic, often with a relapse of therapeutic as well as illicit. Substances that are known symptoms. Subjects were screened with structured clinical to increase dopaminergic activity (e.g., amphetamines) interview (SCID) to confirm the diagnosis of schizophre- induce an experience of pleasure or thrill (Koepp et al. nia, and also to rule out other comorbid conditions such as 1998), while those that tend to block dopaminergic ac- mood disorders, substance abuse and mental retardation. tivity (e.g., antipsychotics) lead to unpleasant or dys- An attempt was made to include equal numbers of “dys- phoric feelings, also known as neuroleptic dysphoria phoric” and “non-dysphoric” responders, and form two (Van Putten et al. 1981; Awad 1993; Voruganti et al. comparable matched study groups. The dysphoric predis- 1997). Experimental research in animals seems to sub- position was established through reviewing subjects’ past stantiate the clinical observations, and indicated that treatment history, and their scores on drug attitude inven- nucleus accumbens (NAc) and mesolimbic pathways tory (DAI), a rating scale used to identify dysphoric re- are the primary neural substrates, and dopamine is the sponders. DAI is an established rating scale for quantify- key neurotransmitter involved in the regulation of plea- ing subjective tolerability of antipsychotic drugs, and the sure responsivity (Fibiger et al. 1990; Taber et al. 1995; cumulative score on the scale ranges between ϩ10 and Wise 1996; Heimer et al. 1997). An integrated theory Ϫ10 (Awad 1993). The shorter version of the scale was ad- suggests that altered dopaminergic activity in the brain ministered on earlier occasions while the subjects were re- reward pathways leads to drug addiction in certain situa- ceiving antipsychotic drugs (Voruganti et al. 2000). For the tions, and drug aversiveness in others (Wise 1988; Koob purpose of this study, subjects who received a negative 1997). Recent developments in the fields of molecular score (0 to Ϫ10) were designated as “dysphoric” respond- biology and neuroimaging have helped to test these pu- ers, and those who received a positive score (0 to ϩ10) tative mechanisms, through performing in-vivo imaging were considered as “non-dysphoric” responders. The de- studies, often complemented with various pharmaco- mographic and clinical characteristics of the two groups logical challenge tests (Laruelle et al. 1999; Volkow et al. are summarized in Table 1. 1997). Imaging striatal dopamine D2 receptors has The dysphoric and non-dysphoric groups were emerged as a reliable tool, especially in establishing the clearly distinct from each other in terms of their past link between chemical and therapeutic profiles of antip- DAI scores, but were not significantly different in age, sychotic drugs (Tamminga and Holcomb 2001). duration of illness, or the length of drug free interval. The focus of the present study was to investigate one These results ensured that the groups were properly aspect of this relationship, i.e. the link between dopa- matched and comparable, without the confounding ef- minergic dysfunction and dysphoria, in a clinical popula- fects of age, sex, length of illness, or the duration of tion. Using a case controlled study design, we recruited drug free interval. two matched groups of drug free schizophrenic pa- tients—one group with a history of persistent dyspho- ric responses to previous neuroleptic therapy, and the METHODS other without such problems. The specific aims of the investigation were, Study Procedure 1. to induce dopamine depletion with the aid of alpha- The study procedures described below received ap- methyl paratyrosine (AMPT), and monitor the con- proval from the institutional review board, and were sequent changes in mental status through carrying carried out in accordance with the declaration of Hels- out serial measurements of the individual’s subjec- inki. All the consented subjects were hospitalized and tive responses over a 96-hr period, comprehensively evaluated with a detailed history, full 2. to measure striatal dopamine D2 receptor binding ra- physical examination, routine blood tests, electrocar- tios with 123IBZM, using single photon emission diogram and urinary screen for illicit drugs, prior to the computerized tomography (SPECT), and initiation of AMPT protocol. The study was planned as 3. to examine the association between baseline striatal a 96-hr clinical experiment, consisting of three phases: dopaminergic function and the magnitude of AMPT- an initial 24-hr assessment phase (to carry out the base- induced dysphoric responses. line evaluations), followed by a 48-hr AMPT-induced 644 L. Voruganti et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 5 Table 1. Sample Description (n ϭ 21) Non-dysphoric Dysphoric responders1 responders1 Clinical Variable (n ϭ 6) mean Ϯ sd (n ϭ 6) mean Ϯ sd Differences 1. Age (years) 35.33 Ϯ 7.28 38.8 Ϯ 10.6 ns 2. Sex (Males : Females) 4:2 4:2 ns 3. Duration of illness (years) 7.56 Ϯ 4.88 6.66 Ϯ 1.66 ns 3. Duration of drug free interval (months) 4.83 Ϯ 2.92 4.66 Ϯ 3.66 ns 4. Global assessment
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