Subjective Effects of AMPT-induced Dopamine Depletion in Schizophrenia Correlation between Dysphoric Responses and Striatal D2 Binding Ratios on SPECT Imaging

Voruganti, L. N. P.; Slomka, Piotr J.; Zabel, Pamela; Costa, Giuseppe; So, Aaron; Mattar, Adel; Awad, A. George

doi:10.1016/s0893-133x(01)00263-9

Cited by 85 publications

(57 citation statements)

References 51 publications

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“…Above and beyond their dietary effects, opioid antagonists may also contribute to weight reduction by reasons of diminished hypeinsulinemia and improved insulin sensitivity (Cucinelli et al, 2002;Fruzzetti et al, 2002). Overall, these findings support the hypotheses that contrary to dopamine antagonism that worsen reward function (Knable et al, 1997;Voruganti et al, 2001;Voruganti and Awad, 2004), blockade of opioid receptors may actually improve it and that these agents can be successfully used in clinical settings.…”

Section: Opioid Antagonists May Improve Hedonic Deficits In Patients supporting

confidence: 61%

“…Their therapeutic properties are, however, tarnished by serious side effects, including those resulting from dopamine blockade in the cortical and subcortical areas with secondary worsening of reward and motivational deficits (Knable et al, 1997;Voruganti et al, 2001;Voruganti and Awad, 2004). In contrast, SGAs produce net increases in dopamine activity in the cortical dopaminergic pathways and substantially lesser blockade (in comparison to FGAs) of the limbic dopaminergic areas (Stahl, 2002).…”

Section: Advantageous Therapeutic Properties Of Sgas Have Been Questimentioning

confidence: 99%

“…Schizophrenia could be considered such a disorder (Figure 5a). One obvious factor is higher rates of peripheral glucose intolerance and insulin resistance observed in some schizophrenic patients (Mukherjee et al, 1996;Ryan et al, 2003) that could lead to CNS insulin and leptin resistance with the ensuing consequences as discussed above.There are several lines of evidence that point to deficits of the brain circuits mediating reward and reinforcement in schizophrenic patients (Voruganti et al, 2001;Juckel et al, 2003;Voruganti and Awad, 2004). From a neuroanatomical perspective, reward circuitry structures including NAc, amygdala, and PFC have been reported to be abnormal in schizophrenia in neuropathological Bogerts et al, 1985;Lauer and Beckmann, 1997;Lauer et al, 2001;Selemon et al, 2002), in structural (Breier et al, 1992;Sigmundsson et al, 2001;Kawasaki et al, 2004), and in functional (see Table 2 for summary) neuroimaging studies.…”

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confidence: 99%

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Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

138

142

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Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

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Section: Opioid Antagonists May Improve Hedonic Deficits In Patients supporting

confidence: 61%

Section: Advantageous Therapeutic Properties Of Sgas Have Been Questimentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

138

142

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“…93 In unmedicated patients with schizophrenia, AMPT led to a small but significant improvement of psychotic symptoms. 94,95 In 12 drug-free symptomatic patients with schizophrenia who had previously been treated with neuroleptic medication, AMPT also induced dysphoric symptoms. 95 In a sample of 10 patients with cocaine abuse, AMPT tended to reduce the cocaine-induced feelings of 'high' (P¼0.10).…”

Section: Acute Tryptophan Depletionmentioning

confidence: 99%

Monoamine depletion in psychiatric and healthy populations: review

2003

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A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine depletion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications. The evidence also suggests that ATD and APTD affect different cognitive functions, in particular different memory systems. Few studies investigated cognitive effects of the procedures in patients. Patients who are in remission for longer may also be vulnerable to ATD and AMPT, but the relationship with prior treatment is much weaker. For these patients, individual vulnerability markers are the more important determinants of depressive response, making these techniques potentially useful models of vulnerability to depression. Molecular Psychiatry (2003) 8, 951-973.

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“…Recently, we reported data from a comprehensive study of the phenomenology of dysphoria, including its relation to other extrapyramidal symptoms and striatal dopamine D 2 binding ratio, which was carried out using the same experimental AMPT paradigm (17). In this focused investigation, subjective responses to AMPT ingestion were systematically monitored and documented through serial administration of the Addiction Research Center Inventory (18), the Drug Attitude Inventory (19,20), and the Profile of Mood States (POMS) (21).…”

Section: Experimental Studies Involving Chemical Probesmentioning

confidence: 99%

Is Neuroleptic Dysphoria a Variant of Drug-Induced Extrapyramidal Side Effects?

Voruganti

Awad

2004

Can J Psychiatry

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Objectives: Neuroleptic drugs induce psychological side effects such as dysphoria, cognitive impairment, and loss of motivation. These side effects were largely underrecognized and trivialized in the past as variants of extrapyramidal side effects (EPSEs). We review the recent literature on the subject and clarify the relation between neuroleptic-induced dysphoria and EPSEs. Methods:We critically examined clinical, interventional, neuroimaging, and basic science studies published in the past 10 years, delineating the temporal, phenomenological, biochemical, and neuroanatomical relation between dysphoria and EPSEs.Results: Subjective responses occur within 4 to 6 hours of neuroleptic use, whereas acute dystonia is often observed within 24 hours and parkinsonian syndrome after 5 to 7 days. Neuroleptic-induced dopaminergic blockade mediates both dysphoria and EPSEs. However, impaired dopamine function in the nucleus accumbens seems to give rise to dysphoria, whereas blockade of D 2 receptors in the nigrostriatal system is responsible for EPSEs. Conclusion:The earlier notion that neuroleptic dysphoria is a variant of EPSEs was simplistic and speculative. Exploring the differences rather than dwelling on the similarities will likely enhance our understanding of dopamine's role in the origin of varied side effects and in their distinctive characteristics. Clinical Implications· Clinical monitoring of the side effects of antipsychotic drugs should include specific inquiry into aspects of subjective tolerability. · If unchecked, poor subjective tolerability may lead to nonadherence to prescribed treatment, clinical instability, and other adverse consequences. · Exploring the nature of both spontaneous and iatrogenic dysphoria outside the context of schizophrenia and neuroleptic therapy will broaden our understanding and appreciation of its implications. Limitations· Studies of neuroleptic dysphoria in particular and subjective responses to medications in general have been few and far between. · In vivo studies involving neurochemistry of the brain are hampered by technical limitations, which prevents the drawing of firm associations between clinical events and neurobiological correlates. · Little has been known about the nature of dysphoria occurring in clinical situations apart from neuroleptic therapy.

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Subjective Effects of AMPT-induced Dopamine Depletion in Schizophrenia Correlation between Dysphoric Responses and Striatal D2 Binding Ratios on SPECT Imaging

Cited by 85 publications

References 51 publications

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Monoamine depletion in psychiatric and healthy populations: review

Is Neuroleptic Dysphoria a Variant of Drug-Induced Extrapyramidal Side Effects?

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