Carbohydrate Reward and Psychosis Current Neuropharmacology, 2011, Vol. 9, No. 2 371intense craving, aches and pains, sweating and palpitations the dopaminergic neurones in this part of the brain are seen. A contrasting cluster of symptoms is seen in tobacco in post mortem studies of people who have died withwithdrawal: notably craving and urges to smoke, irritability, Parkinson’s disease .reduced concentration, increased appetite and constipation PATHWAYS OF ADDICTION TO FOOD. Although the nature of these withdrawal states may bequite different, the time course over which the symptoms are The mesolimbic dopaminergic pathway is activated byexperienced is roughly consistent, with the intensity peaking drugs and substances that people ingest, inject, snort orafter three to four days, then gradually declining after one to smoke that, ultimately, cross the blood brain barrier, afterthree months of abstinence. entry into the circulation. Over the last two decades, other evidence has implicated this pathway in weight control andPHYSIOLOGY OF ADDICTION eating behaviour. This evidence comes from a number of In the last thirty years the origin of clinical symptoms of different studies. These include microdialysis, rodent basedaddiction has been linked to a part of the brain responsible research of the mesolimbic pathway that have shown thatfor subconscious behaviour and motivation, and a specific exposure to food results in dopamine release. Although theneurotransmitter: dopamine. The dopaminergic system is quantity is less than what occurs in response to drugs ofcomposed of two major pathways: (1) the nigrostriatal system abuse, such as amphetamines . The magnitude ofthat projects from the substantia nigra in the basal ganglia to dopamine release, in rodent models, is about 10 fold greaterthe corpus striatum and (2) the mesocorticolimbic dopamine with a more rapid rate of initial rise, after an amphetaminesystem, which emanates from the ventral tegmental area of bolus, compared to the release which follows a meal, mixedthe mid brain to the nucleus accumbens and olfactory in macronutrients .tubercle (in the ventral striatum), medial pre-frontal cortex It is also recognised that the brain’s primary fuel in theand amygdale (found in the temporal lobe) . These non-fasting state is glucose, and changes in venous glucoseneural pathways each have their own functions, which have concentrations trigger changes in the firing of dopaminergicbeen understood by their association with the symptomclusters that accompany disease states in their respective neurones in the striatum . Other studies point to a direct physiological effect of plasma glucose on dopamine releaseanatomical regions. The mesocorticolimbic projection is most in neuronal tissue. For example, Koshimura incubated nerveoften implicated in the pathophysiology of addiction and cells in high concentrations of glucose, and found thatsubconscious reward pathways. In human and animal studies, depolarisation and dopamine release was enhanced . Inadministration of substances of abuse increases dopamine addition, rodent studies have demonstrated that restrictedconcentrations in the nucleus accumbens, considered themain component of the brain reward system . An feeding coupled with intermittent sucrose availability leads to up-regulation of the dopamine transporter in the nucleusintravenous bolus of cocaine, for example, causes increased accumbens and ventral tegmental area . Sucroseextracellular concentrations of dopamine, blocking re-uptake consumption has also reliably induced signs of addiction inby nerve terminals in the nucleus accumbens. In contrast, rodents, with demonstrated anxiety and somatic symptomsopioids, nicotine and alcohol act upstream, stimulating (withdrawal) following abstinence, or after naloxone (anneurones in the ventral tegmental area, which ultimatelyinfluence the nucleus accumbens, by releasing dopamine at opiate antagonist) administration . Although high fat rodent diets also stimulate dopamine release in the nucleusnerve terminals into the synaptic cleft and activating the accumbens, similar withdrawal symptoms were not observednucleus. These three drugs either act directly on the cell when these animals were forced to abstain or treated withbodies of these ventral tegmental neurones or block naloxone . In humans, carbohydrate craving has ofteninhibition by GABA interneurones . been reported, although a full withdrawal syndrome has Also, extracellular dopamine release in the striatum (from not yet been described. We portrayed one individual whopsychostimulants) and subjectively feeling “high” or demonstrated a likely food withdrawal syndrome followingeuphoric  are closely linked, in human brain imaging abstinence from sugar and carbohydrate . Anotherstudies. Although dopamine is often described as the example is given by Atkins, in his well known book,“pleasure chemical”, this role is currently debated. Some portraying an obese individual who suffers from craving andsuggest that dopamine release in the nucleus accumbens has agitation relieved by sugar, that eventually resolves withinless to do with reward, but is more likely to reinforce, weeks after starting his carbohydrate restricting diet .strengthen and initiate movement required to attain the Tolerance or need for an increased quantity of aeventual reward, such as rolling a cigarette . substance to get the same ‘hit’ is a dominant feature of The nigrostriatal pathway, which includes the substantia addiction and may reflect reduced sensitivity to dopamine bynigra, is best known for its relationship to the degenerative post-synaptic neurones in the nucleus accumbens. Anatomicaldisorder, Parkinson’s disease, characterised by a cluster of changes found following Positron Emission Tomographymotor and non-motor symptoms. Motor symptoms include a studies of those who suffer from drug addiction showcharacteristic ‘pill-rolling’ tremor, shuffling gait, brady- evidence of adaptation, with an increased concentration ofkinesia (slowing of motor movements), and rigidity. Non- dopamine receptors compared to controls . Such changesmotor manifestations consist of depressed mood, cognitive in the accumbens also occur in obese individuals .impairment along with autonomic and sleep disturbances. Of all the food groups, carbohydrate is commonlyReplacement of dopamine, in precursor form (levodopa), ascribed addictive properties , and within this class, tablepartially relieves many of these symptoms. Degeneration of
372 Current Neuropharmacology, 2011, Vol. 9, No. 2 Thornley et al.sugar or sucrose . This disaccharide is composed of two Given the association between dopaminergic neuralchemically linked monosaccharides: glucose and fructose. paths and addiction and psychosis, at a clinical level we mayGlucose is the primary energy source of the brain and other expect a close relationship between the two disorders. Forvital organs, compared to fructose which has stronger example, in one summary, the prevalence of smoking wassensory qualities, percieved as about twice as sweet as between 80 and 90% in people treated in hospital withsimilar concentrations of glucose. Fructose, unlike glucose, schizophrenia . Numerous epidemiological studiesis taken up preferentially in the liver, and so, is almost absent describe the co-occurrence of schizophrenia and other formsin peripheral blood . of addiction, such as to alcohol, metamphetamine and opiates. . Further, the presence of illicit drug use in people The mechanism by which sucrose induces dopamine with schizophrenia predicts relapse, treatment resistance andrelease is uncertain, however, two possibilities are need for further hospital treatment .commonly cited . First, sugar may be ingested, absorbedand the glucose transported to the brain from the circulation, Researchers have concluded that no drug with significantwith subsequent dopamine release. Second, direct sensory antipsychotic action has been identified that does not have ainput from taste and other sensory input in the mouth may significant affinity for the D2 receptor . In the spinalprovoke dopamine release. When rodents are “sham fed” – fluid of psychotic patients, maintained on a variety of 11allowed to feed, but not digest food by having it pass out of different antipsychotic drugs, seventy percent blockade ofthe body via a gastric fistula - concentration-dependent the D2 receptor in vitro correlated to therapeutic freedopamine release follows . Further release of dopamine neuroleptic levels . The altered side effect profilesoccurs during digestion and absorption of glucose, which is attributable to newer antipsychotic agents have been linkedpotentiated by glucose-mediated insulin release . Such to their briefer occupancy of the D2 receptor site (in contrastfindings reiterate why fructose may be an important to older agents, which bind for longer) along with increasedcontributor to food addiction, owing to its sweeter taste. serotonergic effects.Importantly, fructose (unlike glucose) does not appear tostimulate insulin release, a hormone associated with post- For a long time, activity in the dopaminergic system has been difficult to directly assess in human subjects, butprandial satiety. recently, positron and photon emission tomographic What are the clinical features of drug induced dopamine techniques have enabled this pathway to be studied in detail.release in human subjects? Two principal effects are Several connections between dopamine and psychosis arecommonly described . First, release is accompanied by described. First, amphetamine induced dopamine release ispleasure, or the feeling of a ‘hit’ and behaviours that produce exaggerated in people with schizophrenia; second, afterthis are reinforced, forming a vicious cycle of increasing amphetamine administration, dopamine release is associatedsubstance use. In addition, the increase in dopamine concentra- with psychotic symptoms; and third, these changes intion focuses the individual on sensory elements (‘cues’) dopaminergic physiology in people with schizophrenia haveassociated with drug taking. Such elements often initiates been detected in patients never treated with antipsychoticsubconscious, Pavlovian stimulus-response drug taking when drugs . This last finding indicates that such phenomenaan individual is subsequently exposed to them again . are unlikely to represent neuroadaptation to antipsychotic medication.NEURAL PATHS ASSOCIATED WITH PSYCHOSIS What is the consequence of excess ‘reward’ or As well as playing a role in addiction, dopamine has been ‘re-inforcement’ from dopamine release? Recent theoriesreferred to as the “wind of the psychotic fire”, when suggest that in people with schizophrenia, dopamine releasedescribing its association with the pathophysiology of leads to aberrant salience or focussing on innocuous stimulischizophrenia . Evidence for dopamines importance . Symptoms of hallucinations and psychosis emerge,emerges from clinical practice - for example, treatment of resulting from a patient’s attempt to explain the increasedpatients with Parkinson’s disease using therapeutic doses of attention they give to such stimuli. This mechanism may alsolevo-dopa can result in a drug-induced psychosis in a small explain the negative symptoms of schizophrenia, such asproportion of these patients . Conversely, drugs used to social withdrawal and lack of motivation. The increasedtreat psychoses such as schizophrenia inhibit dopaminergic “noise” in the reward pathway, due to aberrant dopaminepathways, and may result in unwanted Parkisonism. release, may drown out the normal linkage and learning that Antipsychotic or ‘neuroleptic’ drugs have a specific accompanies behaviours that lead to reward from dopaminemechanism of action. After entry into the circulation they release .diffuse across the blood-brain barrier. There, they bind to HYPOTHESISand block neural circuits, specifically interfering with theaction of dopamine on mesolimbic and mesocortical D2 If dopamine is the principal neurotransmitter mediatingreceptors . Greater specificity for the blockade of both re-enforcing behaviour and reward from ingestion ofserotonin receptor subtype 5-HT2A is a feature of atypical food, what are the likely consequences of blocking thisantipsychotic agents, such as clozapine and olanzapine. action with antipsychotic drugs? Our hypothesis links theAlthough dopaminergic dysfunction is highlighted most increased prevalence of obesity found in people treated withfrequently in the pathophysiology of psychosis, other neural anti-psychotic agents and the known pharmacodynamicpaths are also implicated, such as the glutaminergic and properties of such drugs - blocking dopamine effects inserotonergic  ones. the reward centre of the mid-brain. We speculate that to
Carbohydrate Reward and Psychosis Current Neuropharmacology, 2011, Vol. 9, No. 2 373compensate for the reduced reward after taking neuroleptics, Our theory focuses on the centrality of the dopaminepatients exaggerate the stimulation of this pathway by receptor blockade of antipsychotic drugs and theirincreasing their food intake, or use of other addictive simultaneous effects on weight gain and psychosis. Onesubstances. potential flaw in this theory is the differential effects onSUPPORT FOR THIS HYPOTHESIS weight gain of different drugs. For example, in studies in which patients are followed for less than one year Rodent studies have supported our hypothesis that of treatment, a clear hierarchy of weight gain liabilityantipsychotic drug use enhances feeding behaviour. In occurs, with clozapine>olanzapine>risperidone>ziprasidone=general, long term exposure of rodents to antipsychotic aripiprazole . Although all of these drugs block D2 receptors,agents is associated with weight gain , although some they vary substantially in the amount of serotonergic,short term studies show inconsistent results. The most histaminergic and adrenergic activity they exhibit. Such aconclusive study showed both a dose response effect finding may indicate that other pathways or neurotransmitters(increased weight gain with increased dose), and reversal of are more likely to be causally implicated in weight gain sidethis effect with bromocriptine, a specific dopamine (D2) effects than the dopaminergic path. However, in studiesreceptor agonist . Four antipsychotic drugs consistently which observe weight gain in patients treated for more thanproduced weight gain (thioridazine, trifluoperazine, halop- one year, such differences between drugs are less marked,eridol, and sulpiride), whilst chlorpromazine and fluphenazine and some of the between drug heterogeneity may bedid not. Another study documented increased food consump- explained by between-study variation in dosing .tion in rodents treated with olanzapine, an atypical anti-psychotic medication, compared to untreated controls IMPLICATIONS. How might our theory improve care for people with In human subjects, weight gain commonly occurs in psychosis? We speculate that if addiction and psychosisassociation with antipsychotic use, however the mechanism share common features and a common neuroanatomicalunderlying this effect is not well understood. Several pathway, with dopamine release and disordered reward andexplanations are proposed, including increased appetite, motivation, a key treatment for reducing the severity ofleading to excess energy intake . Metabolic changes, psychosis may involve reducing stimulation of the mid brain.which lead to reduced metabolic rate, such as insulin If antipsychotic drugs exert their effect, principally, byresistance, have also been described [3, 39]. For example, blocking the effects of mesolimbic dopamine release, weweight gain has been consistently reported with clozapine – a expect that reduced release of dopamine in this pathway mayretrospective study of 82 patients, followed up to 90 months, result in similar beneficial effects on psychotic symptoms inshowed a cumulative incidence of a 10% weight gain in 80% people affected by schizophrenia. Although still contro-of subjects, with a 20% weight gain observed in 38% . versial, we speculate that food may be a key stimulant of thisMany other studies have confirmed such findings and some disordered pathway, and altering diet may improve psychosisauthors link weight gain with clinical improvement in mental and reduce the need for antipsychotic treatment. If blockingstate [41, 42]. The mechanism underlying these changes in the effects of free dopamine reduces psychotic symptoms,weight has remained uncertain, with a number of neurotrans- then reducing dopamine release is likely to induce a similarmitters and hormones implicated  within serotonergic, effect. Offering treatment for other addictions (not onlyhistaminergic and adrenergic pathways . food) to limit dopamine release also follows from our theory. We speculate that if dopaminergic neural transmission is Surprisingly, evidence for nutrition interventions toblocked by antipsychotic drugs in patients with schizophrenia, improve psychotic symptoms has received little attention.compensation may occur, with patients adapting by carrying Peet speculated that the co-occurrence of schizophreniaout behaviours that stimulate dopamine release (from food or and diabetes, even in drug naive patients, suggests that thedrug intake) in an effort to maintain homeostasis, achieving two disorders share a common aetiology . One studythe same feeling of reward, satisfying hunger or drug reports high levels of sugar consumption in patients withwithdrawal symptoms. Evidence for such an effect can be schizophrenia, although the authors are uncertain whetherfound in animal experiments which demonstrate dulling this is a cause or consequence of treatment for the diseaseeffects of antipsychotic drugs on chemical or electrical . Dietary treatment for patients with schizophreniastimulation of mid- brain reward paths . Also, animal usually consists of reducing long term cardiovascular andstudies of amphetamine and cocaine self administration diabetes risk, rather than being viewed as an integral part ofshow that short term compensatory increases occur after reducing psychotic symptoms. To our knowledge, the effectneuroleptic treatment . An older study showed that the on psychopathology of reducing sugar or carbohydraterewarding qualities of food were blocked by neuroleptics in consumption among a cohort of people with schizophreniahungry rats . Although many recreational drugs induce has not been studied.dopamine release, the ubiquity of carbohydrate containingfood may make this the most common means of If a dietary approach to treating psychotic symptoms wascompensating for the action of antipsychotic drugs. People suggested, what might this regime look like? Glycemic indexwith schizophrenia often, however, may use other drugs to (GI) describes the rate of absorption of glucose from carbo-compensate for dopamine blockade, and indeed substance hydrate. High GI carbohydrate foods, such as white bread,(cocaine, cigarette, alcohol, methamphetamine) abuse and sugar and refined cereals, cause a ‘spike’ in insulin andpsychosis commonly coexist. blood glucose (followed by a dip). Low GI carbohydrate
374 Current Neuropharmacology, 2011, Vol. 9, No. 2 Thornley et al.foods, such as wholegrain bread and most vegetables (or CONCLUSIONfoods containing little carbohydrate at all, such as nuts, seeds Our theory provides a parsimonious and testableand meat), produce a slower insulin response and thus a hypothesis, linking the action of antipsychotic agents withmore steady supply of glucose to the blood. Low GI diets commonly reported side effects. It also explains the commoninduce weight loss and improve blood glucose control in co-occurrence of schizophrenia with addiction, obesity andpeople with diabetes. A recent meta-analysis showed that diabetes. The common link drawn between eating, psychosispeople following a low GI diet had more weight loss than and mid-brain dopaminergic reward, logically, suggests thatother diets . Other meta-analyses indicate a lower risk of psychosis may be improved, by modifying carbohydratechronic diseases such as cancer and cardiovascular disease consumption. We consider that such an idea should be testedoccur in people following low GI diets . We speculated in clinical trials.that one indicator of the addictive potential of food is theglycaemic index, based on the principle that ‘time-to-reward’ ACKNOWLEDGEMENTS(or in pharmacokinetic terms, rate of rise of plasma concen- The authors thank Hayden McRobbie and Rogertration) predicts the addictive potential of a substance . Marshall for helpful comments on manuscript drafts.Although this scale discounts the importance of sugarcontent, due to the presence of fructose which has little effect REFERENCESon blood glucose. The two best known diets based on  Batel, P. Addiction and schizophrenia. Eur. Psychiatry, 2000, 15,modifying carbohydrate consumption include the glycaemic 115-122.index and the Atkins diet. 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