The psychological and neurochemical mechanisms involved in the placebo response; news about genetic responders' predictors.
Introduction
Psychological Mechanisms
Neurobiological Mechanisms
Genetic Responders' Predictors
Summary
Introduction
In recent times, there has been increasing interest in investigating placebo effects by rigorous research methods, especially in the past decade with the progress of the brain imaging technologies. This new interest is due to the better understanding of what placebo means, obtained reconsidering placebos and placebo effects, shifting the focus from the inert content to the set of sensory and social stimuli, associated with its administration, that tell the patient that a beneficial treatment is being given. Indeed real placebo effect is a psychobiological phenomenon mediated primarily through distinct but interrelated mechanisms: cognitive factors such as patient expectations of the benefit of a treatment, the quality of the patient-doctor relationship, the treatment environment and associative learning (conditioning) relatively to the context and the formulation of application. Interestingly, intensive research has revealed how these psychological mechanisms trigger complex neurobiological phenomena involving the activation of distinct brain areas as well as peripheral physiology, including the release of endogenous substrates. It is worth noting that the placebo effect is also a significative component of every active treatment, when the therapeutic context promotes the onset of expectancy in the patient for the good results of the therapy. Furthermore the overall therapeutic effect is not merely the sum of a specific effect and an independent nonspecific effect; contextual factors can interact with drug-specific effects in modifying biological and psychological pathways of action. In other words, when a drug is given, the very act of administering (ie, the psychosocial context) may perturb the system and change the response to the drug.
references
3: Finniss et al Placebo Effects: Biological, Clinical and Ethical Advances. 2010
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
5: Rief et al Mechanisms involved in placebo and nocebo responses and implications for drug trials. 2011
The so-called “open/hidden” drug paradigm
There is a way to overcome the interference between drugs and placebo/expectation effects. This can be done by, so to speak, ‘silencing’ the expectation mechanisms, for example, by eliminating the placebo (psychosocial) component by making the patient unaware that a medical therapy is being carried out, and then analyzing the pharmacodynamic effect of the treatment, free of any psychological contamination. To do this, drugs are delivered through hidden infusions by machines. Such infusions can be administered using computer-controlled infusion pumps that are preprogrammed to dispense drugs at a desired time. The crucial factor is that the patients do not know that the drug is being injected, so they ought not have expectations of a therapeutic response. If the drug is really effective and has only specific pharmacodynamic action, there should be no difference between its open and hidden administration, for it does not act on expectation-activated neurotransmitters. In contrast, if the drug has no specific pharmacodynamic action and it only interferes with expectation-activated neurotransmitters, its hidden administration should abolish the observed effect completely. Indeed, a trial conducted by Benedetti et al Potentiation of placebo analgesia by proglumide. 1995 showed that a CCK antagonist induced stronger analgesia than a placebo, suggesting that it was a good analgesic. However, this conclusion proved to be erroneous because a hidden injection of the same CCK antagonist was totally ineffective, showing that it had no intrinsic analgesic pharmacodynamic action, but instead, it enhanced placebo-activated release of endogenous opioids. A lot of studies, for example Overt versus covert treatment for pain, anxiety, and Parkinson's disease. 2004 reveal that hidden administration of the drug reduces the analgesic effect of nonsteroidal anti-inflammatory drugs to nonsignificance and even reduces, to a substantial extent, the effects of opioids, like reported by this study The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. 2011 . This phenomenon is not restricted to analgesic use; similar effects have also been reported for treatments in other domains, such as in motor function in Parkinson’s disease and responses in anxiety-related disorders.
references
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
5: Rief et al Mechanisms involved in placebo and nocebo responses and implications for drug trials. 2011
The power of placebo
Understanding how placebo effects work clinically in relevant patient populations over time has not kept pace with the recent research into mechanisms of placebo effects, which has mainly involved laboratory experiments done over short durations with healthy participants. In the case of clinical populations, the study of long-term placebo responsiveness has been limited to RCTs. However, these studies rarely included groups of participants receiving no treatment to control for natural history and regression to the mean, making it difficult to discern a genuine placebo effect. Several meta-analyses like this Is the Placebo Powerless? — An Analysis of Clinical Trials Comparing Placebo with No Treatment. 2001 have attempted to address the presence and magnitude of placebo effects in RCTs, including some studies in which no-treatment control groups were used. These analyses concluded that placebo effects are small and limited to subjective outcomes when placebos are used as a control condition in RCTs. However, placebo effects are much larger in studies that investigate placebo mechanisms. This finding is not at all surprising given that the mechanistic experiments use controlled manipulations of verbal instructions and context that might be more representative of normal clinical practice than a clinical trial setting. Furthermore the open-hidden study design has provided a means of exploring the interaction between placebo effects and responses to active treatments. This analysis has not been possible in standard RCTs designed to assess treatment efficacy, since they only compare the response to placebo with the response to the index intervention without providing an understanding of the interaction between the two. However, more studies of placebo effects in specific clinical settings are needed before use of treatments with the primary aim of promoting placebo responses can be recommended as evidence-based practice.
reference
3: Finniss et al Placebo Effects: Biological, Clinical and Ethical Advances. 2010
Psychological Mechanisms
Expectations
This theory postulates that placebo response is related to patients’ expectations of improvement, which are connected to the changes that take place. In general, expectation is aimed at preparing the body to anticipate an event to better cope with it, and as such offers a clear evolutionary advantage. For example, the expectation of a negative outcome is aimed at anticipating a possible threat, thus increasing anxiety, whereas the expectation of a forthcoming positive outcome may reduce anxiety and/or activate the neuronal networks of reward mechanisms. Indeed, there is ample support for a role of both anxiety and reward mechanisms in placebo responsiveness. Volkow found that patients who expected to receive treatment showed more significant changes in brain metabolic activity than those patients who expected to receive placebo although both groups were given an active drug. Kirsch noted that when individuals have expectancies that are contrary to the pharmacological effect of a drug, the effect of expectation overrides that of the drug. Expectations are unlikely to operate alone, and several other factors and mechanisms have been identified, such as memory and motivation. In addition, in this study Therapeutic Factors in Psychotherapy. 2006 Frank analyzed the healing process within the context of patient’s expectations, and proposed that hope is the primary mechanism of change in psychotherapy. Indeed, hope can be defined as the desire and expectation that the future will be better than the present.
references
1: Koshi et al Placebo Theory and Its Implications for Research and Clinical Practice: A Review of the Recent Literature. 2007
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Expectation of reward
Expectations of future events may induce physiological changes through reward mechanisms. These mechanisms are mediated by specific neuronal circuits linking cognitive, emotional, and motor responses, and are traditionally studied in the context of the pursuit of natural (eg, food), monetary, and drug rewards. There is compelling experimental evidence, based on placebo studies with Parkinson’s patients and in experimental pain, that the mesolimbic dopaminergic system may be activated in some circumstances when a subject expects clinical improvement after placebo administration. Thus, expectation may be closely tied to a tonic activation of tegmental or prefrontal dopaminergic neurons, which project to the dorsal and ventral striatum. In the expectation phase, prior to reward, there is uncertainty, and this is reflected in sustained dopaminergic activation, which is maximized when the probability of reward is 0.5. It is known that with a 0.5 probability of reward, 29% of dopaminergic cells are tonically activated. Conversely, both occurrence and nonoccurrence lead to virtually no tonic activation. There is also phasic dopaminergic activation which takes place after reward, and this is stronger when the reward has come as a surprise. Therefore, uncertainty appears to heighten reward mechanisms in this brain reward circuitry model. Based on this information, the following neurobiological placebo mechanism has been proposed. When an interaction (e.g., positive verbal suggestion) creates the possibility of a reward, which in the case of placebo administration is represented by the therapeutic benefit, certain cortical neurons become active in relation to reward probability. These cells send direct excitatory glutamatergic inputs to dopaminergic cell bodies along with indirect inhibitory gamma amino butyric acid inputs. The combination of these signals arriving at the dopaminergic neurons via direct and indirect pathways contributes to the probability of tonic activation. This model was confirmed by a brain imaging study Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects. 2007 in which both positron emission tomography and functional magnetic resonance imaging were used. By using a model of experimental pain in healthy subjects, it was found that placebo responsiveness was related to the activation of dopamine in the nucleus accumbens, as assessed by using in vivo receptor-binding positron emission tomography with raclopride, a D2-D3 dopamine receptor agonist. The very same subjects were then tested with functional magnetic resonance imaging for activation in the nucleus accumbens to monetary rewards. The larger the nucleus accumbens responses to monetary reward, the stronger the nucleus accumbens responses to placebos. Those who have a more efficient dopaminergic reward system would also be good placebo responders.
references
2: Enck et al New Insights into the Placebo and Nocebo Responses. 2008
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Conditioning
This theory suggests that placebo response represents a form of classical conditioning that is based on learning through association. Pavlov noticed that dogs were salivating to a neutral stimulus such as ringing a bell (conditioned stimulus), which was previously associated with food (unconditioned stimulus). Several studies have shown that conditioning can occur in humans, too. For example, patients with headache taking regular aspirin (unconditioned stimulus) can associate the shape, color, and taste of aspirin (conditioned stimulus) to pain decreases. After several associations, pain decreases when patients are given a placebo that looks and tastes like aspirin. In this study A conditioned response model of the placebo effect predictions from the model. 1980 Wickramasekera argued that not only pharmacological agents can be classically conditioned when associated with previously ameliorative effects that occurred in these settings, but also neutral places (e.g., doctor’s offices, hospitals), persons (e.g., doctors, nurses), things (e.g., syringes), and rituals (e.g., physical examinations). Furthermore, Phil and Altman showed that the strength of conditioned response increases with the increasing number of paired associations. Therefore the placebo effect is a learning phenomenon that may be based on different mechanisms, from unconscious conditioning to cognitive learning such as building and reinforcement of expectations.
references
1: Koshi et al Placebo Theory and Its Implications for Research and Clinical Practice: A Review of the Recent Literature. 2007
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Social learning
Social learning is a form of learning, in which individuals in a society learn from one another by observation and imitation. This study Placebo analgesia induced by social observational learning. 2009 shows that it produced response that were similar to those induced by directly experiencing the benefit through the conditioning procedure, whereas verbal suggestions alone produced significantly smaller effects. Thus, social observation is as powerful as conditioning in producing substantial placebo responses.
reference
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Reinforced Expectation
In some conditions involving a conditioning procedure, placebo responses have nevertheless been found to be mediated by expectations, thus suggesting that the conditioning procedure acts by reinforcing expectations rather than generating an unconscious Pavlovian response. For example, Montgomery and Kirsch in Classical conditioning and the placebo effect. 1997 applied a protocol in which subjects were given cutaneous pain through iontophoretic stimuli. They were surreptitiously given stimuli with reduced intensities in the presence of a placebo cream (conditioning procedure), but were then divided into two groups. The first group did not know about the stimulus manipulation, whereas the second was informed about the experimental design and learned that the cream was inert. There was no placebo analgesic effect in this second group, which suggests that conscious expectation is necessary for placebo analgesia. This is a very important point, as it indicates that expectation has a major role, even in the presence of a conditioning procedure. By considering the important role of expectations in placebo responsiveness in Parkinson patients and the robust placebo responses obtained through previous apomorphine conditioning, these data suggest that reinforcement of expectations, that is, cognitive learning, is involved.
reference
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Neurobiological Mechanisms
A major insight from the recent publications on placebo is that there seems not to be a single neurobiological or psychobiological mechanism which is able to explain placebo and nocebo phenomena in general. Instead, we have learned that different mechanisms exist by which placebo or nocebo responses are steered across diseases and experimental conditions.
table from reference 3: Finniss et al Placebo Effects: Biological, Clinical and Ethical Advances. 2010
Pain
Placebo Analgesia (role of endogenous opioid and dopaminergic systems)
Pain transmission is inhibited by a descending pain modulating system that originates in the cerebral cortex. In fact, several cortical areas have been found to be activated by placebo administration, such as the anterior cingulate cortex and the dorsolateral prefrontal cortex. This activation then extends into the whole descending pain modulating system, involving the hypothalamus, the periaqueductal gray, and the rostroventromedial medulla, and reaches down to the spinal cord in which inhibition of dorsal horn neurons is likely to occur. Neuropharmacological studies have shown that this system is opioidergic, for opioid antagonists block placebo analgesia, and in vivo receptor binding has shown activation of m-opioid receptors during placebo analgesia. The dopaminergic reward system, in which dopaminergic neurons in the ventral tegmental area project to the nucleus accumbens, is also involved. Scott et al in Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses. 2008 studied the endogenous opioid and the dopaminergic systems in different brain regions, including those involved in reward and motivational behavior. Subjects underwent a pain challenge, in the absence and presence of a placebo with expected analgesic properties. By using positron emission tomography with 11C-labeled raclopride for the analysis of dopamine and 11C-carfentanil for the study of opioids, it was found that placebo induced activation of opioid neurotransmission in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Both dopaminergic and opioid activity were associated with both anticipation and perceived effectiveness of the placebo. Large placebo responses were associated with greater dopamine and opioid activity in the nucleus accumbens, which indicates that these two neurotransmitters play a key role in the modulation of the placebo response.
references
2: Enck et al New Insights into the Placebo and Nocebo Responses. 2008
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Nocebo Hyperalgesia (role of CCKergic system)
figure 1 from Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans. 2010
(a,b) Schematic illustration of key brain regions involved in generating a pain experience (green, blue and purple) with core brain regions that comprise the cognitive and descending pain modulatory networks (blue) (a) and a description of the various factors that influence the pain experience listed in the text boxes (b). (a) The regions highlighted in blue indicate the core descending endogenous pain and cognitive modulatory networks that many of these factors, including placebo and nocebo effects, use to elicit their influence on nociceptive processing and resultant pain perception. The hippocampal region (purple) is important for amplifying pain experiences during nocebo or increased anxiety. © Schematic illustration indicating where endogenous opioid and dopamine neurotransmission occurs in the human brain during placebo analgesia. Note the overlap with many of the brain regions involved in cognitive modulation of pain, and for some brain regions (NAc) there is a bidirectional response of both opioid and dopamine release that produces either placebo (increased release) or nocebo (decreased release) effects. vmPFC, ventromedial prefrontal cortex; Amy, amygdala; Hypo, hypothalamus; Hipp, hippocampus; S2, secondary somatosensory cortex; S1, primary somatosensory cortex; dlPFC, dorsolateral prefrontal cortex; rACC, rostral anterior cingulate cortex; mACC, midanterior cingulate cortex; CCK, cholecystokinin.
Anxiety (and correlations with Pain)
Anxiety has been found to be reduced after placebo administration in some studies. If one expects a distressing symptom to subside shortly, anxiety tends to decrease. In one functional magnetic resonance imaging (fMRI) study Placebo in emotional processing-induced expectations of anxiety relief activate a generalized modulatory network. 2005 , it was found that placebo treatments can modulate emotions. A significant and robust placebo response (reduced unpleasantness) was found when the subjects thought that they had been treated with the anxiolytic drug, whereas no response occurred if they thought they had received the anxiolytic blocker. fMRI showed that regional blood flow changed in both the anterior cingulate cortex and lateral orbitofrontal cortex, which are the very same areas also involved in placebo analgesia. This suggests that similar mechanisms might be at work in the placebo response of emotional stimuli and in placebo analgesia. The best evidence that anxiety takes part in placebo responses is shown by the nocebo hyperalgesia. Expectations of a negative outcome, such as pain increase, may result in the amplification of pain, and several brain regions, such as the anterior cingulate cortex, the prefrontal cortex, the insula, and the hippocampus, have been found to be activated during the anticipation of pain in a variety of studies. These effects are opposite to those elicited by positive expectations, in which subjects expect pain reduction. Therefore, directed attention has a key role. In the case of anxiety-induced hyperalgesia, in which attention is focused on the impending pain, the biochemical link between this anticipatory anxiety and the pain increase is represented by the CCKergic systems. Conversely, in stress-induced analgesia a general state of arousal stems from a stressful situation in the environment, so that attention is now focused on the environmental stressor. In this case, there is experimental evidence that analgesia results from the activation of the endogenous opioid systems.
reference
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Parkinson's Disease (role of dopamin in motor striatum)
The manipulation of expectations has been found to affect the placebo responses in PD as well, thus indicating that expectation has an important role not only for placebo effects affecting sensory input but also motor output. For example, in a study by Benedetti et al Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses. 2003 , patients implanted for deep brain stimulation, a highly effective surgical treatment for PD, were tested for the velocity of movement of their right hand according to a double-blind experimental design in which neither the patient nor the experimenter knew whether the stimulator was turned off. Therefore, as it occurs for pain, in this case also, motor performance can be modulated in two opposite directions by placebos and nocebos, and this modulation takes place on the basis of positive and negative expectations about motor performance. To induce robust placebo responses in Parkinson patients, a pharmacological preconditioning is usually needed, for example with the anti-Parkinsonian agent, apomorphine. De la Fuente–Fernandez et al Expectation and Dopamine Release: Mechanism of the Placebo Effect in Parkinson's Disease. 2001 assessed the release of endogenous dopamine using positron emission tomography (PET) with raclopride, a radiotracer that binds to dopamine D2 and D3 receptors, competing with endogenous dopamine. In this study, Parkinsonian patients were aware that they would be receiving an injection of either active drug (apomorphine) or placebo, according to classical clinical trial methodology. After placebo administration, it was found that dopamine was released in the striatum, corresponding to a change of X200% in extracellular dopamine concentration and comparable to the response to amphetamine in subjects with an intact dopamine system. The release of dopamine in the motor striatum (putamen and dorsal caudate) was greater in those patients who reported clinical improvement. Although all patients showed dopamine placebo responses, only half of the patients reported concomitant motor improvement. These patients also released larger amounts of dopamine in the dorsal motor striatum, suggesting a relationship between the amount of dorsal striatal dopamine release and clinical benefit. This relationship was not present in the ventral striatum, that is, in the nucleus accumbens, in which all patients showed increased dopamine release, irrespective of whether they perceived any improvement. Accordingly, the investigators proposed that the dopamine released in the nucleus accumbens was associated with the patients’ expectation of improvement in their symptoms, which could in turn be considered a form of reward. Their finding was later corroborated by similar results :http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967525/ obtained with the use of sham transcranial magnetic stimulation as a placebo Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: The contribution of expectation. 2006 . Similar strong placebo responses were obtained:http://www.nature.com.offcampus.dam.unito.it/neuro/journal/v7/n6/full/nn1250.html through apomorphine preconditioning just before intraoperative recording of single neuron activity in the subthalamic nucleus Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. 2004 . These patients showed a significant decrease in neuronal firing rate associated with a shift from a bursting to a non-bursting pattern of discharge.
reference
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Alzheimer's Disease (role of prefrontal control)
One of the features of AD is the impairment of prefrontal executive control. Specific aspects of this control can be tracked down to definite prefrontal areas, for example, abstract reasoning to dorsolateral frontal regions and inhibitory control to orbital and medial frontal areas. Interestingly, the very same regions have been found to be activated by placebo-induced expectation of benefit, such as pain reduction. In AD, the frontal lobes are severely affected, with marked neuronal degeneration in the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex. It is therefore reasonable to also expect in these patients a loss of placebo responsiveness. Benedetti et al Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective. 2006 studied Alzheimer patients at the initial stage of the disease and after 1 year to see whether the placebo component of the therapy was affected by the disease. This component was correlated with both cognitive status, as assessed using Frontal Assessment Battery (FAB) test, and functional connectivity among different brain regions, as assessed using electroencephalographic connectivity analysis. In fact, it was found that Alzheimer’s patients with reduced FAB scores showed reduced placebo component of an analgesic treatment. In addition, the disruption of the placebo component occurred just when reduced connectivity of the prefrontal lobes with the rest of the brain was present. The neuroanatomical localization of placebo- and expectation- related mechanisms should alert us to the potential disruption of placebo mechanisms in all those conditions in which the prefrontal lobes are involved, for example, other forms of dementia such as vascular and frontotemporal dementia, or any prefrontal cortex lesion.
reference
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Immune System (role of conditioning and neuroendocrine system)
The behavioral conditioning of immune responses is based on the intense crosstalk between the CNS and the peripheral immune system, as demonstrated by Expectations and associations that heal: Immunomodulatory placebo effects and its neurobiology. 2006 . Commonly, in these approaches, experimental animals are presented with a novel taste (e.g., saccharin) as conditioned stimulus (CS) in the drinking water, and subsequently injected with an agent that produces changes in immune status (unconditioned stimulus, UCS). When the CS (saccharin solution) is re-presented at a subsequent time point, the animals avoid drinking the saccharin, which is termed ‘‘conditioned taste aversion’’ (CTA). Concomitantly, the animals demonstrate a modification of immune parameters that commonly mimics the actual UCS effect. Experimental evidence also suggests that behavioral conditioning of immunopharmacological drug effects is possible in humans Behavioral conditioning of immunosuppression is possible in humans. 2002 . Conditioned cyclosphosphamide-induced leucopenia has been reported, along with a conditioned immune response to the cytokine interferon-g, as well as conditioned suppression of the ex vivo production and mRNA expression of interleukin-2 and interferon-g, and of the proliferation of peripheral lymphocytes. Furthermore it was demonstrated by this study Behavioral Conditioning of Antihistamine Effects in Patients with Allergic Rhinitis. 2008 that the antihistaminergic properties of the H1-receptor antagonist desloratadine can be behaviorally conditioned in patients suffering from allergic house-dust-mite rhinitis, as analyzed by subjective symptom score, skin prick test, and decreased basophile activation. Interestingly, subjective symptom score and skin reactivity, but not basophile activation, was reduced in patients who where conditioned but not re-exposed to the novel-tasting drink served as a CS. By contrast, only conditioned patients who were re-exposed to the CS also demonstrated significant inhibition in cellular immune activation. These data support earlier observations indicating that conscious physiological pain and motor mechanisms are mainly affected by patients’ conscious expectations, whereas unconscious physiological processes, such as hormone release or immune functions, appear to be mediated by behavioral conditioning.
reference
2: Enck et al New Insights into the Placebo and Nocebo Responses. 2008
Genetic Responders' Predictors
In experimental and clinical approaches, the presence of placebo responses typically varies tremendously among individuals. There is therefore a great need to detect specific psychological, neuroendocrine, or genetic conditions that render subjects particularly susceptible to placebo effects. This is particularly important for diseases for which drug development has been compromised by rising placebo response rates. Moreover, deeper knowledge is needed regarding the differences in placebo mechanisms between diseases and physiological and psychological systems. Placebo effects have been shown to be substantial not only for psychological outcome variables (e.g., pain sensations) but also for biological parameters (e.g., dopamine release in Parkinson’s disease, forced expiratory volume in asthmatic disease, and antihistamine response in allergic reactions). However, the mechanisms that steer placebo responses can differ between systems (e.g., there may be a greater impact of expectation on subjective outcomes but a greater impact of conditioning on biological parameters).
reference
5: Rief et al Mechanisms involved in placebo and nocebo responses and implications for drug trials. 2011
Serotonin in Social Anxiety Disorder
There is some experimental evidence that some genetic variants related to serotonin affect placebo responses in psychiatric disorders. For example, Furmark et al in A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety. 2008 used functional neuroimaging to examine neural correlates of anxiety reduction resulting from placebo treatment in patients with social anxiety disorder (SAD). Brain activity was assessed during a stressful public speaking task using PET before and after an 8-week treatment period. The patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703-T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. It was found that the reduced stress-related activity in the amygdala that accompanied the placebo response could be observed only in subjects who were homozygous for the long allele of the 5-HTTLPR (l/l) or the G variant of the TPH2 G-703-T polymorphism (G/G), but not in carriers of short (s/l;s/s) or T alleles (T/G;T/T). In addition, the TPH2 polymorphism was a significant predictor of clinical placebo response, with homozygosity for the G allele being associated with greater improvement in anxiety symptoms.
references
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
6: Furmark et al A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety. 2008
On the basis of the action of placebos on monoamines of the reward circuitry and because monoaminergic signaling is under strong genetic control, Leuchter et al in Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. 2009 examined the relationship between placebo responses and polymorphisms in genes encoding the catabolic enzymes catechol-O-methyltransferase and monoamine oxidase A in subjects with major depressive disorder. Much of the research on reward signaling has focused particularly on phasic monoaminergic neurotransmission. Phasic DA signals occur in bursts and may be an indicator of reward expectancy. Phasic NE signaling is increased by tasks with high motivational value and modulates DA phasic activity. Increases in phasic DA and NE activities are transient, however, lasting only minutes from the start of a task. For placebo analgesia in normal subjects or temporary improvement in motor function in patients with PD, phasic DA and NE activity may be sufficient to mediate a placebo effect, which itself is shortlived. In clinical situations such as MDD, however, placebo responses are sustained over days or weeks in many individuals, and it is unlikely that transient phasic increases alone would sustain longer-term effects. Tonic DA and NE activities, which are sustained in the extracellular space over longer periods, may play a greater role in placebo response in clinical settings. Tonic NE and DA levels are predominantly regulated by catabolism of these neurotransmitters. Norepinephrine is a substrate for MAO-A, which is localized primarily in the LC and performs oxidative deamination of monoamines intracellularly. Dopamine is primarily catabolized by catechol-O-methyltransferase (COMT), which is present in the PFC and other dopaminergic projection areas, where it performs O-methylation in the extracellular space. Because tonic NE and DA levels modulate phasic neuronal firing, activity of MAO-A and COMT may be important modulators of reward signaling and of the placebo response. Tonic levels of both neurotransmitters are strongly related to well-described common functional genetic polymorphisms. Monoamine oxidase A activity is known to be associated with common single-nucleotide polymorphisms (SNPs) in the X-linked MAO-A gene coding sequence: one common haplotype includes multiple SNPs in exon 8, including an Fnu4HI G/T polymorphism at position 941 (rs6323). Females homozygous with 2 T alleles (or hemizygous males with one) have as much as a 75% reduction in MAO-A activity compared with those with the G allele(s), and heterozygotes have intermediate levels of activity. Catechol-O-methyltransferase activity is determined in part by common SNPs in the coding region: one of the most common leads to an amino acid substitution of methionine (Met) for valine (Val) at position 158, with the low activity COMT genotypes (Met-Met) associated with as much as a 75% reduction of activity compared with the high-activity variants. Monoamine oxidase A genotype was related to degree of improvement among MDD subjects treated with placebo. There were robust differences among subjects by genotype, with those subjects possessing the higher-activity form of MAO-A (those with 1 or 2 MAO-A G alleles) showing significantly less improvement during placebo treatment than subjects with lower activity forms of the enzyme (T alleles). Although the precise explanation for this finding is not known, it suggests that lower basal noradrenergic tone diminishes the rewarding effects of placebo administration. The numerically highest placebo response rate was seen in the heterozygotes (G/T genotype), suggesting that optimal signaling in LC pathways to achieve placebo response may be performed with intermediate or higher NE tone. With regard to Val158Met COMT polymorphisms, Met-Met subjects showed a statistical trend toward less improvement during treatment with placebo than did those with Val-Met or Val-Val alleles. This finding suggests that higher dopaminergic tone would diminish the ability to mount a placebo response. MAO-A plays a prominent role in emotional regulation. Recent research indicates that individuals with low-activity forms of MAO-A demonstrate greater emotional reactivity in response to negative social cues, higher trait interpersonal hypersensitivity, and greater anterior cingulate activity in response to social exclusion. Increased emotional reactivity to social cues in individuals with low-activity MAO-A could be consistent with the association between low-activity MAO-A and placebo response, in that emotional reactivity in the treatment situation is posited to be central to the placebo response. About the COMT, subjects who were homozygous for the Met allele have been reported to have higher sensory and affective ratings of pain than those with at least 1 Val allele, and the Met-Met subjects also tended to show diminished mu-opioid system responses to pain than those with Val alleles. Both of these findings would be consistent with subjects having the Met-Met genotype being less likely to have a placebo response when experiencing painful stimuli. These subjects may be more prone to rate not only pain, but also the affective components of distress, more highly than those heterozygous or homozygous for the Val allele.
references
4: Benedetti et al How Placebos Change the Patient's Brain. 2010
7: Leuchter et al Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. 2009
Dopamine in Irritable Bowel Syndrome
In another recent study Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome. 2012 , Hall et al. hypothesized that the functional COMT val158met polymorphism is associated with the response to placebo treatment in IBS, given that COMT has an effect on dopamine levels in the prefrontal cortex, a brain region activated during placebo response. Dopamine is cleared from the synapse either by the dopamine reuptake transporter (DAT), or degradation by monoamine oxidases A and B, or catechol-O-methyltransferase (COMT). Whereas reuptake is the primary mechanism of dopamine clearance in the striatum, in the prefrontal cortex, DAT is less abundant, rendering COMT activity critical in regulating prefrontal dopamine signaling. Previously, the team investigated IBS placebo responses in a clinical trial which had three arms: 1) a no-treatment arm that controlled for regression to the mean and normal fluctuations in illness (‘‘waitlist’’), 2) a placebo treatment arm which used a validated placebo acupuncture device administered in a businesslike no frills clinical context (‘‘limited placebo’’), and 3) a limited placebo arm augmented with a supportive warm provider who expressed confidence in the effectiveness of the treatment (‘‘augmented placebo’’). The two types of placebo interventions, limited and augmented, created a comparison of incremental components of the placebo effect in a manner that could be considered analogous to dose dependent. In this study, it is demonstrated that IBS patients homozygous for the COMT val158met methionine allele (met/met) were the most responsive to placebo treatment. Heterozygous (val/met) patients showed an intermediate response, and homozygous valine (val/val) patients showed essentially no placebo mediated symptom improvement. Their regression analysis showed that as the number of COMT val158met met alleles increased progressively from 0 to 1 to 2, and COMT activity decreased, theoretically making more dopamine available in the prefrontal cortex, placebo responses increased in a linear fashion.
These results are in contrast with the precedent study in which the homozygous metionine (met/met) patients showed less improvement during placebo treatment. I think this fact can be due to the different kind of pathology considered in this two studies. Maybe lower DA tonic levels allow a greater reward signalling, which represent an advantage for the therapy in MDD, while in IBS is more desirable an higher dopamine tone in the prefrontal cortex. Kathryn Hall, and the other authors of the last cited study, wrote that the previous studies which looked for genetic link to the placebo response, like the one written by Leuchter et al., were elusive. Those lacked the critical notreatment control and did not found a statistically significant relationship between COMT and placebo response. Furthermore they believe the study on the serotonin-related genes polymorphisms is significative, but the biomarkers found are relevant only for SAD placebo treatment and not necessarily for the placebo response mechanism in general.
reference
8: Hall et al Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome. 2012
Summary
Placebo mechanisms such as expectation and behavioral conditioning induce neurobiological alterations that interact with the biochemical pathways of pharmacologic treatments. These findings have implications for the design of clinical trials. The effects found in drug arms of trials represent not only the sum of specific and nonspecific effects but also the interaction between the underlying mechanisms. Placebos may have the same biological mechanisms of action as active drugs, thus further obscuring the boundary between specific and nonspecific mechanisms of action. Although our understanding of the mechanisms involved in placebo and nocebo phenomena has increased, we are only at the beginning with respect to determining the implications for clinical research and clinical practice. More information about predictors of placebo and nocebo responses is needed, and ethically acceptable applications of the relevant mechanisms should be developed for the benefit of patients.
However since the psychosocial context surrounding the patient (including the patient–clinician interaction and the therapeutic procedure) can be enhanced to improve these placebo effects, it is ethically acceptable, not to mention clinically relevant, to provide a supportive clinical encounter that relieves anxiety and promotes positive expectations along with honest disclosure of the expected benefits of a medically indicated treatment.
reference
5: Rief et al Mechanisms involved in placebo and nocebo responses and implications for drug trials. 2011
References
Reference 1: Koshi et al Placebo Theory and Its Implications for Research and Clinical Practice: A Review of the Recent Literature. 2007
Reference 2: Enck et al New Insights into the Placebo and Nocebo Responses. 2008
Reference 3: Finniss et al Placebo Effects: Biological, Clinical and Ethical Advances. 2010
Reference 4: Benedetti et al How Placebos Change the Patient's Brain. 2010
Reference 5: Rief et al Mechanisms involved in placebo and nocebo responses and implications for drug trials. 2011
Reference 6: Furmark et al A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety. 2008
Reference 7: Leuchter et al Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder. 2009
Reference 8: Hall et al Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome. 2012
