Placebo Pills For Depression Treatment.

Introduction

Major Depressive Disorder (MDD) is characterized by low mood, low self-esteem, anxiety, and having no motivation to do day-to-day tasks. Just like any other illnesses, treatments are being made mainly targeting symptom reduction. To do so, researchers have attempted to explain how the illness comes about. Biologically speaking, Schildkraut (1965) raised the catecholamine hypothesis which states that low levels of noradrenaline directly affects serotonin levels, which affect emotion and sleep. Additionally, the cortisol hypothesis also arose, stating that normalizing the levels of this stress hormone decreases depressive tendencies. Unfortunately, there is no way of determining the definite cause for the disorder. It is more of a multifactorial interaction that brings this about. Numerous antidepressants have been produced due to said biological hypotheses and findings. Such drugs are prescribed by one’s general practitioner (GP) if said symptoms are to be classified as moderately severe to extremely severe cases. While they are used to aid patients, they also bring side effects depending on how the body responds to the chemical compound.

Furthermore, the discontinuation of the usage also causes withdrawal symptoms which may last up to two weeks. To be legalized, they undergo through control stages with the Food and Drug Administration (FDA). These stages usually consist of clinical trials, which compares the effect of the drug to a control group, undergoing through the placebo effect. The Placebo Effect is defined as “the study of psychosocial context specific to a particular trial situation that includes expectation of clinical improvement and conditioning” (Colloca & Benedetti, 2006). The concept dates back to the Pavlovian Conditioning (1890), that is based on the principle of “animals can provide insight into human behaviour”. If dogs can be conditioned to salivate with a ring of a bell, then humans can also be conditioned to behave a certain way with a specific stimulus. With this, a link can be seen between the placebo effect and the disorder. If a patient can be conditioned to think that a sham pill will improve his condition, it may, in fact, take effect to a certain extent.

Zubieta et al. (2015) found out that a sham pill described as an antidepressant is able to reduce depressive symptoms. Moreover, further research (Khan & Brown, 2015) suggests that a patient’s positive expectation intensifies this, leading to a faster improvement in his condition. If such phenomenon is found to be effective, it would be more advantageous as the patients will be less prone to side effects and withdrawal symptoms, as they are not actually taking the chemical compound that triggers these effects. With this, it is possible that sham pills may be prescribed, as this also reduces the production costs of antidepressants. Although this serves as an alternative, it is also important to take note of counterclaims and ethical issues in examining: To what extent does the placebo effect play a role in treating major depressive disorder?

Research

With the rising popularity of the placebo effect, it is possible to seek sham pills as an alternative to actual medication in treating Major Depressive Disorder (MDD).

The Mechanism of the Placebo

The placebo group will be given a sham pill, described to possess the same power as the antidepressant itself. Doing so, allows the researcher to determine the effect of the actual drug as the sham pill is assumed to have no effect at all. However, the concept of the placebo effect says otherwise. The mechanism undergoes three stages: Unconditioned stimulus (UCS) creates an unconditioned response (UCR) - For example, a patient is told that a certain stomach virus causes nausea. Analogously, the patient is told that serotonin helps boost mood. UCS is linked to create a conditioned stimulus (CS) - Being confused, the patient may attribute the nauseating feeling to what he previously ate, such as chocolate. Similarly, the GP will then say that the pill will help improve his mood as it contains serotonin level enhancers. CS creates a conditioned response (CR) - Thinking that the chocolate made him nauseous, eating chocolate from then on will make him feel like throwing up. In relation to the placebo effect, taking the pill will boost his mood. In essence, the mind is conditioned in such a way that the pill is accountable for improving the mood of the patient, despite the lack of the actual chemical intake.

Since the patient is conditioned to a specific stimulus, he will then adapt and behave a certain way. In addition, the adaptation to pills can also be attributed to the early stages of the patient’s life. Acquiring the behaviour may have been due to Operant Conditioning, in which the behaviour is learned by imposing consequences. There are four key concepts regarding the phenomenon:Positive Reinforcement - The target will receive something they like from the perceiver, so long as the behaviour is instigated. For example, when a child (target) takes cough syrup, the mother (perceiver) gives him candy as a reward. Negative Reinforcement - The target will be deprived of what they like when the behaviour is not brought about. When a child does not take cough syrup on time, the mother takes away his favourite toy. Positive Punishment - The target will be given something they do not like when the behaviour is not induced. Similar to the aforementioned situation, the mother may give him a curfew. Negative Punishment - The target will be stripped of what they do not like when the behaviour is done. When the child takes the medicine, the mother will take away the curfew. These key concepts may have been done before, perhaps with a different medication. With the chemical intake, the body starts to heal — thus staving off the disease. The imposed consequences may have conditioned the patient to think that the act of taking medicine is an essential step to recuperate. If a patient is conditioned to think that a pill will help reduce depressive symptoms, it is possible that the body will adapt to this conditioning. However, studies have shown that sham drugs are effective to a certain extent, and may depend on the severity of the disorder.

The Power of Placebo

A sham pill is able to reduce depressive symptoms because the patient is conditioned to think that taking a pill will improve their condition. Zubieta et al. (2015) published a study aiming to see whether an active placebo group (AP) would be more effective in reducing the depressive symptoms compared to an inactive placebo group, (IP) in a sample of thirty-five participants. The said patients have not had any sort of medication before the said study. During the first phase, the AP was given a sham pill described as an antidepressant, while the IP was given a sham pill without description. At the end of each week, the patients were given a questionnaire regarding their symptoms, and a Positron Emission Tomography (PET) scan. During the scan, AP was injected a saline solution described as a mood booster, while the IP received nothing. During the second phase, they were all prescribed an SSRI antidepressant that lasted for 10 weeks. The team found a significant symptom reduction in AP. The study truly provides great insight as it features an experimental design, therefore providing causality between symptom reduction and the placebo. It is important to take note, however, that the sample cannot be generalized to the greater population as it is too small. Moreover, the age group and gender weren’t specified. Another factor could also be cultural differences, which could lead to subjective diagnoses for the study. While the placebo effect suggests great potential as a possible alternative to antidepressants, its efficiency varies depending on the severity of the disorder. With antidepressants, placebo responses usually account for 30%-40% of the drug’s effect (Peciña, 2015).

For more severe patients, the effectivity is less attributed to the placebo response and more to the actual chemical compound. On the other hand, for less severe patients, the effectivity is mostly attributed to the placebo response (Boyles, 2008). However, a meta-analysis (Kirsch, 2002) counteracts this claim. With data coming from the Food and Drug Administration (FDA), the scope focused on the clinical trials of six generations of a certain antidepressant. 75% of the improvement came from the placebo groups. Interestingly, half of the trials were kept from the public, leaving only the FDA and drug companies aware of it. Moreover, only 43% of the drug showed a significant edge over the sham drugs, and 57% were failed trials. Critics of this study argued however that he has only studied the data of those who are diagnosed to be less severely depressed. He conducted another meta-analysis with data from 2008, only to discover a 0. 7 difference between the placebo and moderately severe patients, and a 4. 36 difference between the placebo and extremely severe patients. In essence, he concluded that both differences in the findings were still relatively insignificant. The evidence is strong as it used a multitude of studies in analysing the concept. In addition, Kirsch has included trials that were not published, increasing the validity and decreasing inconsistencies within his conclusion. However, he did not take into consideration cultural differences. Although the main focus of his meta-analyses was to correlate the efficiencies of the antidepressants and placebos to the severity of the disorder, diagnoses may have differed in the process. Taking into account the different upbringing of each patient and their respective psychiatrists, a patient diagnosed as severely depressed may be classified as moderately depressed by another practitioner. In essence, this could lead to a bias in his data. In addition, the meta-analyses are subject to confirmation bias. One study may define a term differently from the others.

Perhaps, one study may refer to efficiency as a reduction of symptoms whilst another may see this as a mood booster alone. It is possible of course, that there are multiple factors at play when treating the disorder such as the type of antidepressant and the differences of each patient. Kirsch stated, however, that the type of antidepressant does not matter when compared to the placebo groups. There is also no significant difference whether the patients are of different sexes, ethnicity, ages, and whether they possess comorbid conditions (Gartehner et al. , 2011). One may think that this diminishes the doubts surrounding cultural differences. However, differences in ethnicities do not necessarily refer to differences in upbringing. The environment that one has been accustomed to may be different to that of another. All in all, conditioning is truly an essential foundation in the efficacy of the pill. However, the factors that affect the strength is debatable as evidence suggest that it varies from the severity of the disorder to the cultural upbringing of both participants and the GPs.

The Impact of Placebo

Expectation plays a significant role in producing the placebo effect because a strong belief in medication leads to the body not mounting other responses, in order to adapt to the abnormality that is caused by the disorder (Khan & Brown, 2015). For example, a patient expecting that the act of taking a pill will help him “feel better”, may lead to a reduction in depressive symptoms. Therefore, the risk to placebo exposure should be kept to a minimum. To put it simply, the more that a participant is unaware of the possibility of a sham drug in a trial, the more they are prone to claim its promised effects later. Once these expectations are set, the placebo effect tends to continuously exist throughout the experiment. A meta-analysis of experimental trials was conducted with data from 2008 (Khan & Brown, 2015). In a sample of nine trials, all of which used a double-blinded procedure (where both the patient/researcher are unaware of what they are about to receive/give), 79% did not relapse from the placebo group. Conversely, 93% of those who took antidepressants relapsed. Considering that most of the placebo patients did not relapse, it is surprising to see that most of those who had an actual chemical intake revert to their disorder. Moreover, research suggests that depressive relapse tendencies range from 20%-44% depending on the length of treatment, despite the continued use of antidepressants.

Perhaps, the tendency to relapse could be attributed to the chemical intake. Since the body is used to ingesting a pill that increases serotonin levels, a disruption of the intake may lead to the body failing to adapt right away. In relation to expectation, perhaps the patients may have been too dependent on the pill, thus remission may lead to the patient relapsing. It can be inferred from the study, that the expectations of the patients do play a role in treatment, considering that it is done in an experimental setting, hinting a causality between expectation and efficiency. However, it is worth taking into consideration other factors that may have caused the patients to relapse. For example, the patients may have had something bad happen to them all of a sudden. Perhaps, they may have developed a negative way of thinking due to a change in environment. Since the meta-analysis does not state whether the sample was monitored all throughout, the relapses cannot be solely blamed on biological imbalances. The definite cause of MDD cannot be identified. Since it is more of a multifactorial interaction between the biological, cognitive, and sociocultural factors that brings this about, the relapses may have also been caused by the latter. Another related experiment was conducted by prescribing Tianeptine, a selective serotonin reuptake enhancer, which enhances the reuptake of serotonin in the body (Kirsch, 2014). By right, depression should worsen due to the low levels of the neurotransmitter.

Surprisingly, 63% of the patients improved when compared to the patients who took Selective Serotonin Reuptake Inhibitors (SSRI). This efficiency was described to have 50% of the symptoms reduced. He implies that medication doesn’t matter, as the mind does most of the job. Similarly, the evidence is strong as it is an experiment suggesting causality between a positive expectation and symptom reduction. However, it is important to note that a lot of factors may have contributed to Kirsch’s experiment. The severity of the disorder in each participant was not stated. Perhaps, most of them may be less severely depressed, as the effect is attributed more to the placebo response. In addition, these participants may have been taking other forms of treatments such as psychotherapies, in which Kirsch has not mentioned. It is evident that expectation is a key factor in generating the placebo response. It is possible, however, that cognitive dissonance may have arisen.

This is the tendency to make sense of dissenting cognition and behaviour. For example, a smoker still smokes despite his awareness of the susceptibility to lung cancer. Thus, an improved mood may have been attributed to the pill as their expectations were set. Other factors, such as a change in surroundings, may not have been taken into consideration by the researchers and patients as the pill is the easiest, yet logical, explanation. Altogether, it is necessary for the expectations to be set positively in order to strengthen the phenomenon. Without this, it can be inferred that the success rate may diminish significantly, disabling the sham pill to reduce symptoms as effectively.

Ethical Considerations

Although the placebo effect may sound promising, ethical considerations have been raised regarding this. In the field of psychology, these have been established in order to protect the public from potential harm. Section 5. 01 of the American Psychological Association (APA) Code of Conduct states that “Psychologists do not knowingly make public statements that are false, deceptive, or fraudulent concerning their research, practice, or other work activities or those of persons or organizations with which they are affiliated. ” It is evident that psychologists are not allowed to prescribe drugs, in which the patient is not aware of its contents and effects, else it would be considered as deception. However, Section 8. 07 ┈ “ Psychologists do not conduct a study involving deception unless they have determined that the use of deceptive techniques is justified by the study's significant prospective scientific, educational, or applied value and that effective non-deceptive alternative procedures are not feasible. ” ┈ provides justification. In essence, it is important to delay the information in a trial in order to avoid demand characteristics (in which participants may act differently because they are aware of what is happening), so long as the participants are not subject to physical and emotional distress.

Moreover, Section 8. 08 ┈ “Psychologists provide a prompt opportunity for participants to obtain appropriate information about the nature, results, and conclusions of the research, and they take reasonable steps to correct any misconceptions that participants may have of which the psychologists are aware. ” ┈ states that a debriefing procedure is essential in any research. Although the information regarding the main focus of the research is delayed in most of the studies mentioned, the participants were told the likelihood of receiving a sham pill (placebo risk exposure). In essence, the clinical trials that are cited are justifiable despite the question of deception. In the event of receiving a sham drug outside of clinical trials, ethical considerations are still in question as it could result to misinforming the patient regarding the medication he will be taking. Research suggests that views regarding the prescription of placebo pills are dissenting (Bishop, Aizlewood, & Adams, 2014). For one, people who approve of this are looking at the situation practically, in such a way that the ends justify the means. On the other hand, people who disagree argue that the positive outcome is not an excuse to deceive patients. In essence, the sham drug is unlikely to harm the patient, as he is less prone to side effects and withdrawal symptoms, due to the absence of the chemical compound. Moreover, a strong belief in the pill may result to a significant symptom reduction. It is important to remember, however, that conditioning, together with expectation, is essential for the placebo effect to take place. Although the process of attaining the favourable outcome is in question, the placebo pills are still justified as it minimizes the risk of patients getting harmed.

Summary and Conclusion

Summary

The placebo effect is a phenomenon that is brought about by conditioning and expectation. In relation to Major Depressive Disorder (MDD), the placebo response also accounts for symptom reduction. Evidence suggest that placebo pills can be an alternative to existing antidepressants, so long as the patient is deemed to have a strong belief in the medication. The efficacy of placebo pills however, vary depending on the severity of MDD. The more severe that the disorder is, the more it is attributed to the chemical. On the other hand, the efficacy is mostly attributed to the placebo response for less severe patients. Although the sources cited provide insight to the power of placebo, it cannot be generalized to the greater population as most of them may have over-represented individualistic cultures.

Limitations

Examining such ideas can be limited, as there are only a handful of relevant studies available. The studies gathered are timely, and relevant as most of these were conducted within the past decade. These mostly focused on how severity and expectation affect the placebo response. It is important to take note, however, that these studies did not focus on culture, particularly the upbringing of the GPs. Diagnoses may differ from one country to another. A severely depressed patient in the United States may be diagnosed as moderately depressed in China due to the lack of somatic (physical) symptoms (Katon, Ries, & Kleinman, 1984). Since different doctors conducted the studies, they are still subject to difference. Although there is a given prerequisite set of factors and descriptors, the magnitude of the disorder may vary from one’s mindset to another. Burns (2003) also argued that such studies aren’t acceptable because it has no causality. This is because there is no definite way to measure the levels of hormones and neurotransmitters in the body. Therefore, it is impossible to test and identify the relationship between a hormone and a symptom — a cause and effect relationship cannot be established. However, it is also important to note that the link between the placebo effect and antidepressants is mostly attributed to a difference in behaviour. In essence, the efficiency of the sham drugs is not based on regulating hormonal and neurotransmitter levels, but of a change in behaviour such as a happier mood.

Conclusion

The extent as to how efficient the placebo effect is, in treating MDD depends on numerous factors. For one, conditioning the patient must be done as this is the foundation to induce improvement in his condition. Zubieta et. al. (2015) illustrated in their study how the active placebo group was able to feel a significant symptom reduction towards the end of the study. In addition, positive expectations must also be set in order to maximize the phenomenon. This is further observed in Kirsch’s Tianeptine experiment (2014) wherein it revealed that the patients who took Selective Serotonin Reuptake Enhancers had significant symptom reduction throughout the study.

Interestingly, the results went against the prediction that the disorder should worsen due to the enhanced absorption of the neurotransmitter, serotonin. In essence, how the patient is conditioned, and how his expectations are set are vital in the assessment of efficiency. Peciña (2015) and Boyles (2008) suggest that this varies on the severity of the disorder┈with the phenomenon being more accountable for the symptom reduction for those whose disorders are less severe. However, Kirsch’s (2002) meta-analyses suggest that there is no significant difference between the efficacy of sham pills as opposed to antidepressants in the placebo, moderately depressed, and severely depressed groups. Although Peciña and Boyles’ statements are more recent, Kirsch’s meta-analyses synergized numerous studies as the basis, including private trials that decreases possibilities of analytical errors. Additionally, Gartehner et. al. (2011) claimed that there is no significant difference on how the sham drug will take effect, whether the patient is of different age, gender, or ethnicity. Differences in cultural upbringing, however, may somewhat alter the outcome. There is also little to no significant difference in symptom reduction when taking a sham drug as opposed to an actual antidepressant. With all this in mind, the placebo effect truly plays a role in treating MDD to some extent, and can therefore be considered efficient in symptom reduction. Although there is a question of ethics as to whether these could be prescribed, evidence justified that this can be as equally as effective, with the risk of potential physical harm minimized as much as possible. The happiness twin study (Lykken, 1996) suggests that 50% of happiness relies on biological factors, 40% on cognition, and 10% on sociocultural factors. With this, a human’s genetic makeup, together with hormonal and neurotransmitter imbalances only account for 50% of the entire treatment.

The cause of MDD is almost impossible to point out, thus it is less recommended to use only one specific treatment, as it only targets one aspect. Although sham drugs can be an option, eclectic treatments may intensify the effects, thus speeding up the process of his treatment. It is important for the patient to change his way of thinking, with the help of psychotherapies. Additionally, a change in the environment may also help in boosting his low mood levels. Placebo pills are advantageous in such a way that they make the patients less prone to relapse, side effects, and withdrawal symptoms. Although sham drugs can be as effective as actual antidepressants ┈ it can reduce symptoms, but not entirely cure MDD.