Introduction

Antidepressants are the group of medications which are prescribed for the treatment of major depressive disorders (MDD), individually or in combinations with other drugs(Dunner, 2014), depending upon the severity and the condition of disease (Szucs, 2017). They are mainly administered to balance the chemical imbalance of serotonin in the brain. On the basis of their mechanisms of action antidepressants can be categorized in different groups like: a. Selective Serotonin Reuptake Inhibitors (SSRIs) b. Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) c. Tricyclics and tricyclic-related drugs  and d. Monoamine oxidase inhibitors (MAOIs). The mechanism of action of these drug categories is described in Figure 1.

Figure 1. Mechanism of action (MOA) of different Antidepressants. Herein, we can see the MOA of different antidepressants. The aim of an Antidepressant is to stabilize and normalize the neurotransmitters in our brain. Neurotransmitters such as serotonin, dopamine and norepinephrine play a role in regulating our mood(Shaikh et al., 2016).

Similarly, Placebo are the inactive substances without any therapeutic entity. Currently, they are the major agents for various scientific studies aiming to understand various physiological, psychological and chemical mechanism of action of different drugs in pain, immune diseases and mental diseases(Shapiro, 1964). Placebo controlled trial is a major part of modern day medical research, in bizarre and interactive medicinal practice. Recent publications has enlisted placebo as the best option for the treatment of depression(Greenberg, 2017) along with (Josefsson et al., 2014). There is no sufficient evidence to prove that placebo helps to treat the pathophysiological conditions and tissue abnormalities of various diseases, however placebo treatment has some significant outcome in some disease conditions like pain and mild to moderate depression. Hence narrowing of the window of difference between drug-placebo effect has brought a lot of changes in a conduct of clinical trials(Khan and Brown, 2015).

In this review I am going to compare the therapeutic effects of antidepressants and placebo in different states of Depression. I will also place special emphasis on the specific phase of depression, antidepressants prescribed and compare it will the placebo.

Antidepressants VS placebo

Placebo literally means the inert elements which contains no any active substances with pharmacological interventions(Loebel et al., 2014).  However, different publications have shown that there is not any significance difference between antidepressant and placebo in terms of statistical analysis although its lacking the clinical significance(Khan et al., 2002, Kirsch et al., 2008). Similarly, all the clinical data provided to FDA before the improvement of drugs has shown that all antidepressants were found to be highly effective(Penn and Tracy, 2012). Hence, to prove these and find the actual facts, many researches were done and thus obtained data was analyzed to determine the effect of placebo as compared to antidepressants.

Research performed by Kirsch and his group in 2015, Shows that the improvement in patient’s health was 75% when treated with antidepressant which was surprisingly similar to the effect of placebo(Kirsch, 2015). These results were controversial because it questioned about the accuracy of drugs and the data provided to FDA for improvement, since the effectiveness of antidepressants were well established by evaluating various trials(Kirsch, 2015). Hence, they decided to duplicate their study with new set of clinical trials. For this they used the freedom of information act to send requisition to FDA for the data obtained from pharmaceutical company while obtaining approval for six new generations of antidepressants which consists of majority of the prescriptions(Kirsch et al., 2002). The statistics for the effectiveness of the drug over placebo was only 43% and remaining 57% were failed or negative trials. Similar results were also reported previously in the study performed by Khin et. al and Turner et.al,  which has included a. clinical trials done by FDA for all antidepressants. The analyzed results showed that the placebo effect has more than 80% of the total response(Khin et al., 2011, Turner et al., 2008).

Furthermore, they again expanded their research trials in the data, which was submitted to FDA. On analysis of the data they found that the effect of antidepressants and placebo was similar around 82%(Kirsch et al., 2008). The difference between the drug and placebo was very small in both cases.  There was only 1.8-fold difference between them which means that the data is clinically insignificance. It also could not meet the difference as mentioned by The

National Institute for Health and Care Excellence (NICE) guidelines for the NHS in UK which states that there must be three-point difference in between drug and placebo(Excellence and Britain, 2004).  Both the data obtained from the published and unpublished trials could not prove that antidepressants is clinically more significant than the placebo given.

Now these facts arise question on FDA for its approval of the antidepressants. According to the requirement of FDA, pharmaceutical companies should provide all the information regarding the clinical trials before the drugs get approved(Craig et al., 2008). However, around 50% of the clinical trials done by pharmaceutical companies have been unpublished(Chen et al., 2016). Hence, the results were only in between, FDA and pharmaceutical companies. So if there was any issues with those data and trials then firstly the medications should not have been approved. However, there was still unclear about the difference between drug and placebo in terms of   effectiveness and side effects. As the side effect of drug is known it was easy to predict for volunteer and researcher whether the given substance is drug or placebo.

Hence, researchers performed few experiments using active placebos, which mimic the side effect of the drugs to know the effectiveness of the drug. They performed eight studies to compare the effectiveness in between active placebos and tricyclic antidepressants and found that there is non-significant difference in between the two states(Moncrieff et al., 2004). They believe that the decreased difference in between the placebo and the drug is because the patients were known about the side effects and thus they believed that the side effects were because of the drugs effect(Rutherford et al., 2009). This lead to the positive effect of the placebo and hence enhanced its effect. The clinical trial data thus obtained indicates the ability of patients and investigators to assume the chance levels and influence of drugs in the efficacy.

Antidepressants and placebo in initial or moderate case:

Khan and his colleagues performed a research to find the patients response to antidepressants and placebo by analyzing the data from FDA databases(Khan et al., 2002). They analyzed 45 phase II and III antidepressants clinical trial. There was significant difference in between patients treated with placebo and antidepressants in severely depressed patients. In the patients given with antidepressants the magnitude of symptoms reduction corelated significantly with mean initial scores of the Hamilton Rating Scale for Depression (HAMD)(Cusin et al., 2009). By analyzing the data they demonstrated that the severity of depressive symptoms can affect the outcomes or randomized, placebo-controlled clinical trials(Tokuoka et al., 2017). The effects of antidepressants and placebo has similar effect in case of patients with mild and moderate condition. Similar meta-analysis study was performed by Kirsch et al and Turner et al in 2008 using HAMD as outcome measure which showed the placebo-like effect of SSRIs in patients with mild to moderate depression(Kirsch et al., 2008, Turner et al., 2008). They have shown that the HAMD interval was between 7 and 8 in patients with mild to moderate depression(Penn and Tracy, 2012). In both the studies researchers examined the effect of baseline symptoms of antidepressants and placebo. Thus, all the studies found that the greater the baseline symptom severity, the greater the magnitude of the difference favoring antidepressants over placebo. Kirsch et al inferred from their findings that the minimum baseline HAMD score needed to achieve a clinically meaningful Antidepressant/placebo difference is approximately 28(Kirsch, 2015) and that differences are negligible for lower baseline HAMD scores. Thus these findings indicate that the efficacy of antidepressants varies with the symptoms severity. The true drug effect was negligible as compared to placebo in the patients with mild moderate symptom patients.

Antidepressants and Placebo in Severe case:

To compare the effects of antidepressants and placebo in severe cases,  researchers gathered the clinical trials data of different antidepressants submitted to FDA(Khan et al., 2002). They investigated about the data using meta-analysis technique to compare the effect of severity of depression with placebo groups and change in HRSD improvement scores(Fournier et al., 2010). Firstly, they showed that the new generation antidepressants had very low clinical significance. In addition to that they also found that there was no significant difference in improvement score in between patients treated with antidepressants and placebo in moderate depression condition(Kirsch et al., 2008, McAllister-Williams, 2008). Similarly, in severe condition also there was small but clinically insignificant difference. However, in case of most severely depressed patients there was significant improvement by antidepressants as compared to the placebo effect and also the HRSD score was also more than 28. Additional analysis also indicated that the clinical effectiveness of antidepressants increased because of decreased response to placebo rather than increased response to antidepressants. Similar experiment was also conducted by Fountoulakis and Mollera which showed the consistent data(Fountoulakis and Möller, 2011).

These all findings suggests that new generations antidepressants  do not produce the significantly improvement in patients with intial or moderate phase of depression as compared to the placebo. However in case of the patients with most severe depression they show the significant improvements. These findings also show that the reason behind it is due to decreased response to placebo rather than increased response to the drug. The main difference between clinically and statistically significant is that, statistically significant focus on the effect whether its real or has it occurred by chance and it does not have anything to do with the effect size whereas clinically significant mainly has to do with the size of an effect and it has ability to make a change in an individual.

In conclusion from all the experiments conducted by different researchers at different time frame suggests that there is large variation in the size of the placebo response. Similarly, it can be noticed that the effect of placebo with antidepressant depends on several factors like: assessment method, the year of data published, the type of placebo and antidepressant applied and definitely in the severity of depression.