The Validity of Antidepressants: A Critical Look at Antidepressants and the Placebo-Effect
Daniel D. Coppersmith
They have become the most prescribed drugs in the world whose global sales have made them a $19-billion dollar a year industry (Kirsch, 2010). Ten % of Americans now take them (Kirsch, 2010). They have been called miracle drugs and have become a cornerstone of the psychological world. They are antidepressants. These drugs have become an extremely relevant issue with millions of dollars being poured into research and debates raging about their legitimacy among the scientific community. In recent years a great deal of this research has been undertaken seeking the legitimacy of antidepressants. A particular focus of the research has been on unearthing unpublished data sponsored by drug companies . A strong movement has formed against the use, production, and business motives behind antidepressants A significant field of interest for protestors has been studies demonstrating the placebo effect.
The placebo effect occurs when one is told that he/she is being given a treatment, but in reality the individual does not receive the actual treatment. Nevertheless, the individual experiences symptom improvement by just believing that he/she is being treated (Kirsch, 2010). One of the defining features of depression is sentiments of hopelessness (Seligman, 1992). This sense of helplessness is strongly related to the self-fulfilling prophecy. When a depressed patient predicts that they have no hope, this leads the patient to behave in ways that lead them into hopeless and negative situations (Seligman, 1992). One of the defining features of the placebo effect is hope (Kirsch, 2010). Placebo manipulations can offer patients relief from threatening medical conditions. With this information in mind, Irving Kirsch, an accomplished psychologist and professor of psychology, sought information pertaining to the placebo effect and depression. Kirsch and Sapirstein (2010) used the freedom of information act to obtain hidden data about antidepressant studies. When his study was completed, Kirsch writes, “My colleagues and I were let to the inescapable conclusion that antidepressants are little more than active placebos, drugs with very little specific therapeutic benefit, but serious side effects” (Kirsch, 2010, p. 4). The effect of Kirsch's statement would be felt throughout the medical community and needs to be analyzed .
Kirsch performed a meta-analysis in which he and Sapirstein (1998) pooled the results of several previous studies in which placebos had been used to treat depression. Kirsch and Sapirstein (1998) analyzed studies in which depression had been tracked in patients who were not given any treatment so that they could compare the effects of placebos against the rates of spontaneous recovery. Thirty-eight clinical trials involving more than 3,000 patients were examined. The average improvement from antidepressants, psychotherapy, placebo manipulations, and no treatment was calculated.
Kirsch (2010) found significant improvement for patients receiving either drugs or psychotherapy, but there was also improvement for those receiving placebos. The difference between the placebo groups and the no treatment groups was significant, so that no treatment groups reported significantly lower levels of symptom reduction. The significant health improvement in participants who received the placebo clearly demonstrates the placebo's strong effects on wellbeing.
Another surprising feature was found when Kirsch (2010) reexamined the data and looked more specifically at the drug types that had been used in the tests. As Kirsch (2010, p. 12) writes: “In fact, the data was remarkably consistent-much more so than is usually the case when one analyzes different groups of data. Not only did all these medications produce the same degree of improvement in depression, but also, in each case, only 25 percent of the improvement was due to the drug.” This is surprising considering the evolution of antidepressants from MAOIs to the more complex and specific SSRIs. Kirsch (2010) concludes that the newer antidepressants are no more effective than the older medications.
An important speculation that Kirsch (2010) made was that the relatively small difference between drugs and placebos might not be a real drug effect. Rather, it might be an enhanced placebo effect from patients breaking blind and realizing whether they were given a drug or placebo. (Kirsch, 2010, p. 12) In addition, Kirsch (2010) found that the more side effects a patient experiences on the active antidepressants, the more they improve. Kirsch (2010) suggests that side effects bring the antidepressant into the patient's awareness so expectations for improvement are salient. He also proposes that consciously experiencing an antidepressant's unwanted effects creates the expectation that the antidepressant is influencing depression; therefore, the placebo effect was likely to occur. These results are significant to debunking antidepressants because the placebo effect, characterized by hope and positive outlook, is evident in patients notorious for feeling helpless in pessimistic. Kirsch (2010) delved deeper into placebo research as he examined studies that used active placebos. An active placebo is a drug that does not affect the diagnosed illness but still has side effects (Kirsh, 2010,). For most of the depression trials with active placebos, Atropine was used as the active placebo. Atropine is used for the treatment of gastric dysfunctions and has several side effects. Even though its side effects are far less significant than those of antidepressants, it still prevents patients from breaking blind. Kirsch (2010) found that in studies when the use of active placebo occurred, the drug-placebo differences in improvement were not statistically significant. The drug’s side effects provide patients with the experience of side effects, although they are far less significant than those of antidepressants. For future research in this field, participants should be told that are placed in the condition in which they will be receiving a drug for an unrelated issue. Therefore the participants would have no expectations for depression reduction. Thus the experimenters could conclude the degree to which positive expectations play a role in antidepressant effectiveness.
A form of research that displays the lack of positive expectations is antidepressant testing in animals. Two methods of this testing are the Posolt swim test and tail suspension test. In the Porsolt test, a rat is placed in a narrow cylinder from which it cannot escape and is forced to swim. This process induces the rat into a depressed-like state, characterized by immobility (Porsolt, Bertin & Jalfre, 1977). The rat then is given an antidepressant and 24 hour later undergoes a second trial in the cylinder. The rats that receive antidepressants displayed reduced immobility compared to no treatment control groups or rats that received tranquilizers (Porsolt, Bertin & Jalfre, 1977). These results are significant due to the subjects lack of positive expectations, but there are flaws. This test merely measures a physical change in a rodent and does not measure emotional change or serotonin levels in human participants. Another test of antidepressant effectiveness is the tail suspension test. A mouse is suspended by the tail from a lever and the movements of the mouse are recorded (Steru, Chermat, Thierry & Simon, 1985). The initial six minute test is divided into periods of agitation and immobility. The mice are then divided into control and psychotic drug groups. The mice who receive the antidepressants, show a decreased in their duration of immobility. This test has similar significance and flaws as the Porsolt swim test. These tests provide context and backing for the use of antidepressants but do not disprove Kirsch’s claims.
Kirsch helped develop the movement against antidepressants, which has now pervaded the psychotherapeutic community. I saw this firsthand when I sat down with Geoffrey Cohane, a private practice psychologist who also works at McLean Hospital in Belmont. Cohane, who has been practicing for several years, attended Williams College and earned his Ph.D. in clinical psychology at Clark University. Cohane emphasized when discussing antidepressants that “Personally, I would like to see that they are effective because then that is another tool for me when doing counseling” (G.Cohane, personal communication, January, 10, 2011). It was clear though, that Cohane had become wary of antidepressants and said that “they are over prescribed in some regions of the country” (G.Cohane, personal communication, January, 10, 2011). Charles Barber argues that this overprescription cannot be attributed to an improvement in the quality of antidepressant drugs, but rather a change in the cultural environment of the United States. In the past twenty years in the media there has been a more positive and prevalent portrayal of mental disorders and psychiatry (Barber, 2008). This shift has created an environment in which an individual is more likely to think that they are mentally ill. In a study done by the world health organization in 2004, 26% of Americans reported that they suffered from a psychiatric illness in the previous year. This percentage was the largest percentage of the fifteen countries in the survey (Barber, 2008). This rise in belief of mental illness and the emergence of massive pharmaceutical companies, has created the overprescription Cohane described. It was also apparent that he was knowledgeable about the problems that Kirsch was suggesting. Cohane said, “There is the file drawer effect... Researchers are more likely to publish work that backs their hypothesis. So if data doesn’t back their work, many researchers won’t publish data and put it in their file drawer. Thus, only a fraction of the data is out there and the data gets skewed” (G.Cohane, personal communication, January, 10, 2011). Cohane mentioned that several recent articles had demonstrated the lack of effectiveness of big name antidepressants.
Fournier et al. (2010) performed a meta-analysis, in order “To estimate the relative benefit of medication vs. placebo across a wide range of initial symptom severity in patients diagnosed with depression” (Fournier et al , 2010, p. 47). They drew their data from PubMed, PsycINFO, and the Cochrane Library databases from January 1980 through March 2009. The data included references from meta-analyses and reviews. The authors analyzed studies that used randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder. Studies were included if the authors included a medication vs. placebo comparison for at least 6 weeks, if they did not exclude patients on the basis of a placebo washout period, and if they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included.
Fournier et al. (2010)concluded that, “The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial”(Fournier et al , 2010, p. 48). Thus, their conclusion is distinct from Kirsch’s (2010) conclusion as patients with severe depression showed a decreased placebo effect. This conclusion can be attributed to that these patients are less likely to be optimistic. Therefore they are less likely the show the placebo effect, which is based on hope.
In another study focused on antidepressants versus placebo effectiveness in relation to severity of depression. Barbui, Cipriani, Patel, Ayuso-Mateos, and van Ommeren (2011)did a meta-analysis of the efficacy of antidepressants in patients with minor depression. They drew data from MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane ControlledTrials Register and pharmaceutical company websites. After finding six studies that fit their criteria by performing the proper analysis, they were able to conclude “there is unlikely to be a clinicallyimportant advantage for antidepressants over placebo in individualswith minor depression”(Corrado, et. al, 2011). Once again another study demonstrated the lack of efficacy of antidepressants compared to placebos and most importantly the difference between placebo and drug is only evident when depression is severe. Thus, the placebo effect is a problem in cases of mild to moderate depression, but is not as much a problem in severe depression.
A. Khan, Leventhal, S. Khan, and Brown (2002) did an analysis of severely depressed patients and the efficacy of antidepressants and placebos. They drew their data from the Food and Drug Administration database of 45 phase II and III antidepressant clinical trials. They found that “the frequency of statistically significant differences between antidepressants and placebo was higher in the trials that included patients with more severe depression” (Khan et al., 2002). The higher the patient’s initial score of depression on the Hamiltion Rating Scale of Depression Overall, the greater magnitude of symptom reduction. Thus similar to Fournier et al. (2010), the study displayed that the severity of the depression increases the efficacy of the antidepressant and decreases the placebo effect.
It is evident that the current system of prescribing antidepressants cannot be left as is. The reviewed studies highlight the over prescription of antidepressants. This overprescription can be attributed to the shift in acceptance of mental health, the increase in exposure of mental health and the rise of the pharmaceutical business. Still, antidepressants are frequently required when treating severe forms of depression. Several studies display that the placebo-effect decreases when depression has rooted itself deeply into an individual's neural functioning, positive expectation may not be sufficient in alleviating symptoms. Depression is defined by its feelings of helplessness, and sometimes, feelings of hope are not strong enough to overcome cemented cognitive patterns of helplessness. Beck’s cognitive triad states that the self, world and future of a depressed patient are overcome by feelings of hopelessness and helplessness (Beck,1979). Thus in the cases of the severely depressed, hope may have never been present in the first place. Future research needs to be dedicated to the replacement of antidepressants with placebos in patients experiencing less severe forms of depression. If studies continue to find symptom reduction in non-severely depressed patients with the use of placebos, there could be great implications for antidepressants. The credibility of antidepressants could suffer and the number of prescriptions should be scaled down from the current enormous number.
References
Barber, C. (2008). Comfortably Numb: How Psychiatry Is Medicating a Nation (1st ed.). Pantheon.
Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J. L., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: Systematic review and meta-analysis. The British Journal of Psychiatry, 198(1), 11 -16. doi:10.1192/bjp.bp.109.076448
Beck, A. T. (1979). Cognitive therapy of depression. Guilford Press.
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity. JAMA: The Journal of the American Medical Association, 303(1), 47 -53. doi:10.1001/jama.2009.1943
Khan, A., Leventhal, R. M., Khan, S. R., & Brown, W. A. (2002). Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. Journal of Clinical Psychopharmacology, 22(1), 40-45.
Kirsch, I., & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment, 1(2). doi:10.1037/1522-3736.1.1.12a
Ph.D., I. K. (2010). The Emperor’s New Drugs: Exploding the Antidepressant Myth (1st ed.). Basic Books.
RD, P., A, B., & M, J. (n.d.). Behavioral despair in mice: a primary screening test for antidepressants. Archives internationales de pharmacodynamie et de therapie, 229(2), 327.
Seligman, M. E. P. (1992). Helplessness: on depression, development, and death. W. H. Freeman.
Steru, L., Chermat, R., Thierry, B., & Simon, P. (1985). The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology, 85(3), 367-370. doi:10.1007/BF00428203
The placebo effect occurs when one is told that he/she is being given a treatment, but in reality the individual does not receive the actual treatment. Nevertheless, the individual experiences symptom improvement by just believing that he/she is being treated (Kirsch, 2010). One of the defining features of depression is sentiments of hopelessness (Seligman, 1992). This sense of helplessness is strongly related to the self-fulfilling prophecy. When a depressed patient predicts that they have no hope, this leads the patient to behave in ways that lead them into hopeless and negative situations (Seligman, 1992). One of the defining features of the placebo effect is hope (Kirsch, 2010). Placebo manipulations can offer patients relief from threatening medical conditions. With this information in mind, Irving Kirsch, an accomplished psychologist and professor of psychology, sought information pertaining to the placebo effect and depression. Kirsch and Sapirstein (2010) used the freedom of information act to obtain hidden data about antidepressant studies. When his study was completed, Kirsch writes, “My colleagues and I were let to the inescapable conclusion that antidepressants are little more than active placebos, drugs with very little specific therapeutic benefit, but serious side effects” (Kirsch, 2010, p. 4). The effect of Kirsch's statement would be felt throughout the medical community and needs to be analyzed .
Kirsch performed a meta-analysis in which he and Sapirstein (1998) pooled the results of several previous studies in which placebos had been used to treat depression. Kirsch and Sapirstein (1998) analyzed studies in which depression had been tracked in patients who were not given any treatment so that they could compare the effects of placebos against the rates of spontaneous recovery. Thirty-eight clinical trials involving more than 3,000 patients were examined. The average improvement from antidepressants, psychotherapy, placebo manipulations, and no treatment was calculated.
Kirsch (2010) found significant improvement for patients receiving either drugs or psychotherapy, but there was also improvement for those receiving placebos. The difference between the placebo groups and the no treatment groups was significant, so that no treatment groups reported significantly lower levels of symptom reduction. The significant health improvement in participants who received the placebo clearly demonstrates the placebo's strong effects on wellbeing.
Another surprising feature was found when Kirsch (2010) reexamined the data and looked more specifically at the drug types that had been used in the tests. As Kirsch (2010, p. 12) writes: “In fact, the data was remarkably consistent-much more so than is usually the case when one analyzes different groups of data. Not only did all these medications produce the same degree of improvement in depression, but also, in each case, only 25 percent of the improvement was due to the drug.” This is surprising considering the evolution of antidepressants from MAOIs to the more complex and specific SSRIs. Kirsch (2010) concludes that the newer antidepressants are no more effective than the older medications.
An important speculation that Kirsch (2010) made was that the relatively small difference between drugs and placebos might not be a real drug effect. Rather, it might be an enhanced placebo effect from patients breaking blind and realizing whether they were given a drug or placebo. (Kirsch, 2010, p. 12) In addition, Kirsch (2010) found that the more side effects a patient experiences on the active antidepressants, the more they improve. Kirsch (2010) suggests that side effects bring the antidepressant into the patient's awareness so expectations for improvement are salient. He also proposes that consciously experiencing an antidepressant's unwanted effects creates the expectation that the antidepressant is influencing depression; therefore, the placebo effect was likely to occur. These results are significant to debunking antidepressants because the placebo effect, characterized by hope and positive outlook, is evident in patients notorious for feeling helpless in pessimistic. Kirsch (2010) delved deeper into placebo research as he examined studies that used active placebos. An active placebo is a drug that does not affect the diagnosed illness but still has side effects (Kirsh, 2010,). For most of the depression trials with active placebos, Atropine was used as the active placebo. Atropine is used for the treatment of gastric dysfunctions and has several side effects. Even though its side effects are far less significant than those of antidepressants, it still prevents patients from breaking blind. Kirsch (2010) found that in studies when the use of active placebo occurred, the drug-placebo differences in improvement were not statistically significant. The drug’s side effects provide patients with the experience of side effects, although they are far less significant than those of antidepressants. For future research in this field, participants should be told that are placed in the condition in which they will be receiving a drug for an unrelated issue. Therefore the participants would have no expectations for depression reduction. Thus the experimenters could conclude the degree to which positive expectations play a role in antidepressant effectiveness.
A form of research that displays the lack of positive expectations is antidepressant testing in animals. Two methods of this testing are the Posolt swim test and tail suspension test. In the Porsolt test, a rat is placed in a narrow cylinder from which it cannot escape and is forced to swim. This process induces the rat into a depressed-like state, characterized by immobility (Porsolt, Bertin & Jalfre, 1977). The rat then is given an antidepressant and 24 hour later undergoes a second trial in the cylinder. The rats that receive antidepressants displayed reduced immobility compared to no treatment control groups or rats that received tranquilizers (Porsolt, Bertin & Jalfre, 1977). These results are significant due to the subjects lack of positive expectations, but there are flaws. This test merely measures a physical change in a rodent and does not measure emotional change or serotonin levels in human participants. Another test of antidepressant effectiveness is the tail suspension test. A mouse is suspended by the tail from a lever and the movements of the mouse are recorded (Steru, Chermat, Thierry & Simon, 1985). The initial six minute test is divided into periods of agitation and immobility. The mice are then divided into control and psychotic drug groups. The mice who receive the antidepressants, show a decreased in their duration of immobility. This test has similar significance and flaws as the Porsolt swim test. These tests provide context and backing for the use of antidepressants but do not disprove Kirsch’s claims.
Kirsch helped develop the movement against antidepressants, which has now pervaded the psychotherapeutic community. I saw this firsthand when I sat down with Geoffrey Cohane, a private practice psychologist who also works at McLean Hospital in Belmont. Cohane, who has been practicing for several years, attended Williams College and earned his Ph.D. in clinical psychology at Clark University. Cohane emphasized when discussing antidepressants that “Personally, I would like to see that they are effective because then that is another tool for me when doing counseling” (G.Cohane, personal communication, January, 10, 2011). It was clear though, that Cohane had become wary of antidepressants and said that “they are over prescribed in some regions of the country” (G.Cohane, personal communication, January, 10, 2011). Charles Barber argues that this overprescription cannot be attributed to an improvement in the quality of antidepressant drugs, but rather a change in the cultural environment of the United States. In the past twenty years in the media there has been a more positive and prevalent portrayal of mental disorders and psychiatry (Barber, 2008). This shift has created an environment in which an individual is more likely to think that they are mentally ill. In a study done by the world health organization in 2004, 26% of Americans reported that they suffered from a psychiatric illness in the previous year. This percentage was the largest percentage of the fifteen countries in the survey (Barber, 2008). This rise in belief of mental illness and the emergence of massive pharmaceutical companies, has created the overprescription Cohane described. It was also apparent that he was knowledgeable about the problems that Kirsch was suggesting. Cohane said, “There is the file drawer effect... Researchers are more likely to publish work that backs their hypothesis. So if data doesn’t back their work, many researchers won’t publish data and put it in their file drawer. Thus, only a fraction of the data is out there and the data gets skewed” (G.Cohane, personal communication, January, 10, 2011). Cohane mentioned that several recent articles had demonstrated the lack of effectiveness of big name antidepressants.
Fournier et al. (2010) performed a meta-analysis, in order “To estimate the relative benefit of medication vs. placebo across a wide range of initial symptom severity in patients diagnosed with depression” (Fournier et al , 2010, p. 47). They drew their data from PubMed, PsycINFO, and the Cochrane Library databases from January 1980 through March 2009. The data included references from meta-analyses and reviews. The authors analyzed studies that used randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder. Studies were included if the authors included a medication vs. placebo comparison for at least 6 weeks, if they did not exclude patients on the basis of a placebo washout period, and if they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included.
Fournier et al. (2010)concluded that, “The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial”(Fournier et al , 2010, p. 48). Thus, their conclusion is distinct from Kirsch’s (2010) conclusion as patients with severe depression showed a decreased placebo effect. This conclusion can be attributed to that these patients are less likely to be optimistic. Therefore they are less likely the show the placebo effect, which is based on hope.
In another study focused on antidepressants versus placebo effectiveness in relation to severity of depression. Barbui, Cipriani, Patel, Ayuso-Mateos, and van Ommeren (2011)did a meta-analysis of the efficacy of antidepressants in patients with minor depression. They drew data from MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane ControlledTrials Register and pharmaceutical company websites. After finding six studies that fit their criteria by performing the proper analysis, they were able to conclude “there is unlikely to be a clinicallyimportant advantage for antidepressants over placebo in individualswith minor depression”(Corrado, et. al, 2011). Once again another study demonstrated the lack of efficacy of antidepressants compared to placebos and most importantly the difference between placebo and drug is only evident when depression is severe. Thus, the placebo effect is a problem in cases of mild to moderate depression, but is not as much a problem in severe depression.
A. Khan, Leventhal, S. Khan, and Brown (2002) did an analysis of severely depressed patients and the efficacy of antidepressants and placebos. They drew their data from the Food and Drug Administration database of 45 phase II and III antidepressant clinical trials. They found that “the frequency of statistically significant differences between antidepressants and placebo was higher in the trials that included patients with more severe depression” (Khan et al., 2002). The higher the patient’s initial score of depression on the Hamiltion Rating Scale of Depression Overall, the greater magnitude of symptom reduction. Thus similar to Fournier et al. (2010), the study displayed that the severity of the depression increases the efficacy of the antidepressant and decreases the placebo effect.
It is evident that the current system of prescribing antidepressants cannot be left as is. The reviewed studies highlight the over prescription of antidepressants. This overprescription can be attributed to the shift in acceptance of mental health, the increase in exposure of mental health and the rise of the pharmaceutical business. Still, antidepressants are frequently required when treating severe forms of depression. Several studies display that the placebo-effect decreases when depression has rooted itself deeply into an individual's neural functioning, positive expectation may not be sufficient in alleviating symptoms. Depression is defined by its feelings of helplessness, and sometimes, feelings of hope are not strong enough to overcome cemented cognitive patterns of helplessness. Beck’s cognitive triad states that the self, world and future of a depressed patient are overcome by feelings of hopelessness and helplessness (Beck,1979). Thus in the cases of the severely depressed, hope may have never been present in the first place. Future research needs to be dedicated to the replacement of antidepressants with placebos in patients experiencing less severe forms of depression. If studies continue to find symptom reduction in non-severely depressed patients with the use of placebos, there could be great implications for antidepressants. The credibility of antidepressants could suffer and the number of prescriptions should be scaled down from the current enormous number.
References
Barber, C. (2008). Comfortably Numb: How Psychiatry Is Medicating a Nation (1st ed.). Pantheon.
Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J. L., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: Systematic review and meta-analysis. The British Journal of Psychiatry, 198(1), 11 -16. doi:10.1192/bjp.bp.109.076448
Beck, A. T. (1979). Cognitive therapy of depression. Guilford Press.
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity. JAMA: The Journal of the American Medical Association, 303(1), 47 -53. doi:10.1001/jama.2009.1943
Khan, A., Leventhal, R. M., Khan, S. R., & Brown, W. A. (2002). Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. Journal of Clinical Psychopharmacology, 22(1), 40-45.
Kirsch, I., & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment, 1(2). doi:10.1037/1522-3736.1.1.12a
Ph.D., I. K. (2010). The Emperor’s New Drugs: Exploding the Antidepressant Myth (1st ed.). Basic Books.
RD, P., A, B., & M, J. (n.d.). Behavioral despair in mice: a primary screening test for antidepressants. Archives internationales de pharmacodynamie et de therapie, 229(2), 327.
Seligman, M. E. P. (1992). Helplessness: on depression, development, and death. W. H. Freeman.
Steru, L., Chermat, R., Thierry, B., & Simon, P. (1985). The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology, 85(3), 367-370. doi:10.1007/BF00428203