On February 19, 2012, Lesley Stahl’s “Treating depression: is there a placebo effect?” aired on CBS 60 Minutes. Stahl is to be commended for doing an excellent job. During the broadcast, Stahl interviewed Irving Kirsch, Michael Brown, and Michael Thase as well as providing information on new government policies in the UK on treating persons experiencing mild and moderate levels of depression.
During the program, Irving Kirsch provided the bottom line finding from his analyses of FDA data documenting that antidepressants are not effective in treating persons scoring in the mild and moderate ranges of depression. Kirsch indicated that antidepressants are effective for persons scoring in the severe ranges of depression. What Kirsch could have said, which he said in his book, is that even for the severe depressed, there is only a 4 point (out of 51) difference between the placebo and the drug treated. Moreover, comparing those who are mildly depressed with those scoring in the severe range, the same level of improvement occurs for the mildly depressed and those scoring in the severely depressed range. The reason for the finding of better performance for the drug in the severely depressed group is that the severely depressed don’t exhibit much change in response to placebo. Ironically, Michael Thase, the exponent for antidepressants, has admitted that, on drugs, only 47% are in remission. By the way, the program could have discussed spontaneous remission, but did not. Even the severely depressed do recover. Before drugs, the average duration of an episode of depression was 6 months. Over a two year period, 80% of persons on drugs or without drugs will recover.
In the broadcast, the focus of the discussion was on the short term outcomes from the studies evaluating treatment for eight weeks. The outcomes for drugs appear even worse if one examines long term. For example in a study by Maj et al (1992), during a five-year follow-up 72 persons with 76.3% remaining on drug, 75% have relapsed. In a meta-analysis, Williams et al. (2009) reported that for those who fully recover on drug and remain on drug, 45% will relapse during a three year period. Fava and Offindani (2011) and Andrews et al. (2011) have compared relapse rates among those on drug versus those not on drugs. Those on drugs have higher rates of relapse.
Lesley Stahl correctly cautioned that people should not discontinue taking their drugs abruptly. Stahl did not detail the very dramatic drug withdrawal effects. In his book, Kirsch indicates that 20% of persons experience withdrawal symptoms when drugs are discontinued. In fact, in 1994, I argued that the very high rates of depression relapse (around 75% of persons randomized to placebo maintenance) within the 6 months after switch to placebo probably reflects drug withdrawal. The withdrawal symptoms noted in the literature include mania, motor problems in the jaw, nausea, abdominal cramping, headaches, sleep disruption, blurred vision, numbness, twitches and tremors. What is even more disturbing, although Stahl advises supervision from the doctor during withdrawal, request for assistance in drug discontinuation will find the doctor unprepared. There is a literature on how to detox from heroin, alcohol, benzodiazepines. Similar literatures are unavailable for detox from antidepressants.
There was reference to the side effects in the program, but no specification of what the side effects entail. Side effects are not trivial. Most people are aware of the diminished libido and sexual dysfunction associated with antidepressant drugs. They may not be aware of the association with suicidal ideation, for which there is a black box warning for young people and children. Long term, people lose the ability to respond emotionally both to positive and negative stimuli. (This has been verified with brain imagery.) SSRIs are associated with bone loss. (Cells in bone express the protein on which Prozac operates). SSRIs are associated with bleeding problems. (Platelets also express the protein on which Prozac operates.) SSRIs are associated with weight gain, metabolic syndrome, loss of vagal tone, an increase in inflammatory markers, and an increased risk for diabetes.
Stahl did report that the British health system is training more psychotherapists. In the studies evaluating drugs, many have included a psychotherapy control group. Psychotherapy consistently proves as effective as drugs, although drugs sometimes achieve remission more rapidly by several weeks. Moreover, persons treated with psychotherapy, in various studies, are less likely to relapse than those treated and continued on drug. As Kirsch argues in his book, psychotherapy is more cost effective as well.
Stahl also reported that the British are encouraging exercise, which has shown to be effective in preventing and treating depression. While the 15 minute segment was insufficient time to detail other alternatives, there is an emerging literature on dietary interventions (curcumin, omega-3s, Mediterranean diet) that prevent and ameliorate depression. Dietary interventions and exercise, unlike antidepressants which increases risk for diabetes and heart disease, will prevent heart disease and diabetes.
Hopefully America can learn from the British. As Americans move into universal health care coverage, we need to learn from those across the pond how to do it better and more cheaply.
Annotated Bibliography on Outcomes for Treated and Untreated
Andrews, P. W., Kornstein, S. G., Halberstadt, L. J., Gardner, C. O., & Neale, M. C. (2011). Blue again; perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression. Frontiers in Psychology, 2, Article 159, 1-24. Analysis suggests greater relapse in those being treated with antidepressants
Beck, A. T. (1967). Depression: Causes and treatment. Philadelphia: University of Pennsylvania Press. Comments that in the more refined studies estimate is episode of untreated depression lasts about 6-8 months p. 51
Fava, G. A. (2003). Can long-term treatment with antidepressant drugs worsen the course of depression? Journal of Clinical Psychiatry, 64, 123-133. Fava reviewed literature on the increased frequency of episodes and shorter remission periods reported in the new literature compared to older literature. He reviewed studies finding emergence of depressive symptoms in groups who were treated with SSRIs for conditions such as panic disorder but were not depressed. He also reviewed the literature considering the precipitation of mania in individuals taking an antidepressant. He advanced the hypothesis that antidepressants may impair whatever switch mechanism the body has for maintaining equilibrium. He also considered the possibility that people may just become tolerant to antidepressants, which might be a permanent condition. He acknowledged the similarity of his hypothesis to the possibility introduced earlier (1989) by Fredrick Goodwin that drugs will accelerate a natural cycle of mood fluctuation.
Fava, G. A. (2003). Can long-term treatment with antidepressant drugs worsen the course of depression? J Clin Psychiatry, 64(2), 123-133. Speculates on reasons for worse relapse on drugs
Fava, G. A., & Offidani, E. (2011). The mechanisms of tolerance in antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry. doi: S0278-5846(10)00292-7 [pii] speculates on why high relapse rates on medications
Gueorguieva, R., Mallinckrodt, C., & Krystal, J. H. (2011). Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressants and placebo responses. Archives of General Psychiatry, 66 (12), 1227-1237. This study identified the curves in depression scores in those treated with placebo and drug over the 8 weeks of the trial. Both the placebo and drug responders showed a decrease in symptoms of depression over time. (About 76.3% of those receiving drug were responders). However, for the 23.7% of those on drug who were non-responders, the trajectories was either flat or with a positive slope. The authors questioned whether there is subgroup of depressed persons who are worse off on drug.
Kirsch, I. (2010). The emperor’s new drugs: exploding the antidepressant myth. New York: Basic Books.
Klein, D. F., Gittelman, R., Quitkin, F., & Rifkin, A. (1980). Diagnosis and drug treatment of psychiatric disorders: adults and children (2nd ed.) Baltimore: Williams and Wilkins. See page 410-says 8 months average duration of untreated depression
Lehmann, H. E. (1983). Clinical evaluation and natural course of depression. Journal of Clinical Psychiatry, 44, 5-10. Summary statement: “Without antidepressant therapy, episodes of clinical depression last from 2 months to several years, with average around 5 to 6 months. One-third of the patients recover within a year; probably one out of four untreated episodes last more than 2 years. Depressive episodes occur, on the average, every 2 to 3 years.”
Posternak, M.A., Solomon, D. A., Leon, A. C., Shea, M. T., Endicott, J., & Keller, M. B. (2006). The naturalistic course of unipolar depression in the absence of somatic therapy. Journal of Nervous and Mental Disorders, 194 (5), 324-329. Median time to recovery was 13 months for those who did not seek treatment; was 6 months for those who sought treatment
Spijker, J., De Graaf, R., Bijl, R. V., Beekman, A. T. F., Ormel, J., & Nolen, W. A. (2002). Duration of major depressive episodes in the general population: results from The Netherlands Mental Health Survey and Incidence Study. British Journal of Psychiatry, 181, 208-213. 20% of the subjects had not recovered after 24 months-level of treatment did not alter result.
Thase, M. E., Haight, B. R., Richard, N., Rockett, C. B., Mitton, M., Modell, J. G., VanMeter, S., Harriett, A.E., & Wang, Y. (2005). Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. Journal of Clinical Psychiatry, 66 (8), 974-981. After 8 weeks for all but one study which followed for 16 weeks, response rates across drugs range from 62% to 63% and for remission 47%, which is better than placebo with 51% response and 36% remission. Authors estimate that placebo effect may account for 75% of the efficacy in response to an antidepressant drug.
Williams, N., Sampson, A. N., Simpson, K., & Nahas, Z. (2009). Relapse rates with long term-antidepressant drug therapy: a meta-analysis. Human Psychopharmacology, 24, 401-408. Continuation on antidepressant, risk of relapse is 23% in one year, 34% in two years; 45% in 3 years
Zis, A. P., & Goodwin, F. K. (1979). Major affective disorder as a recurrent illness. Archives of General Psychiatry, 36, 835-639. A literature of studies before drug therapy. Those who never experience a second episode: Kraepelin 60%; Pollock 57%; Rennie, 21%, Lundquist, 66%, Stenstedt, 62%
Annotated Bibliography on withdrawal symptoms
Ceccherini-Nelli, A., Bardelllini, L., Cur, A., Guazzelli, M., Maggini, C., & Dilsaver, S. C. (1993). Anti-depressant withdrawal: prospective findings. American Journal of Psychiatry, 150, 165. Examined 10 individuals withdrawn from various antidepressants. Seven exhibited withdrawal symptoms which included cardiac arrhythmia, resting tremor of the jaw, tongue, and upper extremities, insomnia, chills, sweating, nausea, headache.
Haddad, P. (1997). New antidepressants and the discontinuation syndrome. Journal of Clinical Psychiatry, 58, Supplement 7, 17-21. Indicates that patients need to be on SSRIs for 8 weeks before a discontinuation syndrome will be observed; indicates that 20-86% of sample report symptoms; symptoms include dizziness, nausea, lethargy, headache, anxiety, tingling and burning sensations, confusion, tremor, sweating, insomnia, irritability, memory problems, anorexia
Lejoyeux, M., & Adés, J. (1997). Antidepressant discontinuation: a review of the literature. Journal of Clinical Psychiatry, 58 (Supplement 7), 11-15. Mentions: gastrointestinal distress, arrhythmias, anxiety, sleep disturbance, movement disorder, panic attacks, mania or hypomania, delirium, mood changes, dizziness, sensations of tingling and burning in limbs
Littrell, J. (1994). Relationship between time since reuptake-blocker antidepressant discontinuation and relapse. Experimental and Clinical Psychopharmacology, 2 (1), 82-94. This article analyzed results from 11 studies in which persons who had fully recovered from an episode of major depression had their medication discontinued. All studies found high rates of relapse (57% to 100%) within the six months following drug discontinuation. The paper argues that the high relapse rates represented drug withdrawal rather than a reemergence of major depression.
McGrath, P. J., Stewart, J. W., Tricamo, E., Nunes, E. N., & Quitkin, F. M. (1993). Paradoxical mood shifts to euthytmia or hypomania upon withdrawal of antidepressant agents. Journal of Clinical Psychopharmacology, 13(3), 224-225. Report emergence of mania/hypomania in 2% following antidepressant withdrawal in persons without a history of mania/hypomania.
Stoukides, J.A., & Stoukides, C. A. (1991). Extrapyramidal symptoms upon discontinuation of fluoxetine. American Journal of Psychiatry, 148, 1263. Report of man who had taken Prozac for 6 months, upon discontinuation was experiencing muscle spasms and exhibiting protruding tongue movements
Annotated Bibliography on Drug Side Effects
Andersohn, F., Schade, R., Suissa, S., & Garbe, E. (2009). Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. American Journal of Psychiatry, 166(5), 591-598. Increase in diabetes
Bliziotes, M. (2010). Update on serotonin and bone. Journal of Clinical Endocrinology and Metabolism, 95 (9), 2124-4132. Recognizes that there are serotonin transporter on the membranes of cells involved in bone turn over. Indicates that SSRIs are associated with decreased bone mass, increased bone loss, and increased fractures.
Csoka, A. B., Bahrick, A., Mehtonen, O. P. (2008). Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. Journal of Sexual Medicine, 5 (1), 227-233. Discusses case reports of persons experiencing persistent genital anesthesia, loss of libido, and erectile dysfunction following discontinuation of an SSRI.
Fava, M. (2000). Weight gain and antidepressants. Journal of Clinical Psychiatry, 61 (Suppl. 11), 37-41.
Hamer, M., Batty, G. D., Marmot, M. G., Singh-Manoux, A., & Kivimaki, M. (2011). Anti-depressant medication use and C-reactive protein: results from two population-based studies. Brain, Behavior, and Immunity, 25(1), 168-173. Higher C-reactive protein, risk factor for cardiovascular disease
See Kawail, M., & Rosen, C. J. (2010). Minireview: a skeleton in serotonin’s closet? Endocrinology, 151(9), 4103-4108. Contains list of studies finding bone loss with SSRIs
Kivimaki, M., Hamer, M., Batty, G. D., Geddes, J. R., Tabak, A. G., Pentti, J., et al. (2010). Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care, 33(12), 2611-2616. Both weight gain and diabetes increase
Laje, G., Paddock, S., Manji, H., Rush, A. J., Wilson, A. F., Charney, D., & McMahon, F. J. (2007). Genetic marker of suicidal ideation emerging during citalopram treatment of major depression. American Journal of Psychiatry, 164, 1530-1538. 6% (120/1862) of their sample developed suicidal ideation early in treatment. Laje et al. were able to identify alleles for genes associated with the emergence of suicidal ideation
Licht, C. M., de Geus, E. J., Zitman, F. G., Hoogendijk, W. J., van Dyck, R., & Penninx, B. W. (2008). Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Archives of General Psychiatry, 65(12), 1358-1367.
Loke, Y. K., Trivedi, A. N., Singh, S. (2008). Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Alimentary Pharmacology & Therapeutics, 27, 31-40. A meta-analysis finding that SSRIs doubles risk for upper gastrointestinal haemorrhage and when combined with aspirin raises risk to 500%. It should be recognized that there are serotonin transporters on platelets and thus SSRI use can be expected to affect blood clotting.
McCabe, C.,Mishor, Z., Cowen, P. J., & Harmer, C. J. (2010). Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biological Psychiatry, 67 (5), 439-445. Cites anecdotal reports of emotional numbing to aversive and positive experiences in people taking SSRIs. Conducted functional MRI observing the response to positive and negative stimuli in areas of the brain that are known to be activated by emotional stimuli. Healthy individuals who had taken citalopram for 7 days were less responsive to both positive and negative stimuli.
Moore, T. J., Glenmullen, J., & Furberg, C. D. (2010). Prescription drugs associated with reports of violence towards others. PloS ONE, 5 (12), ep. 15337. Analyzes the relative risk of increase in report in violence among those taking various drugs. Risk is elevated for those taking antidepressants and chantix for nicotine withdrawal.
Raeder, M. B., Bjelland, I., Emil Vollset, S., & Steen, V. M. (2006). Obesity, dyslipidemia, and diabetes with selective serotonin reuptake inhibitors: the Hordaland Health Study. Journal of Clinical Psychiatry, 67(12), 1974-1982.
Rosen, R. C., Lane, R. M., & Menza, M. (1999). Effects of SSRIs on sexual function: a critical review. Journal of Clinical Psychopharmacology, 19 (1), 67-85. Reports that as much as 80% may experience sexual dysfunction when taking SSRIs. Symptoms include anorgasmia, erectile dysfunction, diminished libido, and genital anesthesia.
Rubin, R. R., Ma, Y., Peyrot, M., Marrero, D. G., Price, D.W., Barrett-Connor, E., Knowler, W. C. (2010). Antidepressant medicine use and risk of developing diabetes during the diabetes prevention program and diabetes prevention program outcome study. Diabetes Care, 33 (12), 2549-2551. SSRIs doubled the risk of development of Type II diabetes unless an individual was also taking metformin (a drug used to treat diabetes)
Serebruany, V. L., (2006). Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? American Journal of Medicine, 119 (2), 113-116. Indicates there are 120 cited peer reviewed articles documenting risk of platelet malfunction in persons on SSRIs.
Shah, A. (2011). Antidepressant use linked to thicker arteries. Emory University. Atlanta, GA. Retrieved 12/12/11 from http:shared.web.emory.edu/whsc/news/release/2011/04/antidepressants-linked-to-thicker-arteries.html.