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I. Depression Prevalence: Start of Psychotropic Medication Era.

The Epidemiology of Depression, by Charlotte Silverman. Published in 1968. Silverman was chief of epidemiology studies at the NIMH[1], and reported that in the 1940s, less than one per 1,000 was the rate of clinical depression.  Depression is basically a disorder for people 35 and older and statistically the prevalence was uncommon for child-- not reported.

II. Natural Outcomes and Rates.

1.  Researchers at the NYS Department of Mental Hygiene looked at 8,000 “manic-Depressives” admitted to a hospital between 1909 and 1920, whereby they separated out those who had been admitted only for depression.  They found more than 50% had a single episode, another 30% had two or three episodes, and only 17% became chronically ill.[2]

2.  Researcher Rennie reports a 95% recovery rate in those with depression alone, and a median duration of six months. [3]

3.  In a study of 216 first admission “depressives”, the researcher found that half were well within six months, and 75% within 10 months. Further, of those who got well, 60% to 70% never had another episode over the next  20 years.[4]

The Conclusions by NIMH officials and other Leading Figures:

George Winokur, a professor of psychiatry at Washington University, writes in his 1969 book, Manic-Depressive Illness: “In general, assurances can be given to a patient and to his family that subsequent episodes of illness after a first mania or even a first depression will not tend toward a more chronic course.”

Dean Schuyler, who was coordinator of the depressions section at the NIMH in 1974, wrote in this book The Depressive Spectrum: “Most depressive states are self-limiting, that is they will run their course and terminate with virtually complete recovery without specific intervention.”

Paul Wender and Donald Klein, who were leaders in Biological Psychiatry, said in their 1981 book, Mind, Mood and Medicine: “Vital depressive reactions tend to be self-limited, that is they tend to disappear in time.”

III. The Case for Antidepressants

Now with this understanding of depression, that it generally cleared up on its own, and once it did, the majority of people would not have a second episode, the thought was that antidepressants could simply speed up the process. They could get the symptoms to remit faster.

A. The Case for Short-Term Efficacy:

1) First NIMH Study Trials:

a) The Medical Research Council, Britain’s equivalent of the NIMH, studies an MAOI and a tricyclic anti-depressant and found that the tricyclic was modestly superior to placebo, while the MAOI treatment “has been singularly unsuccessful”, as it did not beat placebo (a sugar pill).[5]

b) Then in 1969, the NIMH conducted a review of studies of antidepressant drugs. It concluded the poorer the design, the greater the benefit for the drug. The better the trial design, the lower the rate of improvement for drug-treated patients and the higher the rate of improvement for placebo patients. In well-controlled studies, 61% of drug-treated patients improved (usually in a six week period), versus 46% of drug treated patients.[6]

Thus, a 15% edge, which the NIMH concluded:

“The differences between the effectiveness of antidepressant drugs and placebo are not impressive.”

This led Charlotte Silverman, at the NIMH to confess in 1968:
 “Psychotropic drugs have not yet proved to be very helpful in depression.”[7]

c) This lead NIMH researchers to form a second collaborative depression study of a subgroup of hospitalized depressed patients, comparing them again to a placebo.  By end of study, differences favoring imipramine over placebo were not apparent. However, by excluding black patients who had done poorly, they were able to report that there was a small benefit for the drug.[8]

d) Antidepressant versus Active Placebo: This poor difference cited above led some researchers to think the drugs were not really antidepressants at all, but rather “placebo amplifiers.”[9] The thought was that the drugs provoked physical sensations—sedation, stimulant—that reinforced the patients’ belief that they were getting a magic bullet for the disorder, and that belief was what made the antidepressant slightly better than the placebo.  

So a New England psychologist, Richard Thompson, decided to look at all the trials he could find that had used an active placebo. This is a biological agent not meant to be an antidepressant, but may cause something like dry mouth.  He found seven studies, and he found the drug was superior to placebo in only one of the seven. So no better than an active placebo.[10]

2)  The Second NIMH Trial.

The above research was followed by a second trial, called the NIMH Collaborative Research Program, and had four arms: Interpersonal therapy, cognitive behavior therapy, a tricyclic, and placebo.[11]   Now, after 16 weeks:

 “There were no significant differences among treatments, include placebo, for the less severely depressed and functionally impaired patients.” Only the severely depressed patients fared better on imipramine than on placebo.”

3)  The SSRI Story

 The SSRI Drug Trials. Kirsch, “Initial Severity and Antidepressant Benefits: A meta-analysis of data submitted to the food and drug administration. PLOS Medicine, February 2008, Volume 5, issue 2, 260-268.

This group of researchers, using freedom of information requests, obtained data on all clinical trials submitted to the U.S. FDA for the six most widely prescribed SSRIs from 1987 to 1999. There were 47 trials in all they analyzed. Only 20 of 47 showed any measurable advantage for the drug; in the other 27, either they were the same or better for placebo. When they grouped all patients together, they found on average patients on drugs improved 10 points on the Hamilton scale, and placebo patients slightly more than 8 points. The difference was 1.8 points, and the British health agency had recently decreed that anything less than 3 points was clinically irrelevant. They concluded:

“Recent meta-analysis shows SSRIs have no clinically meaningful advantage over placebo.”

The only group they found any benefit for was the “most severely depressed patients.”

“There is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients.”

B. The Case For Maintenance Therapy

Now, given that the initial conception of depression was that people got better anyway, and that drugs were simply to speed up the recovery process, there wasn’t the idea that you should stay on the drugs. So really, no case for maintenance therapy arose for years.

IV. The Case Against Antidepressants

A. Long-term Outcomes: the chronicity data

Now since nearly everyone was thought to get better in depression, little thought at first about improving long-term outcomes. Most people recovered and returned to complete pre-morbid functioning.

1. 1968. DiMascio. Effects of imipramine on individuals varying in level of depression. AJP 1968, 127 (sup):55-58.

The first hint that exposure to antidepressants might make patients more chronically ill came in 1968, with a research report that first use of a tricyclic in patients who had only slightly ill subsequently had an increase in depression levels.

2. 1973, Van Scheyen, Recurrent vial depressions. Pscyiatric Neurol Neurochir, Mar-Apr, 76 (2):93-112.

Next, a researcher did a naturalistic follow-up study of patients treated either with an antidepressant or no drug. He found that treatment with a tricyclic antidepressants was associated with an increased number of recurrences. In other words, the depression was more likely to come back. He wondered:

"Whether such an increased number of depressive phases would not be regarded as a side effect or a paradoxical effect which, after protracted therapy, is produced by the tricyclic antidepressants so far most commonly used.”

3. 1981. Kovacs, Depressed outpatients treated with cognitive therapy or pharmacotherapy. A one-year follow-up. Jan, 38 (1):33-39.

No placebo group, but there is a finding that after one year, those treated with drugs were more symptomatic and twice as many had relapsed than those treated with cognitive behavior therapy.

4. 1986. Blackburn, A Two-year naturalistic follow-up of depressed patients treated with cognitive therapy, pharmacotherapy, or both. Journal of affective disorders 10 (1986), 67-75.

This is a UK study of 40 or so patients. At end of two years, we had these results:

44% of drug-treated group were depressed
8% of cognitive therapy group were depressed

In the drug group, 78% had suffered at least one relapse in the two-year follow-up, versus 23% of cognitive therapy group. So relapse is three times as high.

5. BIG NIMH trial. Shea, Course of depressive symptoms over follow-up; findings from the National Institute of  Mental Health Treatment of Depression collaborative research program. Archives of General Psychiatry. 1992;49:782-787.

This is the follow-up to the study to the one that found no short-term benefits except for the severely ill. The follow-up findings were even more worrying:

                                                18-month relapse rates for           Recovered and well at
                                                those recovered at 8 weeks          18 months (all patients)
Cognitive behavior                              36%                                                     30%
Interpersonal therapy                          33%                                                     26%
Placebo                                               33%                                                     20%
Imipramine                                          50%                                                     19%

So we see here a substantial increase in relapse rates for the drug treated patients, and stay well rates are lowest for the drug group.

Key was also social functioning. When you looked at all patients in the aggregate, social functioning was found to be “superior in the interpersonal” group than to either CBT or drug. But it wasn’t superior to the placebo group.

Researchers from the State University of New York revisited the data by looking at drop outs. They concluded that if you add this group into your data: 

“Patients receiving a antidepressant were the most likely to see treatment following termination, highest probability of relapse and exhibited the fewest weeks of reduced or minimal symptoms during the follow-up period.”

6. 1993, Frank, Efficacy of Treatments for Major Depression. Psychopharmacology Bulletin, vol. 29, 4, 457-475.

These are researchers at University of Pittsburgh. This is a review of the literature. They wrote:
            “The number of studies that have looked at the efficacy of drug therapy on the long-term wellness of the                      patient with major depressive disorder is limited. The data available are, in general, not very positive.”

The problem was that this form of care just wasn’t producing good long-term outcomes. Only about 50% of patients initially responded to the drug, and then even among the good responders, long-term outcomes weren’t good. That’s what the NIMH trial had showed, and in this review, they found other studies that showed the same thing.

Two other studies reviewed by Frank:
            * In one trial, only 48% of the good responders, when maintained on the drugs for two years, stayed well.
            * In another, only 32% remained well.

The Problem:  Even the good responders kept on the drugs were descending into second and third episodes, and it was even worse for drug-treated patients who were then withdrawn from the drugs, which was the recommended form of care. So staying on drugs ended up in recurrent illness, and going on drugs and then withdrawing seem to end up in recurrent illness as well.

Researchers were faced with the questions of: why did it used to be that people got well and many stayed well; and why had the course of the illness changed?

7. The Star*D trial.
Rush, Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A star*D report. Am. J. Psychiatry (2006): 163:11: 1905-1916.

Finally, the NIMH in the late 1990s mounted a new trial to study the outcomes of drug-treated outpatients. Here they are:

            3,671 patients entered into the trial.
            36.8 percent saw their symptoms remit in first three months.
            Of those who remitted, 50% relapsed within 12 months.
            At end of year, only 18% who initially remitted and stayed well.
            If included study drop-outs, only about 11% of beginning group and stayed well.
They then kept trying those who didn’t remit on a new regimen, and in that way got many initial non-responders to remit. But each step ends up with fewer and fewer patients.

Editorial, Star*D: What Have We Learned. Am. J. Psychiatry, (2007): 164:2:201-203.
In an editorial titled “What Have We learned,” the study investigators concluded:
     “This highly representative clinical sample of depressed outpatients has revealed that major depression is often           chronic, severe and associated with substantial general and psychiatric comorbidity.”

B. Fava Raises the Worsening the Course Question

1. 1994. Fava. Do Antidepressant and anti-anxiety drugs increase chronicity in affective disorders?” Psychotherapy and Psychosomatics 61 (1994):125-31.

 He writes:
“Within the field of psychopharmacology, practitioners have been cautious, if not fearful, of opening a debate on whether the treatment is more damaging than the cure . . . I wonder if the time has come for debating and initiating research into the likelihood that psychotropic drugs actually worsen, at least in some cases, the progression of the illness which they are supposed to treat.”

“Do antidepressants drug sensitize (the brain) to depression.”  While they may provide some benefit over the short term, he worried that “long-term use of antidepressants may also increase the biochemical vulnerability to depression.”

2. American Response. This was reported in Psychiatric News, May 20, 1994.

A trio of American doctors told him to knock it off. They said: “The industry is not interested, the NIMH is not interested, and the FDA is not interested. Nobody is interested.”

3. 1995, FAVA, Holding On: Depression, sensitization by antidepressant drugs, and the prodigal experts.” Psychotherapy and psychosomatics, 63:137-141.

He now steps forward with a biological explanation.

“Drug treatment may recruit processes that oppose the initial acute effects of a drug or of receptor alterations. When drug treatment ends, these processes may operate unopposed, at least for a time.”

This is the reason why “abrupt drug removal is associated with a variety of potentially untoward responses.” So you see the problem with drug withdrawal, but at the same time, he noted, there is also a “loss of anti-depressant effect with long-term treatment.”

So if you stay on drugs, not so good, and if you go off, even worse.  Now he raises this question: At some point, can the brain ever renormalize?

Best evidence was that it took at least “several months” may be needed “to reestablish a pre-drug level of neurophysiological and neuropsychological homeostasis.” He noted that with schizophrenia, you get tardive dyskinesia, which is a kind of irreversible brain damaged, and wonders if at some point with antidepressants you get “irreversible receptor modifications” that make you more vulnerable to depression.

4. 1998 paper by Viguera and Baldessarini. Discontinuing antidepressant treatment in major depression. Harvard Review of psychiatry, 1998:5:293-306.

This paper looked at rates of relapse following discontinuation of drugs. And what it found basically proved Fava’s point, and that was that longer you are on drugs, the more the receptor modifications might become irreversible and thus make you prone to chronic illness. As Fava later noted, they had reported that:

            “Whether one treats a depressed patient for three months or three years, it doesn’t not matter when one                      stops the drugs. A statistical trend suggested that the longer the drug treatment, the higher the likelihood of                relapse.”

5. 2003. Fava’s, Can Long-term treatment with antidepressant drugs worsen the course of depression?” Journal of Clinical Psychiatry 64 (2003): 123-133.

Fava run’s through the literature.

a) The literature showed “very unfavorable long-term outcome of major depression treated by pharmacologic means.”
b) the literature showed “tolerance to drugs with maintenance therapy”, and by that he meant the drugs lose their efficacy.
c) The literature showed that once you relapse, you increasingly have trouble finding any drug that works
d) The literature showed that  “withdrawal symptoms” that increased risk of relapse.

As a result, he said, depression was being reconceptualized as “a chronic disease”, and concludes: “At present, it is impossible to know whether antidepressant drugs fail to improve the long-term course of depression or worsen its course.”

 C. Confirming Evidence: What happens to people diagnosed with major never exposed to antidepressants?
Naturalistic Studies

Now how can we answer that question? What it would be good to see is how untreated patients fared over the long-term in naturalistic settings. And the point here is those not getting drugs are not patients who worry about getting placebo, but think they might get better on their own.

So can we go back and find patient pools where you had a lot of patients present with depression, and then some chose to go on drugs at first treatment and others did not, and then we can find which group did better over the long-term. That will give us some sense of how the drug-treated course at first admission compares to the natural outcomes course.

1. Ronalds, The outcome of anxiety and depressive disorders in general practice. British Journal of Psychiatry 1997:17: 427-433.

This is a British study in which the data was extracted from a larger inner-city practice with 13,000 patients. They identified 148 who presented with a first episode of depression and anxiety. 95 with no drugs and 53 with drugs.

Measured on Hamilton score. Now those who didn’t go on drugs, on average, weren’t quite as ill as those on drugs. However, after six months, those not on drugs doing much, much better than those who got treated with drugs. Even the amount of their improvement was much greater: 62% reduction in their Hamilton score, versus 33% for those on drugs.

2. 1998. Goldberg, The effects of detection and treatment on the outcome of major depression in primary care, a naturalistic study in 15 cities. British Journal of General Practice, 48, 1840-1844.

This is a study funded by the World Health Organization. They looked at outcomes in 540 patients, divided into four groups. Three where depression was recognized, and treated either with drugs, sedatives, or no drugs, and then undetected. They hypothesized that those treated with drugs would do best, sedative second best, then detected/no drugs, and undetected/no drugs. They were followed for a year.  Here are the results:

                                    Well                 Cont. Depression     Another Diag. Remained
                                                                                                                     Mentally ill
Antidepressants           31.3%                          51.6%              10.9%              62.5%
Sedatives                     24.5%                          44.9%               14.3%             58.2%
No Drug                       39.5%                          25.2%              24.4                49.6%
Unrecognized              41.7%                          28.3%               20.0%            48.3%

So opposite of what they expected. Key is drug treated individuals did worst, and individuals with no drugs did the best. They conclude:

“The study does not support the view that failure to recognize depression has serious adverse consequences.”

3. 2000. Weel-Baumgarten, “Treatment of depression related to recurrence:10-year follow-up in general practice.” Journal of Clinical Pharmacology and Therapeutics 25, 61-66.

This was a study by Netherlands researchers in which they went back and looked at patients diagnosed with major depression before 1985, and thus when many people weren’t put on drugs. They found 222 patients, with follow-up records going for 10 years.

Here are the results:
                               Number            One episode           Two Episodes            More than two
Initial Drug                  134                  67 (50%)            26 (19%)                    41 (31%)
Initial No Drug               88                  67 (76%)              9 (10%)                    12 (14%)

So this is fascinating. If you look at the no initial drug treatment group, you see that 76% had one episode and that was it. This is the old course of the disorder. Another 9% had only two episodes. Only 14% had three or more episodes and thus began to end up in the chronic category.

Now here drug treatment was much less than in U.S. and overall pretty favorable outcomes. But 31% of those initially treated with antidepressants ended up in the chronic category—the risk was more than doubled.

They concluded gently:
“A diagnosis (of depression) does not necessarily mean a need for treatment. Even when a diagnosis of major depressive disorder has been made, spontaneous recovery should be considered for a number of cases in general practice and watchful waiting could prove worthwhile.”

4. 2003. Dewa. Pattern of antidepressant use and duration of depression-related absence from work. British Journal of Psychiatry (2003): 183, 507-513.

This Canadian study’s premise: it was curious that with the increase in treatments for depression, it was strange that in Canada there was a rise in disability for depression.   They speculated that “under-treatment” was a cause, and therefore conducted a study to see if there was an association between antidepressant use and return to work for those who went on short-term disability for depression. Their hypothesis was that those who got the drugs would be more likely to return to work quickly, and also that fewer would move on to long-term disability.

So they do an observational study using administrative date from three major Canadian financial and insurance sector companies. They have a combined workforce of 63,000 employees. The study period is from 1996 to 1998. After 10 days of missing work in a row for an illness, can go on short-term disability. If not better in sick months, go on long-term disability.

The results for the 1,281 people who went on short-term disability:
                        Number       Returned           Long-term           Quit/retired
                                              to Work            Disability          Fired
Non-drug         565              471 (83.4%)        52 (9.2%)         41 (7.3%)
Drug                717              524  (73%)         136 (19.0%)      56 (7.8%)

In terms of time they spent on short-term disability, it was 77.3 days on average for he non-drug group, and 104.7% for the drug group.  They wrote:

 “Those who did not use antidepressants returned to work sooner than those who did . . . Does the lack of antidepressant use reflect a resistance to adopting a sick role and consequently a more rapid return to work?”

2004. Patten. The Impact of antidepressant treatment on population Health. Population Health Metrics, 2004, 2:9. 

This is an epidemiological study drawn from two longitudinal health studies done by the government of Canada. One is called the National Population Health Survey and the other is the Canadian Community Health survey. These two studies collected data from 1994 to 2000.

The studies drew on health records of 130,000 people including 9508 that were diagnosed with depression.  The results:


Those off drugs spent on average (the median) 10.8 weeks depressed each year. Those on drugs spent on average 18.7 weeks depressed each year.

Relapse rates in remitters:
In addition, if you looked at people who were symptom free for a year, who then developed major depression in the following year, it was 11.1 percent relapse rates for those who were on drugs, and 3.5% for those off drugs.

Bottom line:
Nearly twice as symptomatic, and for those who got well for a year, a three times higher relapse rate.

They note that their findings are consistent with Fava’s hypothesis that “antidepressant treatment may lead to a deterioration in the long-term course of mood disorders. This hypothesis, although not widely accepted, predicts that episode duration and incidence would be higher in those reporting antidepressant use than in those not using these medications.”  They concluded:  “that future research is needed to address the lack of epidemiological evidence confirming the population-health benefits of increased antidepressant treatment.”

D. National Disability Data

We noticed in the Canadian study on returning to work that the researchers had spoken about the increased number of people disabled in Canada due to depression. So now let’s see if we see it in other countries as well.

1. 2000. Moncrieff, Trends in sickness benefits in Great Britain and the contribution of mental disorders. Journal of Public Health medicine, 22, 1, 59-67.

From 1984 to 1995, there was a 244% increase in disability due to mental disorders. And the big one is depression and neurotic conditions. They went up from a total of 40 million days of incapacity to 120 million days of incapacity. Three fold increase as Prozac came in.

2. 2004. Helgason. Antidepressants and pubic health in Iceland. British Journal of Psychiatry, 184, 157-162.

They raise the question: Has (extensive use of antidepressants) had any impact on public health and the burden of depression?

Study. Iceland has population of 286,000. They looked at number of prescriptions of SSRIs, outpatient visits, and admissions to psychiatric departments for period of 1989-2000. Antidepressant use in Iceland begins with Prozac in 1988.

The number of patients admitted to psychiatric facilities increased 3.9% annually.
The total number of admissions (some patients coming back more frequently) increased 5.4% per year.
The number of out-patient consultations increased 2% per year.
The percentage of the population disabled by depressive disorders rose from .4% to .7%. (1/250 to 1/143.)
They concluded that if the drugs were useful, one would expect they would have “reduced disability, morbidity and mortality.” Instead, they had found increased disability and morbidity.”

3. 2005. Rosenheck. The Growth of psychopharmacology in the 1990s. Evidence-based practice or irrational exuberance. International Journal of Law and psychiatry, 28: 467483.

This Yale researcher, typically doing Veteran’s Administration research, broke from typical interests to reports on two dramatic increases in disability during the 1990s, which is a period that use of antidepressants soared.

a) SSA Disability benefits for affective disorders more than doubled,
                 1994:  425,138
                 2002:   939,711
And as a percentage of adult population, from 1: 357 to 1 : 227:

b) National Health Interview Survey
The proportion of working age Americans who reported themselves to be disabled due to depression increased from .10% to .30% during the 1990s.

The percentage who report themselves unable to work because of depression rose from .7%  to 2.1 percent. 

VI. Depression Transformed


NIMH Fact sheet: “Major depressive disorder is the leading cause of disability in the U.S. and established market economies worldwide.” Now hits 5% of the U.S. adult population in any year.

In 1999, the APA Textbook of Psychiatry, Essentials of Clinical Psychiatry, said:  It used to be thought that “most patients would eventually recover from a major depressive episode. However, more extensive studies have disproved this assumption.”  Today, it says, after a first episode:

Only 50% recover within six months

Only 15% of unipolar patients will only have one episode; 85% will have at least a second

Between 15% and 54% of patients now have three or more episodes, and with each new episode remissions become “less complete and new recurrences develop with less provocation.”

Depression, the APA concluded, “is a highly recurrent and pernicious disorder.”

Psychiatric medications were initially attempted as an intervention to quicken the rate of recovery, as NIMH head Dr. Dean Schuyler explained, with recovery rates exceeding 50% within a few months, it was difficult to “judge the efficacy of a drug, a treatment [ECT] or psychotherapy…”.  The depressive course of the illness “will run their course and terminate with virtually complete recovery without specific intervention.”[12]

VII.  No Chemical Imbalance:

There have been numerous studies done showing differences in levels of cerebrospinal fluid, blood plasma and platelets, urine samples and differences via post mortem brains; however, every study showing any difference has been riddled with design flaws and nonreplicated results that have not stood the test of time- and there is no chemical imbalance causing any psychiatric disorder.[13]  With regards to Depression and Serotonin, Dr. Steven Rose, a Professor and neuroscientist at Open University, United Kingdom, reported a study of serotonin levels in psychiatric patients compared with psychiatric nursing staff. Both groups had the same levels, but only the patients reported feeling depressed. [14]  Further, the monoamine and catecholamine theory of depression also failed to be supported by several Yale University trials, whereby, they found no direct chemical role for depression, despite numerous depletions and differing anti-depressant combinations.[15] 

These drugs are not like “insulin for diabetes.” They do not serve as a corrective to a known biological abnormality.  Instead, psychotropic medication work by powerfully changing, often blocking, neurotransmitter transmission in the brain.[16] This thwarting of normal transmission is what causes the drugs to be so problematic in terms of their side effects.   

1) In the 1970s, two physicians at McGill University, Guy Chouinard and Barry Jones, offered a biological explanation for why patients that seem to be helped and improve in the short term, end up being chronic patients and disabled in the long term.  The brain responds to SSRIs, neuroleptics and other psychotropic medications that block and disrupt normal neuro-functioning as though they are a pathological insult. To compensate, brain cells increase the density of receptors often by the pre and post synaptic nerve, sometimes as much as 90%.[17] The brain is now “supersensitive” to as a result, and the person has become more biologically vulnerable to symptom than he or she would be naturally. The two above Canadian researchers wrote regarding anti-psychotics, these drugs “can produce a supersensitivity that leads to both dyskinetic and psychotic symptoms. An implication is that the tendency toward psychotic relapse in a patient who had developed such a supersensitivity is determined by more than just the normal course of the illness. [18]  Other researchers have concluded this up and down regulation also occurs with nearly all classification of psychotropic medications, including SSRI’s like Prozac.[19]

2. MRI-imaging studies have powerfully confirmed this hypothesis. During the 1990s, several research teams reported that psychotropic medications drugs cause atrophy of the cerebral cortex and an enlargement of the basal ganglia, as well as other changes to the structure of the brain.[20], [21], [22] In 1998, investigators at the University of Pennsylvania reported that the drug-induced enlargement of the basal ganglia is “associated with greater severity of both negative and positive symptoms” for psychotic patients. In other words, they found that the drugs cause morphological changes in the brain that are associated with a worsening of the very symptoms the drugs are supposed to alleviate.[23]

This is analogous to what happens in tardive dyskinesia (TD), in which dopaminergic (DA) receptors in the nigro neostriatal pathway are up-regulated (i.e. the DA receptors become more numerous and sensitive) secondary to chronic DA blockade, thereby causing the random purposeless movements seen in TD, the Dopaminergic receptors in the meso limbic pathway (thought to mediate the positive symptomatology, such as voices and delusions) become more sensitized and numerous (i.e. up-regulated).

When the person removes the Serotonergic or Dopaminergic blocking agent, particularly abruptly, it 'unmasks' the now up-regulated receptors resulting in a 'tardive’ or ‘rebound’ or ‘supersensivity’ symptom.[24]

Researchers have found the same is true for other categories of psychiatric medications, including anti-depressant medications, such as Selective Serotonergic Reuptake Inhibitors[25],[26]. In those cases, they call the upregulation of the serotonergic system, “Tardive dysphoria”[27] and “oppositional tolerance.”[28],[29]  The researchers note, “in the era prior to pharmacotherapy, poor outcome in mania was considered a relatively rare occurrence, however, modern outcome studies have found that a majority of bipolar patients evidence high rates of functional impairment.” They discussed the deterioration in outcomes by concluding that “medication-induced changes” may be at least partly responsible for the worsening outcomes. Antidepressants may cause a “worsening of the course of illness” while the antipsychotics may lead to more “depressive episodes” and “lower functional recovery rates.” Negative drug effects (side effects) may “explain the cognitive deficits in bipolar disorder patients.”[30]  Harvard researchers observed that prognosis for depressed bipolar patients was once considered “relatively favorable”, but contemporary findings suggest that “disability and poor outcomes are prevalent.” They note “neuro-pharmacological-neurotoxic factors” might be “causing cognitive deficits” in patients.[31]

Although the studies cited above provide a rationale for not using psychotropic medications, there is a long line of evidence in the research literature quite mainstream in that there are severe negative side effects, many known and some becoming more known by the general public or even by most psychiatrists.  This research shows psychotropic medications, over time, produce these results:

a) They increase the likelihood that a person will become chronically ill, symptomatic and psychologically dependent .
b) They cause a host of debilitating negative effects (side effects listed below).
c) They can lead to early death by suicide and general cognitive decline (see attached).

3.  Neuroscientists have followed the maxim of Donald Hebb (neurons that fire together wire together) and have focused on the encoding relationship within the brain.  In particular, two types of receptors for the neurotransmitter glutamate have been extensively explored: AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors and NMDA (N-methyl-D-aspartate receptor) receptors.  The story on long term potentiation (the term for memory formation) involves coordinated activity of the AMPA and NMDA receptors.  AMPA receptor mimics the effects of the neurotransmitter glutamate[32], whereby there are several types of glutamatergic ion channels in the central nervous system (e.g. AMPA, kainic acid and  NMDA) channels.

In the synapse, these receptors serve very different purposes. AMPA can be used experimentally to distinguish the activity of one receptor from the other in order to understand their differing functions[33]. AMPA generates fast excitatory postsynaptic potentials (EPSP)[34]. AMPA activates AMPA receptors that are non-selective cationic channels allowing the passage of Na+ and K+ and therefore have an equilibrium potential near 0 mV

With the knowledge of the particular mechanism for learning, Joe Tsien began making modifications of the relevant proteins involved in the process and ended up with the “Doggie Howser” mouse: a super-smart mouse that out performed all of the other mice on memory tasks[35].  What Tsien did was to over-express a particular version of a subunit of the NMDA receptor: the NR2B subunit.  (Tsien manipulated the neuron’s DNA so that more of the NR2B protein was produced.)

Elsewhere other researchers have paid attention to the impact of antidepressants (Selective Serotonin Reuptake Inhibitors- SSRI) on which versions of the NMDA receptor subunits are used to create the NMDA receptor.  Turns out long term use of antidepressants decreases the supply of these NR2B subunits so that NMDA receptors rely on NR2A instead of NR2B version of the protein at least in the amygdala[36].  With aging, the brain does increase its use of NR2A subunits, but antidepressants (SSRIs) accelerate this effect.

The impact of long term antidepressants on decreasing NR2B subunits does have functional consequences.  Joe LeDoux is the neuroscientist who has worked out the particulars in the amygdala on how a rat learns to associate a light with shock when the two stimuli are repeatedly paired (i.e. fear conditioning).  Initially, LeDoux and colleagues showed that antidepressants impair the acquisition of fear memories.  It is also known that unlearning the association between the light and the shock (i.e. extinction), also involves new learning.  According to a study by LeDoux and colleagues, long term exposure to antidepressants makes it harder to unlearn fear memories as well[37].  Moreover, in their study, the deficit capacity to unlearn the association was correlated with deficit amounts of NR2B subunits.  LeDoux and colleagues concluded that the addition of antidepressants to exposure therapy, for extinguishing fear memories, is counter-productive.

LeDoux et al. did not examine whether similar reliance on NR2A rather than NR2B subunits is happening elsewhere in the brain when an organism is exposed to antidepressants.  However, others have examined the impact of long term exposure to antidepressants and found NR2B deficits in other brain areas besides the amygdala[38].  Both studies by Ampuero et al. and Boyer et al. suggest that a decrease in NR2B proteins is found in the cortex as well after long term exposure to antidepressants[39] [40].  However, there are not many studies. 

Naturally, with aging, more NR2A subunits replace the NR2B subunits.  Accelerated cognitive decline that mimics natural aging is an accurate and documented effect of SSRI antidepressant usage.  Interestingly, dietary consumption of Magnesium threonate can increase NR2B subunits[41] [42]. 

VIII.  Harmful Side Effects from Psychiatric Medications

1. In addition to making patients chronically ill, psychiatric patients today suffer from a host of physical illnesses–cardiovascular problems, obesity, thyroid dysfunction, etc.–which, researchers admit, are due to “toxicity from medications.”[43]

More specifically to SSRIs:
a) Tardive dyskinesia. The most visible sign of tardive dyskinesia is a rhythmic movement of the tongue, which is the result of permanent damage to the basal ganglia, which controls motor movement. People suffering from tardive dyskinesia may have trouble walking, sitting still, eating, and speaking. In addition, people with tardive dyskinesia show accelerated cognitive decline. NIMH researcher George Crane said that tardive dyskinesia resembles “in every respect known neurological diseases, such as Huntington’s disease, dystonia musculorum deformans, and postencephalitic brain damage.”[44] Tardive dyskinesia is most often associated with anti-psychotic medications; however, in recent years researchers and psychiatrists have noted there are numerous psychiatric medications, including SSRIs like Zoloft and Prozac, MAOIs such as Nardil, Tricyclics like Elavil and Tofranil, Lithium, and even anxiolytics like Xanax and stimulant medication Ritalin and Adderall can have this effect.[45] It appears in five percent of patients treated with standard neuroleptics in one year, with the percentage so afflicted increasing an additional five percent with each additional year of exposure..[46] The risk of developing this possible life threatening effect from the anti-psychotic medication increases with higher doses and longer duration.[47]

b) Akathisia. This is an inner restlessness and anxiety that many patients describe as the worst sort of torment. This side effect has been linked to assaultive, murderous behavior and is a cause of suicide.[48], [49], [50], [51], [52]

c) Emotional impairment. Many patients describe feeling like “zombies” on psychotropic medications, what some has researcher’s have called this a “spell binding effect.”[53]  Other research notes “significant emotional blunting”, leading to reduced ability to express feelings,[54] and “apathy syndrome” due to the negative consequences of the medication, whereby it is often unrecognized despite the medication causing social and academic problems in adolescents.[55]

d) Cognitive impairment. Various studies have found that psychiatric medications reduce one’s capacity to learn, retain information, and can impair types of different therapy, not only to neurological impairment and damage[56], but others indicate due to state learning. As Duke University scientist Richard Keefe said in 1999, these drugs may “actually prevent adequate learning effects and worsen motor skills, memory function, and executive abilities, such as problem solving and performance assessment.”[57]  Greater than 30% of patients on long term use of anti-depressants were found to have negative cognitive effects (e.g. apathy, inattentiveness, forgetfulness, word-finding problems, mental slowness, fatigue, sleepiness, sedation, and “Attention Deficit Hyperactivity Disorder” symptoms.[58]

e) Other side effects of SSRIs and other psychiatric medications include a vast array of negative effects on a striking number of physical systems. These include: drowsiness, dizziness, lethargy and drowsiness; nausea and coffee ground vomiting; diarrhea, constipation black stools, and stomach pain (G.I.);  heartburn, dry mouth, increased saliva production, increased appetite, weight gain, worsening anxiety, agitation, and restlessness; difficulty falling asleep and or staying asleep; disrupted sexual reproduction and a decrease in sexual interest or ability by as much as 75%[59], vision problems, muscle or joint pain, dry or discolored skin, difficulty urinating, muscle stiffness, confusion, fast or irregular pulse, sweating, unusual and uncontrollable movements of face or body, faintness, seizures, Parkinsonian symptoms (may double the risk of Parkinson’s Disease)[60] with slow movements and shuffling gait, “unfitness to drive”[61], hives, itching, difficulty breathing or swallowing; an increased incidence of blindness, fatal blood clots, arrhythmia, heat stroke, swollen breasts, leaking breasts, obesity, sexual dysfunction, damage to sperm and reproductive systems, skin rashes and seizures, unusual mood and mental changes, obsessive suicidal thoughts, suicide attempts, violence and aggression, and finally early premature death. [62],[63] [64], [65], [66] [67][68] [69] [70]

f) Patients using anti-psychotic medications for psychosis now commit suicide at 20 times the rate they did prior to the use of neuroleptics, and when researcher’s completed the largest study ever done to address suicide in psychotic patients, they concluded that the 10% lifetime rate of suicide is incorrect, noting it is approximately 4%, and that psychiatric medications appears to be a causal factor for suicide. [71] 

But increases in suicide from psychotropic medications also are very apparent with the use of SSRI medications, with the risk averaging from twice as likely (200% increase) all the way up to a eight fold increase with patients who use Paxil (800% increase),[72] [73] whereby, researchers analyzed the data from six large studies published in the Journal of the Medical Association (JAMA).  The results showed such medications were unable to beat taking sugar pill (placebo) for mild and moderate symptoms of depression.  Earlier and other studies also showed similar results in that taking such medications causes increases in suicide.  For example, Wyeth, makers of Effexor, was required to send a “dear doctor” letter out on August 22, 2003, that stated:

“In clinical studies in pediatric patients (ages 6 to 17), efficacy was not established for major depressive disorder (MDD) or generalized anxiety disorder (GAD), and there were increased reports among those patients on Effexor XR, vs. placebo, of hostility and suicide-related adverse events, such as suicidal ideation and self-harm. Effexor and Effexor XR have not been and are not now recommended for use in pediatric patients.”

As a result of the lack of effectiveness and increase in suicide and aggression for nearly all SSRIs, Great Britain banned all but one for children, although they acknowledged the one left was not significantly effective by comparison to placebo.[74]  Further evidence discovered that the makers of the SSRI’s like Paxil hid additional data regarding the causal link between Suicide and using SSRIs.[75]

IX.  Alternative- Risk-Benefit Treatment

1) In the largest treatment study ever conducted with youth 12-17 years old with depression, which compared using anti-depressants with and without psychotherapy with teens already screened out for suicidal ideation, the following suicide ideation results emerged:

14.7% of those receiving an anti-depressant alone (Prozac) became suicidal.
8.4% of those receiving Prozac and talk therapy became suicidal.
6.3% of those receiving talk therapy alone reported suicidal ideation.

Treatment without medication was reportedly the safest, despite a pharmacist who “offered encouragement” and was not blind to the study treatment (TADS Team, 2004, p.809), and of the teens who were not suicidal at the onset of the study, 15% became suicidal, which doubled the risk of suicidal ideation. Further, this study demonstrated that talk therapy may partly-- but not completely-- offset the suicide-enhancing effects of Prozac.  Lastly, over 80% of all the participants had improved significantly “almost entirely” regardless of treatment offered.[76]

2) Dr. Irving Kirsch conducted the gold standard meta-analysis research upon the effectiveness of anti-depressant by comparison to placebo (a sugar pill), and indicated of the:

“2,318 patients who had been randomly assigned to either antidepressant medication or placebo in 19 double-blind clinical trials…the placebo response was constant across different types of medication (75%), and the correlation between placebo effect and drug effect was .90. [meaning] …data indicate that virtually all of the variation in drug effect size was due to the placebo characteristics of the studies.”[77]

3) Other researchers confirmed that using anti-depressant medication is no more clinically beneficial than taking a sugar pill, and any drug response can be replicated within a placebo.[78] [79]

[1] The Epidemiology of Depression, by Charlotte Silverman. Published in 1968. Silverman was chief of epidemiology studies at the NIMH

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[3] Rennie, T. Prognosis in manic-depressive psychoses, American Journal of Psychiatry 98:801. (1942).

[4] Lundquist, G. Prognosis and course in manic-depressive psychoses, Acta Pscychiatrica Neurol. (Suppl 35), 1945.

[5] Medical Research Council, Clinical trial of the treatment of depressive illness. British Medical Journal, 1965; 881-886.

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[8] 1970. Raskin, Differential Response to chlorpromazine, imipramine, and placebo. A study of subgroups of hospitalized depressed patients. Archives of General psychiatry. August 23 (2):164-173. 1970. This is called the Second Collaborative Depression Study, funded by the NIMH.

[9] R. Thomson, Side Effects and Placebo amplification. British Journal of psychiatry, 1982; 140:64-68.

[10] R. Thomson, Side Effects and Placebo amplification. British Journal of psychiatry, 1982; 140:64-68.

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[12] Whitaker, R., (2010). Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and The Astonishing Rise of Mental Illness.  New York, NY: Random House.

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[19] Chronic Citalopram and Fluoxetine Treatments Upregulate 5-HT2C Receptors in the Rat Choroid Plexus

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[27] El-Mallakh, R.S., Gao, Y. and Roberts, J. (2011)., Tardive dysphoria: The role of long term antidepressant use in-inducing chronic depression.  Medical Hypotheses, 76(6):769–773.

[28] Andrews, P.W., Kornstein, S.W., Halberstadt, L. J., et. al. (2011). Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression. Frontiers in Psychology, 159(2): 1-24.

[29] Fava, G.A., & Offidani, E. (2011)). The mechanisms of tolerance in antidepressant action, Progress in Neuro-Psychopharmacology and Biological Psychiatry. 35:1593–1602.

[30] Zarate, C. (2000). Functional impairment and cognition in bipolar disorder  Psychiatric Quarterly 71:309-29.

[31] Huxley, N. (2007). Disability and its treatment in bipolar disorders. Bipolar Disorders. 9:183-96.

[32] Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008).Neuroscience. 4th ed. Sinauer Associates. pp. 128–33. ISBN 978-0-87893-697-7.

[33] Dinh, L; Nguyen T; Salgado H; Atzori M (2009). "Norepinephrine homogeneously inhibits alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate- (AMPAR-) mediated currents in all layers of the temporal cortex of the rat". Neurochem Res 34(11): 1896–906. doi:10.1007/s11064-009-9966-z. PMID 19357950.

[34] Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008).Neuroscience. 4th ed. Sinauer Associates. pp. 128–33. ISBN 978-0-87893-697-7.

[35] Wang, D., Jacobs, S. A., & Tsien, J. Z.  (2015).  Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline.  Expert Opinion and Targeted Therapeutics, 18 (10), 1121-1130.

[36] Boyer, P. A., Skolnick, P., & Fossom, L. H.  (1998).  Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNA in mouse brain: a quantitative in situ hybridization study.  Journal of Molecular Neuroscience, 10, 219-233.

[37] Burghardt, N. S., Sigurdsson, T., Gorman, J. M., McEwen, B. S.  & LeDoux, J. E. (2013).  Chronic antidepressant treatment impairs the acquisition of fear extinction.  Biological Psychiatry, 73(11), 1078-1086.

[38] Wyneken, U.  (2010).  Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex.  Neuroscience, 169 (1), 98-108.

[39] Ampuero, E., Rubio, F. J., Falcon, R., Sandoval, M., Diaz-Veliz, G., Gonzalez, R. E., Earle, D., Dagnino-Subiabre, A., Aboitiz, F., Orrego, F., & Wyneken, U.  (2010).  Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex.  Neuroscience, 169 (1), 98-108.

[40] Boyer, P. A., Skolnick, P., & Fossom, L. H.  (1998).  Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNA in mouse brain: a quantitative in situ hybridization study.  Journal of Molecular Neuroscience, 10, 219-233.

[41] Abumaria, N., Yin, B., Zhang, L., Li, X. Y., Chen, T., et al. (2011).  Effect of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala.  Journal of Neuroscience, 31, 14871-14881.

[42] Abumaria, N., Luo, L., Ahn, M., & Liu, G.  (2013).  Magnesium supplement enhances spatial-context pattern separation and prevents fear overgeneralization.  Behavioral Pharmacology, 24, 255-263.

[43] Kupfer, D. (2005). The increasing medical burden in bipolar disorder. JAMA,  293(20): 2528-2530.

[44] Crane, G. (1973). Clinical psychopharmacology in its 20th year. Science, 181:124-128. Also see American Psychiatric Association, Tardive Dyskinesia: A Task Force Report (1992).

[45] Glenmullen, J. (2001), Prozac blacklash: overcoming the dangers of Prozac, Zoloft, Paxil and other anti-depressants with safe, effective alternatives. Simon & Schuster, New York, NY.  ISBN 0-684-86001-5

[46] Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161(3):414-425

[47] Crimson ML, Argo TR, Buckley PF. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York, NY: McGraw- Hill; 2011:1147-1172.

[48] Shear, K et al. (1982). Suicide associated with akathisia and deport fluphenazine treatment. Journal of Clinical Psychopharmacology, 3:235-6.

[49] Van Putten, T. (1987). Behavioral toxicity of antipsychotic drugs. Journal of Clinical Psychiatry, 48:13-19.

[50] Van Putten, T. (1975). The many faces of akathisia. Comprehensive Psychiatry ,16:43-46.

[51] Herrera, J. (1998). High-potency neuroleptics and violence in schizophrenia. Journal of Nervous and Mental Disease, 176:558-561.

[52] Galynker, I. (1997). Akathisia as violence. Journal of Clinical Psychiatry, 58:16-24.

[53] Breggin, P. (2008) Medication Madness. St. Martin’s Press.

[54] Opbroek, A, et al, Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotion responses?, International Journal of Neuropsychopharmacology (2002), 5, 147-151.

[55] Barnhart, W. et al, SSRI induced apathy syndrome: a clinical review, Journal of Psychiatric Practice. May, 2004, Vol. 10, 3, 196-199.

[56] Chronic Antidepressant Treatment Impairs the Acquisition of Fear Extinction" by Nesha S. Burghardt, Torfi Sigurdsson, Jack M. Gorman, Bruce S. McEwen, and Joseph E. LeDoux (doi: 10.1016/j.biopsych.2012.10.012).. 

[57] Keefe, R. (1999). Do novel antipsychotics improve cognition? Psychiatric Annals, 29:623-629.

[58] Maurizio Fava et al have published a very important paper in J Clin Psych 2006;67:1754-1759.

[59] Effects of SSRIs on sexual function: a critical review. Rosen RC, Lane RM, Menza M,  J Clin Psychopharmacology. 1999 Feb; 19(1):67-85.

[60] Steele, H., Antidepressants increase risk of Parkinson’s Disease. News Health. April 28, 2007. http://www.earthtimes.org/articles/show/57016.html#

[61] J Clin Psych 67:11 :1776-1781 Antidepressants and Driving Ability: Results from a Clinical Study. Alexander Brunnauer et al

[62] Kirchner V, et al, Selective serotonin reuptake inhibitors and hyponatremia: review and proposed mechanisms in the elderly. J Psychopharmacol. 1998;12:396–400.

[63] Goldstein BJ, Goodnick PJ. Selective serotonin reuptake inhibitors in the treatment of affective disorders, 3: tolerability, safety, and pharmacoeconomics. J Psychopharmacol. 1998;12(suppl B):S55–S87.

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[65] Waddington, J. (1998). Mortality in schizophrenia. British Journal of Psychiatry,173:325-329.

[66] Joukamaa, M, et al. (2006) Schizophrenia, neuroleptic medication and mortality. British Journal of Psychiatry, 188:122-127.

[67] McLean, T., Depression drugs could harm sperm, Agence France, September 25, 2008.

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[69] Online. www.medicinenet.com,  April, 14, 2015.

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[71] Healy, D et al. (2006). Lifetime suicide rates in treated schizophrenia. British Journal of Psychiatry, 188:223-228.

[72] Fournier, JC, DeRubeis, R., et al, Antidepressants drug effects and depression severity: A patient level meta-analysis.  JAMA, 2010. 303, 1, 47-53.

[73] D. Fergusson, S. Doucette, at el, Association between suicide attempts and SSRI: Systematic review of randomized control trials, In Primary Care, British Medical Journal, Feb. 18, 2005.

[74] Boseley, S., Drugs for depressed children banned., The Guardian, December 10, 2003.  http://www.guardian.co.uk/uk_news/story/0,3604,1103563,00.html

[75] Drug company ‘hid’ suicide link., BBC News Online. January 29, 2007. http://news.bbc.co.uk/2/hi/health/6308871.stm

[76] The Treatment for Adolescents With Depression Study (TADS): Long-term Effectiveness and Safety Outcomes
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[77] Kirsch, Sapirstein, Listening to Prozac but Hearing Placebo: A Meta-Analysis of Antidepressant Medication Prevention & Treatment, Volume 1, Article 0002a, posted June 26, 1998

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Testimony of Dr. Irving Kirsch and Dr. David Antonuccio on the efficacy of antidepressants with children. 
February 2, 2004

I am collaborating with Dr. David Antonuccio and clinical psychology graduate student Amanda Drews in reviewing the published literature evaluating the efficacy of antidepressants in depressed children.

There are a total of 12 published randomized clinical trials in the entire world literature (see studies marked with an * in the reference list). Eight of these 12 trials failed to find any significant benefit of medication over inert placebo. Only 4 of the RCTs claimed significant differences between drug and placebo, and these did so only on clinician rated measures, not patient rated measures.

Of the 12 published randomized trials, 4 assessed SSRIs, 7 assessed tricyclics, and one assessed both SSRIs and tricyclics. Four of the five SSRI-placebo comparisons indicated significant differences. None of the TCA-placebo comparisons showed significant differences.

Three of the clinical trials did not report means and/or standard deviations, leaving 9 for meta-analysis. When these nine studies are combined, the placebo response is 87% of the drug response. It is 75% of the SSRI response and 97% of the tricyclic response.

Thus, the meta-analysis indicates that tricyclics have no significant pharmacological effect on depression in children. The effect of SSRIs is statistically significant, but it is not clinically significant. Overall, the effects of antidepressant medication are weaker in children than in adults (cf. Kirsch & Sapirstein, 1997; Kirsch et al. 2002). These conclusions are consistent with those found in all 7 prior reviews of the effects of antidepressants in depressed children (Ambrosini et al., 1992; Dujovne et al., 1995; Fisher & Fisher, 1996; Hazell et al., 1995; Kastelic et al., 2000; Michael & Crowley, 2002; Sommers-Flanagan & Sommers-Flanagan, 1996).

These results were drawn from studies with design flaws that typically favor the study drug. For example, they frequently exclude placebo responders before random assignment, rely on ratings by clinician's who have a vested interest in the outcome, and are likely to be unblinded by medication side effects (Antonuccio et al., 1999; Antonuccio et al. 2002). Furthermore, these results are drawn from the published literature, which is subject to publication bias and ?file drawer? problems, meaning that many studies with negative results do not to get published. Adding unpublished studies, most of which have negative results, will surely shrink the difference between antidepressants and placebo even further.

In order to evaluate the cost effectiveness of antidepressant use in children, the committee must consider the benefits as well as the risks. Clinically meaningful benefits have not been adequately demonstrated in depressed children. Therefore, no extra risk is warranted. An increased risk of suicidal behavior is certainly not justified by these minimal benefits. Neither are the established increased risk of other commonly reported side effects, which include agitation, insomnia, and gastrointestinal problems.

The highest possible standard should be applied to scientific data involving drug treatment of children because children are essentially involuntary patients. Those of you on the committee who are parents know this to be true, because when your children have prescription medication for something that ails them, you make them take it as prescribed, whether they want to or not.

Children given antidepressant medication often do get better but so do children given placebo. Thus, the clinical trial data suggest that improvement is due primarily?perhaps entirely-- to the placebo effect. Instead of medication with demonstrated side effects and minimal effectiveness, children can be offered interventions like exercise and cognitive behavior therapy that have been found to produce therapeutic effects on depression without the medical side effects and risks (e.g., Clark et al., 1999).

Please be careful to ensure that our children are not exposed to risk without commensurate benefit.

(Studies included in the meta-analysis denoted with an asterisk)

Ambrosini, P.J., Bianchi, M.D., Rabinovich, H., & Elia, J. (1993). Antidepressant treatment in children and adolescents: I. Affective Disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 1-6.

Antonuccio DO, Burns DD, Danton WG (2002), Antidepressants: a triumph of marketing over science? Prevention & Treatment 5:Article 25. Available at: http://journals.apa.org/prevention/volume5/pre0050025c.html

Antonuccio DO, Danton WG, DeNelsky GY et al. (1999), Raising questions about antidepressants. Psychother Psychosom 68(1):3-14.

*Boulos, C., Kutcher, S., Marton, P., Simeon, J., Ferguson, B., and Roberts, N.  (1991).  Response to desipramine treatment in adolescent major depression.  Psychopharmacology Bulletin, 27, 59-65.

Clarke, G.N., Rhode, P., Lewinsohn, P.M., Hops, H., & Seely, J.R. (1999). Cognitive-behavioral treatment of adolescent depression: Efficacy of acute group treatment & booster sessions. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 272-279.

Drews, A., Kirsch, I., & Antonuccio, D.O. (in preparation). A meta-analysis of antidepressants trials for depressed children: Small benefits, large stakes. 

Duvjone, V.F., Barnard, M.U., & Rapoff, M.A. (1995). Pharmacological and cognitive-behavioral approaches in the treatment of childhood depression: A review and critique. Clinical Psychology Review, 15, 589-611.

*Emslie, G., Rush, J., Weinberg, W., Kowatch, R., Hughes, C., Carmody, T., and Rintelmann, J.  (1997).  A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression.  Archives of General Psychiatry, 54, 1031-1037.

*Emslie, G., Heiligenstein, J., Wagner, K., Hoog, S., Ernest, D., Brown, E., Nilsson, M., and Jacobson, J.  (2002).  Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial.  Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1205-1215.

Fisher, R.L. & Fisher, S. (1996). Antidepressants for children: Is scientific support necessary? The Journal of Nervous and Mental Disease, 184,99-102.

*Geller, B., Cooper, T., Graham, D., Marsteller, F., and Bryant, D.  (1990).  Double-blind, placebo-controlled study of nortriptyline in depressed adolescents using a "fixed plasma level" design.  Psychopharmacology Bulletin, 26, 85-90.

*Geller, B., Cooper, T., Graham, D., Fetner, H., Marsteller, F., and Wells, J.  (1992).  Pharmcokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder.  Journal of the American Academy of Child and Adolescent Psychiatry, 31,34-44.

Hazell, P., O'Connell, D., Heathcote, D., Robertson, J., & Henry, D. Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. British Medical Journal, 310, 897-901.

Kastelic, E.A., Labellarte, M. J., & Riddle, M.A. (2000). Selective serotonin reuptake inhibitors for children and adolescents. Current Psychiatry Reports, 2, 117-123.

*Keller, M., Ryan, N., Strober, M., Klein, R., Kutcher, S., Birmaher, B., Hagino, O., Koplewicz, H., Carlson, G., Clarke, G., Emslie, G., Feinberg, D., Geller, B., Kusumakar, V., Papatheodorou, G., Sack, W., Sweeney, M., Wagner, K., Weller, E., Winters, N., Oakes, and McCafferty, J.  (2001).  Efficacy of paroxetine in the treatment of adolescent major depression: A randomized, controlled trial.  Journal of the American Academy of Child and Adolescent Psychiatry, 40, 762-772.

Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23. Available at:http://journals.apa.org/prevention/volume5/pre0050023a.html

Kirsch I, Sapirstein G (1998), Listening to Prozac but hearing placebo: a meta analysis of antidepressant medication. Prevention & Treatment 1: Article 0002a. Available at:http://www.journals.apa.org/prevention/volume1/pre0010002a.html

*Kramer, A. and Feiguine, R.  (1981).  Clinical effects of amitriptyline in adolescent depression.  Journal of the American Academy of Child Psychiatry, 20, 636-644.

*Kutcher, S., Boulos, C., Ward, B., Marton, P., Simeon, J., Ferguson, B., Szalai, J., Katic, M., Roberts, N., Dubois, C., and Reed, K.  (1994).  Response to desipramine in treatment of adolescent depression: A fixed-dose, placebo-controlled trial.  Journal of the American Academy of Child and Adolescent Psychiatry, 33, 686-694.

Michael, K.D. & Crowley, S.L. (2002). How effective are treatments for children and adolescent depression? A meta-analytic review. Clinical Psychology Review, 22, 247-269.

*Preskorn, S., Weller, E., Hughes, C., Weller, R., and Bolte, K.  (1987).  Depression in prepubertal children: Dexamethasone nonsuppression predicts differential response to imipramine vs. placebo.  Psychopharmacology Bulletin, 23, 128-133.

*Puig-Antich, J., Perel, J., Lupatkin, W., Chambers, W., Tabrizi, M., King, J., Goetz, R., Davies, and Stiller, R.  (1987).  Imipramine in prepubertal major depressive disorders.  Archives of General Psychiatry, 44, 81-89.

*Simeon, J., Dinicola, V., Ferguson, B., and Copping, W.  (1990).  Adolescent depression: A placebo-controlled fluoxetine treatment study and follow-up.  Progress in Neuro-psychopharmacology and Biological Psychiatry, 14, 791-795.

Sommers-Flanagan, J. & Sommers-Flanagan, R. (1996). Efficacy of antidepressant medication with depressed youth: What psychologists should know. Professional Psychology: Research and Practice, 27, 145-153.

*Wagner, K., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M., Childress, A., Donnelly, C., and Deas, D.  (2003).  Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder.  Journal of the American Medical Association, 290, 1033-1041.      

New York Times, October 2, 2007
Talk Therapy Pivotal for Depressed Youth , By BENEDICT CAREY

A talking cure for depression called cognitive behavior therapy appears to cancel the risk of suicidal thinking or behavior associated with taking antidepressant medication, according to the most comprehensive and long-running study to date of depression treatment among adolescents.

The study, which followed for a year more than 600 adolescents being treated for chronic depression, found that four in five recovered entirely, or nearly so, when treated over nine months with medication, talk therapy or a combination of the two.

Patients taking medication showed significant signs of improvement up to six weeks earlier than those who received talk therapy alone, but were about twice as likely to report feeling suddenly suicidal. The combination of the two therapies, the authors found, produced the most rapid recovery and protected against sudden suicidal urges.

For several years experts have been debating the risks to children and adolescents who take antidepressants like Prozacand Paxil. In 2004, health regulators required that all labels for antidepressants carry prominent warnings that the drugs were associated with increased risks of suicidal thinking and behavior in young patients, a link that many psychiatrists say has been blown out of proportion, scaring off patients who could benefit from drug treatment.

In this study, antidepressants lowered the risk of suicidal thoughts and actions over all, but significantly less so than talk therapy.

“What this study shows, convincingly and for the first time, is that there are very good options for a child who is thought to be at risk for suicidal thinking,” said Kevin Stark, a psychologist at the University of Texas, who was not involved with the research. “Psychosocial therapies do work on their own, with time. But they also help prevent relapse, and this shows that they can help make drug treatment safer.”

In the study, which began in 1999, researchers recruited 654 youths ages 12 to 17 who had been moderately to severely depressed for up to a year or longer. The adolescents were randomly assigned to be treated with Prozac, the antidepressant made by Eli Lilly; cognitive behavioral therapy for a weekly hourlong session; placebo pills; or a combination of Prozac and talk therapy.

After 12 weeks, about three in four of the patients receiving both talk therapy and medication were rated as “much better” or “very much better,” and two-thirds taking just the drug fared just as well. Talk therapy by itself was no better than the placebo.

After four months, about two-thirds of those receiving any treatment were rated as much or very much improved — significantly better than a typical response to placebo pills.

By nine months, 8 in 10 adolescents had shaken off their depression, entirely or almost entirely, no matter the treatment.

Talk therapy was a safer alternative. Almost 15 percent of the patients taking just Prozac reported what were described as “suicidal events,” mainly talk and thoughts of suicide so alarming that doctors called in the patients and, often, altered dosages.

The rate of such events for those receiving just cognitive behavior therapy was 6 percent. The results for combination therapy were about the same.

“The message is that medication accelerates recovery, but cognitive therapy protects against these bad reactions, and the combination is the best option,” said Dr. John March, chief of child and adolescent psychiatry at the Duke University Medical Center and the principal investigator for the study.

The talk therapy promoted changes in behavior like getting patients out of bed and doing something that they enjoy, like playing basketball or going to a party. It also provided cognitive therapy, in which patients are taught to diffuse poisonous assumptions like “I’m a loser” or “I’ll never get a girlfriend.”

Experts say it is not easy to find specialists in this therapy outside large cities. The techniques have been widely published in manuals and books, and Dr. March said a good therapist could usually work such techniques into a treatment plan.

“The trick,” he said, “is to be an intelligent consumer and find a skilled therapist who’s willing to work with you on these methods.”

Benedict Carey writes,
"The rate of such [suicidal] events for those receiving just cognitive behavior therapy was 6 percent. The results for combination therapy were about the same."

Not really "about the same."  The actual percentage of patients experiencing suicidal events were:
14.7% of those receiving Prozac alone.
8.4% of those receiving Prozac and talk therapy.
6.3% of those receiving talk therapy alone.

Treatment WITHOUT medication is safer, even according to a biased study like this one!

Looked at another way: 

15% of the patients taking Prozac alone were suicidal during treatment (not BEFORE treatment)
6%  of those receiving talk therapy alone.

For those receiving Prozac + talk therapy,  the rate of suicidality fell from 15% to 8%. 
1)  Prozac doubled the risk of suicide in this study
2) talk therapy may partly (but not completely) offset the suicide-enhancing effects of Prozac.

Other Limitations Noted:
limitations section of the TADS study comparing combined Prozac and CBT, Prozac alone, CBT alone, and placebo for the treatment of adolescent depression, the authors acknowledged that variations in knowledge of treatment received existed across the four groups as well as inequities in contact time with the clinicians. A pharmacotherapist was assigned to each participant in the combined, medication alone, and placebo groups. This person monitored drug dosage and “offered general encouragement about the effectiveness of pharmacotherapy for MDD” (TADS Team, 2004, p. 809). The combined group adolescents also received contact with a cognitive behavioral therapist for 15 sessions. Parents in the combined group participated in psychoeducation groups about depression along with conjoint family sessions. Only the combined group received all of these “extra” components. The authors admit that, because of the inequality in conditions and lack of blinding, the “specific ingredients” of improvement could not be determined.   Read the abstract here:

The Treatment for Adolescents With Depression Study (TADS)
Long-term Effectiveness and Safety Outcomes
Arch Gen Psychiatry. 2007;64:1132-1143.

UPDATE: On the latest Medscape, this highlight came out of some new TADS data...  

"The most recent results from the Treatment for Adolescents with Depression Study (TADS) show that the overall remission rate at 36 weeks was about 60%. The rates were similar in each of the 3 treatment groups: antidepressant fluoxetine alone (55%), cognitive behavior therapy (CBT) alone (64%), or a combination of these 2 therapies (60%)"It would appear that on a small scale, CBT's effectiveness may actually be interfered with with prozac.  CBT alone did much better than prozac in remission rates, but its effectiveness was slightly diminished when combined with prozac.  It would be nice if the sample had been bigger to see if this effect would have been enhanced. 

OK, BUT WHAT ABOUT THE BIGGEST ADULT STUDY ON USING THESE DRUGS FOR ADULTS?The NIMH's ($35 million taxpayer-funded) STAR*D 4-step depression treatment (mostly antidepressants) study is "a piece of work."

1. There was no placebo control in any of the 4 steps of treatment. (In Step One, all participants received Celexa; those who failed to gain remission had the Celexa augmented or replaced with other antidepressants in Step Two; and for those who failed that treatment, they were given another Step Three treatment; those who failed that were given Step Four Treatment.

2. If there had been a placebo-control, we know from other research that the placebo-control would have most certainly equaled or bested each treatment step results, which study authors claim ranged from 37 percent for Step One descending to 13 percent for Step Four. However, when one looks at the primary outcome measure in STAR*D, the Hamilton Rating Scale for Depression (the one that is used in most of these type of studies), they never had higher than 30 percent for each step.

3. In March of 2006, NIMH and STAR*D researchers  triumphantly announced the cumulative success rate of 50 percent for Steps One and Two, neglecting to tell the world that in the time that it took for those two steps (slightly more than 6 months), other researchers have found a spontaneous remission rate (remission with no treatment at all) of 50 percent.

4.STAR*D researchers continued to Steps 3 and 4, with pathetic remission rates of lower than 14 percent for each step. 

5. But in November 2006  they decided to advertise a new cumulative remission rate of 67 percent for all four steps -- neglecting a huge RELAPSE rate (for patients who in previous steps considered to have been successfully treated).

6. While the Wall Street Journal reported a relapse rates of 71.1 percent (by Avery Johnson, "A Study Looks at Resistance to Depression Treatment, November 1, 2006, The Wall Street Journal, p. D9), 
it would be safer to estimate relapse rate at somewhere between 60 to 70 percent. One can say for certain that the relapse rate is HUGE, but one cannot really say exactly how huge because the tables are so poorly labeled and unclear in the published study (A. John Rush, Madhukar H. Trivedi, et al., "Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report," American Journal of Psychiatry 163:11 (November 2006), pp. 1905-1917)

7. What then was the true overall remission rate? A "cumulative sustained recovery rate" of 43 percent was estimated by Craig Nelson in an editorial jointly appearing with the study in the same issue of the American Journal of Psychiatry. Nelson notes while that the STAR*D authors state that after four treatments the cumulative rate is 67%, this does not account for relapse and that he "found a cumulative sustained recovery rate of 43%, (Craig Nelson, "The STAR*D Study: A Four-Course Meal That Leaves Us Wanting More," American Journal of Psychiatry 163:11 (November 2006), pp. 1864-1866.)
Again, because of unclear tables in the published study, there is some ambiguity here, and the cumulative remission rate is probably closer to 40 percent. 

8. The true remission rate is even lower than 40 percent if one takes into account the fairly large number of subjects who dropped out of the study  -- who most likely were not getting anything out of it -- as well as other variables.

9. As bad as all this is, a few years ago it was even sillier. The psychiatry establishment would always quote a 2000 New England Journal of Medicine article that said, "More than 80 percent of depressed patients have a response to at least one medication, although individual antidepressants are effective in only 50 to 60 percent of patients." For those statistics, that particular article referenced a 1998 Archives of General Psychiatry article where there is NO mention at all of this 80 percent statistic.