Depression Talk

 

Question:  How does the use of antidepressants affect the long-term course of depression?

 1. Depression before 1970.

 Source: The Epidemiology of Depression, NIMH. (1968)

 

• Fewer than one in 1000 adults suffered a bout of clinical depression in a year.
• In 1995, only 7,250 first admissions for depression to state and county mental hospitals.
• In 1955, only 38,200 hospitalized for depression.
• Ninety percent are over 35 years old.
• Eighty to ninety percent recovery rate within 12 months.
• More than half no recurrence that requires rehospitalization in long-term followup.
• Only 10 percent chronically ill.

  Perceptions of Depression in 1960s/early 1970s

 

Jonathan Cole (1964):

       “Depression is, on the whole, one of the psychiatric conditions with the best prognosis for eventual recovery with or without treatment. Most depressions are self-limited.” [i]

 

Nathan Kline (1964):

        “In the treatment of depression, one always has as an ally in the fact that most depressions terminate in spontaneous remissions. This means that in many cases regardless of what one does the patient eventually will begin to get better.”[ii]

 

George Winokur (1969):  Washington University

       “Asssurance 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.”[iii]

 

Dean Schuyler (1974, NIMH): 

       Spontaneous recovery rates were so high, exceeding 50% within a few months, that it was difficult to “judge the efficacy of a drug, a treatment (ECT) or psychotherapy in depressed patients.” Most depressive episodes, explained,  “will run their course and terminate with virtually complete recovery without specific intervention.”[iv]

 

II. Short-Term Efficacy of Antidepressants

 A. Tricyclics

       1969. Well-controlled studies:  61% vs. 46%.

             Cole: “The differences between the effectiveness of antidepressant drugs and placebo are not impressive,” it said.[v]

 

      1970. NIMH Trial:

 Tricyclics effective only in psychotically depressed patients. Only 40% of the drug-treated patients completed the seven-week study, and the reason so many dropped out was because their condition “deteriorated.” For many depressed patients, the NIMH concluded in 1970, “drugs play a minor role in influencing the clinical course of their illness.”[vi]

 

 B. Tricyclics versus active placebo

       In six of the seven, there was no difference in outcomes.[vii]

 

C. SSRIs versus tricyclics

  Analysis of FDA data for seven SSRIS on symptom reduction: [viii] (Arif Khan.)

      42% for tricyclics

      41% for SSRIs

      31% for placebo

 

Analysis of symptom reduction of four SSRIs in FDA trials: (Irwin Kirsch)

      9.6 points on Hamilton scale for medicated patients

      7.8 points for placebo.

Difference is seen as clinically meaningless. Clinically meaningful only in severely depressed patients. [ix]

III. The Long-Term Chronicity Problem Appears

 Physicians notice change in course of depression

 German physician H.P. Hoheisel in 1966: Exposure to antidepressants seemed to be “shortening the intervals” between depressive episodes.”

 

Yugoslavian doctor in 1970: These drugs were causing a “chronification of the disease.”

 

Bulgarian psychiatrist in 1970: The tricyclics are changing the disorder to “a more chronic course.”

 The problem is that they are only “partially cured,” and then depression returned more readily.”[x]

 1973: Dutch psychiatrist J. D. Van Scheyen looks back at five-year record of his patients, dividing into those who took a tricyclic and those who didn’t:

“It was evident, particularly in the female patients, that more systematic long-term antidepressant medication, with or without ECT, exerts a paradoxical effect on the recurrent nature of the vital depression. In other words, this therapeutic approach was associated with an increase in recurrent rate and a decrease in cycle duration . . . Should (this increase) be regarded as an untoward long-term side effect of treatment with tricyclic antidepressants?”[xi]

 

 IV. Documenting the Drug-Related Relapse Problem

 

Relapse rates following drug withdrawal:

 

            (1973) British report 50% relapse within six months. [xii]

 

            (1980) U of Penn report 69% relapse within six months. There was “rapid clinical deterioration in most patients”[xiii]

 

            (1984): NIMH reports that 71% of depressed patients relapsed within 18 months.[xiv]

 

 

Longer-term comparative studies

 

(1981): U of Pittsburgh: 35% of patients treated with an antidepressant continually depressed during a 12-month followup, versus 17% treated with cognitive therapy.[xv]

 

 (1986) Scottish investigators: In two-year study, relapse rates were 78% for the drug group versus 23% for their cognitive therapy group.[xvi]

 

1990 (NIMH): At the end of 18 months, the stay-well rate was best for the cognitive therapy group (30%) and lowest for the imipramine group (19%).[xvii]

 

Seymour Fisher and Roger Greenberg, two pharmacologists from the State University of New York, determined that if study dropouts were included in the analysis, the results for the imipramine patients in this NIMH trial “look even worse . . . patients receiving the antidepressant were most likely to seek treatment following termination, produced the highest probability of relapse, and exhibited the fewest weeks of reduced or minimal symptoms during the follow-up period.”[xviii]

 

Fava G:  Do antidepressants and antianxiety drugs increase  chronicity in affective disorders? Psychotherapy and Psychosomatics  1994; 61: 125-131.

Presents important questions for researchers and clinicians, raising possibility that antidepressants and benzodiazepines / barbiturates may induce biological changes which lead to permanent symptoms, albeit less severe than original in some cases. Fava is defender of “drugs + therapy,” and criticizes the benzodiazepine critics whom he calls “the narrow-minded damnation chorus.”  Nonetheless, he acknowledges the results of research showing that chronic administration of xanax (alprazolam) is inferior to exposure therapy, even when alprazolam is COMBINED with exposure therapy.  In a study conducted in Toronto , patients given the benzodiazepine for panic disorder with agoraphobia had long term outcomes that were worse then psychotherapy alone.   Similarly, Fava mentions the findings of the Pittsburgh Study of Maintenance Therapies in recurrent depression, which suggest that patients maintained on low doses of antidepressants become unable to withdraw from drug treatment after three years.  Fava raises questions about whether drugs therefore may be causing more harm than good, by inducing chemical changes which increase the sensitivity of individuals to the behavioral features of anxiety or depression. Benzodiazepines may be sensitizing the brain to anxiety by inducing downregulation
of the GABA A receptor, the putative mechanism responsible for panic attacks.  Fava implies that there may be similar adaptations occurring in the brain, which lead to
permanent residual symptoms of depression.

 

El-Mallakh RS, Waltrip C, Peters  C: Can Long Term Antidepressant Use Be
Depressogenic?  Journal of Clinical  Psychiatry  1999; 60 (4): 263.

Three clinicians in Louisville , KY have written a letter to the Editor at the Journal of Clinical Psychiatry, responding to an article (Rothschild and Byrne)  about loss of antidepressant efficacy despite maintenance therapy with antidepressants.  In the letter, the authors acknowledge the long-noted tendency of antidepressants to induce mania and/or rapid cycling.  They emphasize the tendency of long term effects of drug treatments to vary widely from acute effects.  A possible mechanism that may be responsible for the medication-related induction of chronic depressive symptoms lies in anatomic changes: changes in neuronal number, or changes in synaptic number. The authors cite several studies demonstrating these changes in animals treated with antidepressants.  Either kind of change might render human subjects more susceptible to depressive symptoms over time.  In other words, it is possible that antidepressants  -- just like neuroleptics – induce structural changes in the brain which make symptoms refractory to treatment.

 

Byrne SE, Rothschild AJ: Loss of Antidepressant Efficacy During Maintenance
Therapy: Possible Mechanisms and Treatments.  Journal of Clinical Psychiatry
1998; 59 (6): 279-288.

Authors look at frequency with which antidepressant medication responders begin to experience return of depressive symptoms, despite the continuation (maintenance) phase of drug treatment.  The authors have performed a search of Medline, reviewing
13   double-blind, placebo controlled studies involving treatment with antidepressants
for at least six months, between 1966 and 1997.   They report a frequency of relapsing/recurring symptoms while taking medication of   9 – 57%.  They  also acknowledge that the Hamilton Rating Scale for depression, used in most studies, probably underestimates the frequency of  “relapse” during treatment due to the fact that it emphasizes vegetative features.  The authors acknowledge that many more patients (more than 60%) who are continuing their treatment with antidepressant medication experience the return of, or worsening, of depressed mood, apathy, and fatigue.  They suggest a number of possible reasons for these effects, ultimately concluding that it may be necessary to “raise doses” or  “add more medications” to compensate for the decreasing efficacy of antidepressants.

 

Fava GA: Can Long Term Treatment With Antidepressant Drugs Worsen the
Course of Depression ?  Journal of Clinical  Psychiatry  2003; 64 (2): 123-133.

Author looks at possibility that antidepressants may worse the course of depression in the long term.  He reviews the existing literature (Medline search) to find articles describing the phenomena of tolerance, sensitization, or switching associated with antidepressant therapy.  He concludes that continued drug treatment may “recruit” processes in the brain that oppose the initial acute effects of drug treatment, and which increase vulnerability to relapse during or after the continuation of medication. The author suggests that “antidepressants are crucial in the treatment of major depressive episodes,” but he suggests that they possibly worsen the overall course of the disorder they are intended to relieve.  Concerned about the paradoxical effects of pharmacotherapy (long term treatment makes some patients worse), he suggests that “further study is needed.”

 

Brugha TS, Bebbington PE, MacCarthy B, Sturt E, Wykes T: Antidepressants may not assist recovery in practice: a naturalistic prospective survey.   Acta Psychiatrica Scandinavica 1992; 86: 5-11.

In a study of 130 patients referred to Maudsley hospital for further evaluation of depression, 119 were reassessed after a 4 month period of treatment.  All patients in the study were interviewed within six months of the onset of their first depressive episode, or within six months of a recurrent depressive episode.  Of the 119 patients who were successfully followed up at four months, 13 were admitted to an inpatient unit of the hospital; 3 were admitted to a day hospital program; and all others were continued either in outpatient psychiatric care (54),  the care of their GP (29),  or  no care (19 decided to pursue no further treatment).  Results at follow-up showed a consistent trend (although not robust) for a “worse outcome in those on drug treatment.”  Patients receiving drug treatment in the study were no more ill (no worse) in the study than those who did not receive it.  44 patients in the study were not on medication at the time of the first interview.  16 of them were placed on medication – 30% of these individuals recovered, compared to 50% (28 patients) who remained medication free.  Overall rates of recovery were found to be 71% of untreated (not medicated)  vs.  61% of those on medication.

 

Fava GA: Potential Sensitising Effects of Antidepressant Drugs on Depression.   CNS Drugs 1999; 12 (4): 247-256.

Fava presents evidence to support the hypothesis that antidepressant drugs may sensitise the brain and worsen the long term outcome.  He suggests clinical findings demonstrating unfavorable long term outcomes when patients are treated pharmacologically.  Fava includes the examples of antidepressant-induced depression, anxiety, mania, and/or rapid cycling in some patients; the occurrence of tolerance to the effects of drugs during long term treatment; the existence of withdrawal syndromes following the discontinuation of antidepressant drugs; and the onset of resistance when some patients are later rechallenged with the same antidepressant drug.   Fava supports the use of antidepressants as a treatment for depression, but he believes that the use of these drugs might need to be modified (limited) in order to prevent the deleterious consequences of  sensitization.  He recommends a cost-benefit appraisal of antidepressants, in order to avoid using them for “prophylaxis,” for minor symptoms, or for anxiety.   Fava worries that the current trend of long-term antidepressant administration may be counter-productive, due to the induction of brain changes which contribute to diminishing drug response over time.

 

 V. The Biology of Relapse and Chronicity

       An Italian, Giovanni Fava: sums up the worry:

 Antidepressant drugs in depression might be beneficial in the short term, but worsen the progression of the disease in the long term, by increasing the biochemical vulnerability to depression . . . use of antidepressant drugs may propel the illness to a more malignant and treatment unresponsive course.[xix]^{, [xx]}

 

              He does further research:

 

“Whether one treats a depressed patients for three months, or three years, it does not matter when one stops the drugs. A statistical trend suggested that the longer the drug treatment, the higher the likelihood of relapse.”[xxi]

 

      The biology of it.

      High risk of relapse if go off, and high risk if stay on.

 

VI. With depressed patients becoming chronically ill, psychiatry reconceptualizes depression’s natural course.

     

      (1985) NIMH Consensus Panel on Mood Disorders:

 

      “Improved approaches to the description and classification of (mood) disorders and new epidemiologic studies (have) demonstrated the recurrent and chronic nature of these illnesses, and the extent to which they represent a continual source of distress and dysfunction for affected individuals.”[xxii]

 

      1999: APA’s Textbook of Psychiatry:

 

      It used to be thought  that “most patients would eventually recover from a major depression episode. However, more extensive studies have disproved this assumption.” It was now known, the APA said, that “depression is a highly recurrent and pernicious disorder.” [xxiii]

 

 

VII. Description of new course

 

• One-third of all unipolar patients are non-responders to antidepressants.

 

• Another third are partial responders, and in short term trials they show up as being helped by drugs. But, as NIMH investigators discovered, “resolution of major depressive episode with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course.” This is true even though stay on meds.[xxiv]

 

• The final third of patients see their symptoms remit over the short term, but only about half of this group, when maintained on an antidepressant, stay well for long periods of time.

 

     APA 1999 textbook:   “Only 15% of people with unipolar depression experience a single bout of the illness,” and for the remaining 85%, with each new episode, remissions become “less complete and new recurrences develop with less provocation.”[xxv]

 

 

VII. Confirming Evidence of Drug-Induced Chronicity Over The Long Term

 A. Retrospective Studies

 
 

(2000) Dutch investigators, in a retrospective study of the 10-year outcomes of 222 people who had suffered a “first-episode” of depression, found that 76% of those not treated with an antidepressant recovered and never relapsed, compared to 50% of those prescribed an antidepressant.[xxvi]

 

(2004): Canadian study: Scott Patten, from the University of Calgary, plumbed a large Canadian health database to assess the five-year outcomes of 9,508 depressed patients, and he determined that the medicated patients were depressed 19 weeks each year (this was the mean), versus 11 weeks for those not taking the drugs. 

 

These findings, Patten wrote, were consistent with Giovanni Fava’s hypothesis that “antidepressant treatment may lead to a deterioration in the long-term course of mood disorders.”[xxvii]

 

B. Screening

 

(1998) WHO screening study: In 15 cities, for one year. Four groups. Diagnosed and treated with antidepressant, diagnosed and treated with benzodiazepine, diagnosed and not treated with a psychiatric drug, undiagnosed and untreated.

 

At end of one year, those who had not been medicated enjoyed much better “general health,” their depressive symptoms were much milder, and a lower percentage were judged to still be “mentally ill.” The group that suffered most from “continued depression” were the patients treated with an antidepressant.

 

The “study does not support the view that failure to recognize depression has serious adverse consequences,” the investigators wrote.[xxviii]

 

C. Disability Rates in Studies

 

 

 (1995). NIMH study on natural course of disorder. Identified at risk group, through relatives of people entered in study, and looked at the course of 547 people over six years.

 

Medicated group was three times more likely than the untreated group to suffer a “cessation” of their “principal social role” during that period, and nearly seven times more likely to become incapacitated.

 

While many of the treated patients saw their economic status markedly decline during the follow-up period, only 17% of the unmedicated group saw their incomes drop, and 59% saw their incomes rise. 

 

“The untreated individuals described here had milder and shorter-lived illnesses (than those who were treated), and, despite the absence of treatment, did not show significant changes in socioeconomic status in the long term.”[xxix]

 

 

Canada, 2001. Dewa.  Study of 1,281 people who went on short-term disability for depression.

 

The 564 people who subsequently didn’t fill a prescription for an antidepressant returned to work, on average, in 77 days, while the medicated group took 105 days to get back on the job. Only 9 percent of the unmedicated group went onto long-term disability, versus 19% of those who took an antidepressant. [xxx]

 

 D. Nationwide Disability Rates in Prozac Era

 

• In Britain, the number of days of incapacity due to depression jumped from 38 million in 1984 to 117 million in 1999, a three-fold increase.[xxxi]

 

• Iceland reported that the percentage of its population disabled by depression rose from .4% in 1976 to .7% in 2000. If antidepressants were truly helpful, the Iceland investigators reasoned, then the use of these drugs “might have been expected to have a public health impact by reducing disability, morbidity, and mortality due to depressive disorders.”[xxxii]

 

• In the United States, the percentage of working-age Americans who said in health surveys that they were disabled by depression rose three-fold during the 1990s .[xxxiii]

 

 

VIII. Change in Depression During the Drug Era

 

Pre-Drug: Fairly uncommon disorder, and only 10% become chronically ill.

 

Today: Very common disorder and runs a chronic course.

 

Societal Result:

 

            Major depressive disorder is now the leading cause of disability in the United States for people ages 15 to 44. According to the NIMH, it affects 15 million American adults, and researchers at Johns Hopkins School of Public Health reported in 2008 that 58% of this group is “severely impaired.” [xxxiv]^, [xxxv] That means nearly nine million adults are now disabled, to some extent, by this condition.

 

References

OK, So it looks like it has been getting worse. 
What about all those medications, FDA approvals and Clinical Trials?

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.      

SO WHAT DID THE LARGEST STUDY EVER DONE WITH TEENS (TADS)

SAY ABOUT MY DEPRESSED TEENAGER?

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 Prozac and 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%.

 conclusion:

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.

 

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:
http://archpsyc.ama-assn.org/cgi/content/abstract/64/10/1132?lookupType=volpage&vol=64&fp=1132&view=short

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." One can write a book on the lack of science and duplicity in this study -- but I'll try to stick to key crap:

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.

 SO DO THEY CAUSE MORE SEVERE PROBLEMS?

Black box warning labels DECREASE suicide

No Significant increase since HUGE REDUCTION in SSRI Use!

 

Recently people have been reporting that SINCE the anti-depressant medications have obtained a Black Box Warning Label, indicating they can CAUSE people to feel suicidal, there has been a significant reduction in the use of these drugs, there has been a 16-18% increase in suicides…due to not taking the medications.  THIS IS SIMPLY FALSE AND MISLEADING.

 

While one obvious rebuttal for this antidepressant/suicide story is that correlation does not equal causation -- and researcher Dr. David Antonuccio, PhD makes a good point about neglecting the increase in anti-psychotics for kids (i.e. as well as  many other potential variables) --there is an even MORE GLARING REASON that  Newsweek and other media should be ashamed of itself for suggesting this idea.  Read Below.
         
Only wishful thinking on the part of antidepressant manufacturers leads to a conclusion that the drop in SSRI prescriptions for 5-18 year old in 2004 has resulted in increased suicide for that age group. The researcher who told Newsweek that reduced antidepressant prescribing has led to more suicides in kids is on the advisory board of Eli Lilly (manufacturers of Prozac).  If one examines suicide rates for the entire period from 1999 to 2003, when antidepressant use for this age group was high, one sees that 2004 suicide rates are unremarkable.  According to official CDC statistics, the rate of suicide for CDC's 5-14 age group in 2004 is exactly the same rate as in both 2001 and 2000.  Similarly, the suicide rate for CDC's 15-24 age group in 2004 is actually slightly lower than the 2000 rate. Should there actually ever be a substantive increase in suicide rates, history tells us the likely source will not be a lack of psychiatric treatment but rather social or economic upheavals.

Sources:   If you and Newsweek would like to check out the actual CDC suicide statistics, I have the CDC links and tables that make it clear that suicide rates have not increased after decreased antidepressant prescriptions for 5-18 year-olds.

http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_13.pdf
CDC's National Vital Statistics Report Deaths: Final Data 2003 (which includes data from 1999-2003)

http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_19.pdf
CDC's National Vital Statistics Report: Deaths Preliminary Data 2004

Deaths per 100,000
Intentional self-harm
(suicide)             5-14 years        
2004                       0.7                               
2003                       0.6                   
2002                        0.6                 
2001                        0.7                          
2000                        0.7                   
1999                        0.6                  

Intentional self-harm
(suicide)             15-24 years
2004                       10.1            
2003                         9.7
2002                         9.9
2001                         9.9         
2000                       10.2
1999                       10.1
Intentional self-harm
(suicide)             All Ages       
2004                    10.8                      
2003                    10.8             
2002                    11.0             
2001                    10.8              
2000                    10.4             
1999                    10.5             

"Pharmacoepidemiological studies examining the relationship between trends in sales or prescription fills of SSRIs have consistently shown a relationship between increases in SSRI prescription rates and declines in adolescent suicide rates (9, 35–37). On the basis of those studies, one might expect that the adolescent suicide rate would begin increasing in the wake of the FDA advisory after a decade of steady decline. {p. 890}"

The Newsweek article stated that prescriptions for pediatric depression (ages 5 - 18) dropped more than 50% between 2003 and 2005 -- a 2-year period. This is also not what the article in Am J. Psychiatry stated. It stated that prescription rates for pediatric depression had been steadily rising since 1998, and that after the October 2003 black box warning prescription rates in October 2005 were 58% lower than they would have been had they continued to rise between October 2003 and October 2005 at the same average rate at which they had risen between October 1998 and October 2003. Using their figures, the actual decline in prescription rates for SSRIs for pediatric depression between October 2003 and October 2005 was 45.5%.

Then the article states that "in a parallel development, the number of teen suicides jumped a record 18% between 2003 and 2004." It mentioned no source. It did mention that the CDC will release suicide figures for 2005 in December of this year. This leads me to believe that the Newsweek article used CDC above.

If they used the CDC data for the ages 5 - 14, using only one significant figure (we could use more than one) the increase between 2003 and 2004 is 0.7 / 0.6 = 16.67%.

 

In the 15 - 24 "teenager" age  group the increase between 2003 and 2004 is 10.1 / 9.7 = 4.1%.

 

I would expect to find more teenagers in this group than in the former, and would certainly expect a higher suicide rate in the latter group.When the two age groups are aggregated into one (5 - 24), there was no change, the rate remained 10.8 per 100000.  In this case a reversal from increases in suicide rates over time to no
significant rate change over time. It isn't really a paradox. It is just the result of combining groups of different sizes and comparing aggregates with the separate groups. It looks as someone picked the group that best fit what they wanted and ignored the aggregate data. When discussing teen suicides I think that the 5 - 14 group is the
least significant of the three.

Now this "18 % increase in teen suicides from 2003 to 2004" is being broadcasted all over the place as if it is an actual fact.

Tony Dokoupil’s Trouble in a ‘Black Box’ (July 16 article) importantly addresses the risks and benefits of prescribing antidepressants to children. However, the referenced study is far from “compelling” evidence for removing the FDA Black Box warning and such an interpretation of its findings is misleading.

 

An inspection of this Eli Lily funded study reveals that the precipitous drop in SSRI prescriptions did not occur, as reported, from 2003 to 2005 but rather from February to October of 2005 (over 85% of the drop in the last 6 months of the reported time). The so-called “parallel development” of increased suicides occurred between 2003 and 2004—and therefore had no relationship to the drop in prescription rates reported in this study. Given that the decrease in prescription rates and increase in suicides occurred in different time periods, it begs the question of how such unsubstantiated statements could be made by the experts cited in the a rticle.

Only 3 of 15 clinical trials have shown antidepressants to be superior to a sugar pill on primary measures. Children and parents in those 15 studies reported no advantage of antidepressants over a sugar pill.

Data from the FDA and its British counterpart demonstrate that children and adolescents taking antidepressants are twice as likely to experience suicide-related events. Given the meager results and increased risk for suicide-related events (as well as other serious adverse events), antidepressants are not a good choice for youth struggling with depression—a conclusion reached after an extensive risk/benefit analysis conducted by the American Psychological Association’s Work Group on Psychotropic Medication (e.g first choice).

Given that depression tends to remit over time, and so suicidality, do these studies really prove anything other than that any possible increase in suicidality caused by the medications is insufficient to overwhelm the natural average decrease in suicidality expected to be seen in any depressed population over time?

 

To make the conclusions they are trying to make, that the medications did not increase suicidality or even decreased it, they would have to have a comparison group identified as equally depressed, not given medication, then remeasured later.  They apparently don't have this group so they can't make that conclusion.