SSRI Antidepressants No Better Than Placebo Says JAMA

Placebo effect SSRI Drugs

SSRI Antidepressants
No Better Than Placebo Says JAMA

by Jeffrey Dach MD

A study published in JAMA Jan 5, 2010 reported that SSRI antidepressants are no better than placebo for most cases of depression. The authors reviewed 30 years of data and concluded that “the benefit of antidepressant medication compared with placebo may be minimal or nonexistent in patients with mild or moderate symptoms”.

Of course, this is old news, and reminds me of the famous scene in 1942 film, Casablanca, where Captain Louis Renault declares, ” I am Shocked, Shocked … to find gambling here….Here is your winnings… Oh thank you.”  See clip below:

Better than Placebo for Severe Depression

I should add that the study found antidepressants work better than placebo for severe depression.  This is not surprising, since psycho-stimulants in general have been found useful in treatment of severe or refractory depression.(54-57)

Is Depression Really a Medical Disease?

drugsssriMedically speaking, the term “Depression” is a vague constellation of feelings and symptoms scored by a questionnaire called the Hamilton Depression Score.

How to Score Depression as Mild, Moderate or Severe? Online Tools

There are a number of handy on-line tools for taking the Hamilton Depression Score Questionnaire.  Here is one of them:   For the short 17-item version of the Hamilton questionnaire, scores can range from 0 to 54.   Hamilton scores between 0 and 6 are normal.  Scores between 7 and 17 indicate mild depression, scores between 18 and 24 indicate moderate depression, and scores over 24 indicate severe depression.  According to the Jan 5 JAMA study, if your Hamilton score is less than 24, then placebo is just as effective as  antidepressant drugs.  That means they work about the same as a sugar pill.

paxilpillssuicidedepressionHere are the Hamilton Depression Score Questions (short version):

Mood (Are you sad, hopeless, helpless, worthless?)

Feeling of Guilt (Do you have feelings of guilt, or self reproach?)

Do you have Suicide ideas, gestures or attempts?

INSOMNIA (Do you have difficulty falling asleep, staying asleep?)

WORK AND ACTIVITIES (Do you have thoughts and feelings of fatigue or weakness related to activities,  or decreased or Stopped activities or working because of present illness?)

Do you have Slowness of thought and speech; Do you have difficulty concentrating; slow movements)?

AGITATION (Do you have Fidgeting,  Playing with hands, hair, etc,  Moving about, can’t sit still.  Hand wringing, nail biting, hair-pulling, biting of lips etc)?

ANXIETY (Do you have tension and irritability, Worrying,  Apprehension, Fears expressed)?

ANXIETY: SOMATIC (Do you have dry mouth, wind, indigestion, diarrhea, cramps, belching. – Cardio-vascular : palpitations, headaches. hyperventilation, sighing. Urinary frequency – Sweating)?

SOMATIC SYMPTOMS: GASTROINTESTINAL Do you have Loss of appetite, require laxatives or medication for bowels, or medication for gastro-intestinal symptoms?

SOMATIC SYMPTOMS: GENERAL – Do you have Heaviness in limbs, back or head? Backaches, headache, muscle aches. Loss of energy and fatigability?

GENITAL SYMPTOMS -Do you have loss of libido, menstrual disturbances?

HYPOCHONDRIASIS –  Do you have preoccupation with  your health.?

LOSS OF WEIGHT -Do you have weight loss from depression.?

INSIGHT – Acknowledges or denies being depressed.  ?

Overlapping Symptoms- Is it Really Depression ?

As is obvious, many of these feelings or symptoms are somewhat subjective and rather vague, so depression scoring is not an exact science and can be manipulated according to the agenda of the research or questioner. As you can see, many of these Hamilton symptoms overlap with real medical diseases.  For example patients with inflammatory bowel disease or celiac disease would score positive for the GI symptoms even though they may not be clinically “depressed”.  Somatic symptoms of fatigue and muscle pain may overlap with fibromyalgia and hypothyroid symptoms.  Slowness of thought and speech could overlap with a low thyroid condition or a neurological disorder such as B12 deficiency.  Patients in chronic severe pain contemplating suicide may not necessarily indicate clinical “depression”.  Obviously, these patients need pain relief rather than an SSRI antidepressant.

paxil_side_effects_lawsuit_birth_defects_10Hormonal Imbalance Symptoms Overlap with Many of the Hamilton Symptoms

Many women with hormonal imbalance related to pre-menopause  or post menopausal transitions will have mood disorders and symptoms which overlap with many of the symptoms on the Hamilton Depression Score.

For example, the term Premenstrual Dysphoric Disorder is commonly treated with SSRI antidepressants  by mainstream primary care and OB/Gyne Docs.  Premenstrual Dysphoric Disorder is a manufactured term made up by the drug companies to sell SSRI drugs and in reality, attempts to redefine the original term, PMS (premenstrual syndrome).

With the Jan 5, 2010 JAMA article, we now have evidence that Premenstrual Dysphoric Disorder and other common forms of hormonal imbalance are poorly served by SSRI antidepressants.  Using SSRI’s is simply the wrong way. The benefit of SSRI antidepressants for this group is the same as the benefit from placebo. Rather, this group of women should be properly evaluated, and then treated with bioidentical hormones to address their underlying problem.  We have noted considerable success using cyclic natural progesterone in this group of women with PMS and other hormonal imbalances.  In my opinion, natural progesterone is a far better form of treatment with none of the adverse side effects associated with SSRI antidepressants.

Adverse Side Effects of Antidepressants – Placebos Have NONE

When placebo and SSRI antidepressants are compared and found equally effective, the next question relates to adverse side effects.  By definition, placebos have no adverse side effects.  However, this is not true for antidepressants which have the following adverse effects:  Sexual dysfunction, weight gain, insomnia and sleep disturbance are the most troubling adverse effects of SSRI anti-depressant drugs.   Loss of libido and loss of sexual function can be the most serious for young man and women on SSRI drugs, as discussed by Helen Fisher in her 2007 report. entitled,” Lust, romance, attachment: SSRI antidepressants jeopardize romantic love marriage and fertility ” (71)

Induce  Mania or Psychosis in Your Child With SSRI Drugs

Mania and Psychosis are known adverse effect of SSRI antidepressant drugs resulting in 8% of admissions to a general hospital psychiatric ward over a 14 month study period. “Forty-three (8.1%) of 533 patients were found to have been admitted owing to antidepressant-associated mania or psychosis”.(51-52)

Movement Disorders Induced by SSRI Antidepressants (67-70)

Another adverse effect of SSRI drugs is induction of movement disorders such as tardive dykinesia and Parkinson’s.(67-70)

SSRIs and  Suicide Risk

Another troubling adverse effect of SSRI antidepressants is increased suicide first reported by Teicher in 1990.  According to David Healy (Let then Eat Prozac), the original clinical trial data was  manipulated by moving the suicide cases from the treatment arm over to the placebo arm of the study.  This manipulated data was then submitted to the  FDA who conveniently looked the other way.  This disturbing information was presented at a Cornell University Mar 25, 2009 talk by David Healy which can be seen here on You Tube.   

Prozac_Black_box_warning_suicide_jeffrey_Dach_MdBlack Box Warning

As of May 2007, all SSRI drugs now carry a black box FDA warning for increases risk of suicide.(72) (see above image)

SSRI Discontinuation Syndrome / Withdrawal Effects

Withdrawal effects such as dizziness, lethargy, and sleep disturbances upon discontinuing SSRIs may be severe, requiring gradual tapering.(65)  Dr Giovanni Fava concluded in 2015 that SSRI drugs  produce withdrawal effects upon discontinuation, and should be added to the list of drugs such as benzodiazepines, barbiturates, and other psychotropic drugs. He suggests the term ‘discontinuation syndrome‘ minimizes the magnitude of the SSRI risks and should be replaced by the more straightdorward ‘withdrawal syndrome’.(64)

The Army and Military Suicide from SSRIs Antidepressant Use

Another striking finding is the unprecedented increased suicide rate in the military with  widespread use of SSRI’s and other psycho active drugs in the Army.   Again this is a rather sad commentary, and another nail in the coffin for SSRI drugs as being more harmful than helpful.

Lithium Reduces Suicide Risk and is Better Choice

Unlike SSRI antidepressants which increase suicide in the depressed patient, lithium has been shown to reduce suicide rates in multiple population studies, and is therefore might be considered a preferred in the depressed psychiatric patient.  See my two part series on lithium: part one, part two.

SSRI’s Provide Unexpected Clinical Benefit in Ischemic Stroke (58,59)

Dr Timo  Siepmann reported in 2015 that SSRI antidepressants “improve outcomes in acute ischemic stroke.” (58)  The mechanism is thought to be SSRI stimulation of neurogenesis in the hippocampus, and suppression of microglia with anti-inflammatory effect. (58) Treatment with SSRI drugs In animal models of ischemic stroke decreases infarct volume and improves behavioral outcome. (59)

Lithium Neuroprotection in Ischemic Stroke Patients(60-63)

A 2014 placebo controlled study in Clinical Neuropharmacology evaluated the effect of lithium in post-stroke motor recovery.(60)  Forty stroke patients were treated with lithium, 300 mg twice daily for 30 days after the stroke, and another forty given placebo.  Patients in the cortical stroke subgroup regained more than 25% of full function with Lithium treatment compared to only 14.7% in the placebo group.

In an animal model of cerebral ischemia published in 1998 (61), entitled “Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats.” , administration of Lithium Cl for 16 days “significantly improved neurological deficits, including abnormal posture and hemiplegia, measured 24 h after cerebral artery occlusion“. Infarct size was reduced by 56% after lithium pretreatment.  The authors suggest lithium  useful for reducing stroke induced brain damage. (61-62)  Others suggest that  Lithium’s neuroprotection in the stroke patient due to  increased brain-derived neurotrophic factor (BDNF). (63)  Since lithium has been more carefully studied than SSRI antidepressants, with a known track record of benefits preventing suicide, for example, perhaps lithium would be the preferred choice for neuroprotection in the stroke population.

Lithium has no withdrawal syndrome, and does not induce mania states as do the SSRI drugs.  Unlike SSRI drugs which carry a black box warning for increased suicide risk, Lithium prevents suicide.

Update June 2016: Placebo Effects of Antidepressants by Kelly Brogan MD

Update June 8,2015: Antonuccio, David, and David Healy. “Relabeling the Medications We Call Antidepressants.” Scientifica 2012 (2012).

Update Sept 2015: BMJ article: Paxil found no more effective than placebo,
Le Noury Joanna, Nardo John M, Healy David, Jureidini Jon, Raven Melissa, Tufanaru Catalin et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence BMJ 2015; 351 :h4320.

Update June 2016: Cipriani, Andrea, et al. “Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.” The Lancet (2016).(50)  Dr Cipriani says:

“When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents.”(compared with placebo)(50)

SSRI antidepressants (Prozac) Use in Children-Black Box Warning

Prozac_Black_box_warning_suicide_jeffrey_Dach_MdBlack Box Suicide Warning above image courtesy of Eli Lilly makers of Fluoxetine.

Articles with Related Interest:

SSRI Drugs and Overcome Depression Naturally

Protect Your Family from Bad Drugs

Jeffrey Dach MD

Links and References:

Antidepressant Drug Effects and Depression Severity A Patient-Level Meta-analysis by Jay C. Fournier, MA; Robert J. DeRubeis, PhD; Steven D. Hollon, PhD; Sona Dimidjian, PhD; Jay D. Amsterdam, MD; Richard C. Shelton, MD; Jan Fawcett, MD in JAMA. 2010;303(1):47-53.

Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression.

Objective  To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression.
Data Sources  PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews.

Study Selection  Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included.

Data Extraction  Individual patient-level data were obtained from study authors.
Results  Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25.

Conclusions  The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

“What makes our findings surprising is the high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving ADM in clinical practice present with scores below these levels.”

Initial Severity and Antidepressant Benefits: February 26, 2008
A Meta-Analysis of Data Submitted to the Food and Drug Administration
Irving Kirsch1*, Brett J. Deacon2, Tania B. Huedo-Medina3, Alan Scoboria4, Thomas J. Moore5, Blair T. Johnson3 1 Department of Psychology, University of Hull, Hull, United Kingdom, 2 University of

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Depression treatment: We need better not simply more Getting more people into treatment for depression is not enough.  Published on January 5, 2010

Popular Drugs May Help Only Severe Depression By BENEDICT CAREY Published: January 5, 2010

JANUARY 6, 2010.Effectiveness of Antidepressants Varies Widely  By JENNIFER CORBETT DOOREN

Patients with severe depression benefit most from antidepressant medications while those with less-severe symptoms see little or no benefit, according to a new analysis released Tuesday. Researchers combined the results of six studies involving patients ranging from mildly depressed to very severely depressed as rated on the Hamilton Depression Rating Scale, which doctors use to diagnose patients. The analysis, comparing 718 patients assigned an antidepressant or a placebo, is published in this week’s Journal of the American Medical Association.

Robert DeRubeis, a primary author of the analysis and a psychology professor at the University of Pennsylvania, said the bulk of studies evaluating antidepressants involve patients considered severely depressed. Such studies also were used to gain Food and Drug Administration approval for the drugs.

Fewer studies have been conducted involving mildly depressed patients. It isn’t clear how well drugs like Paxil or Prozac work on these patients, who account for a large portion of antidepressant use.

According to the National Institute of Mental Health, depression affects approximately 14.8 million American adults, or about 6.7% of the U.S. adult population, in a given year.  Dr. DeRubeis said patients in the severely depressed group had scores improved by an average of four points when taking a drug like GlaxoSmithKline PLC’s Paxil, compared with the placebo group, a difference considered “substantial.”

He said patients with scores below 23 taking Paxil, or an older drug, imipramine, improved by one point over those taking a placebo. Patients considered to have mild or moderate depression, or a Hamilton score of 18 or less, improved by less than one point. “There is little evidence to suggest that [antidepressants] produce specific pharmacological benefit for the majority of patients with less severe acute depression,” researchers wrote.

Penn Study Shows Antidepressants Work Best for Severe Depression, Provide Little to No Benefit Otherwise.

January 05, 2010 PHILADELPHIA –- A study of 30 years of antidepressant-drug treatment data published today in the Journal of the American Medical Association shows that the benefit of antidepressant medication compared with placebo may be minimal or nonexistent in patients with mild or moderate symptoms. University of Pennsylvania researchers say, however, the benefit of medications is substantial for patients with very severe depression.

Antidepressants Don’t Help Mild Depression: Study

In the 17-item version, nine of the items are scored on a five-point scale, ranging from zero to four. A score of zero represents an absence of the depressive symptom being measured, a score of one indicates doubt concerning the presence of the symptom, a score of two indicates mild symptoms, a score of three indicates moderate symptoms, and a score of four represents the presence of severe symptoms. The remaining eight items are scored on a three-point scale, from zero to two, with zero representing absence of symptom, one indicating doubt that the symptom is present, and two representing clear presence of symptoms.

For the 17-item version, scores can range from 0 to 54.

One formulation suggests that scores between 0 and 6 indicate a normal person with regard to depression, scores between 7 and 17 indicate mild depression, scores between 18 and 24 indicate moderate depression, and scores over 24 indicate severe depression.

Hamilton rating scale for depression 17 questions

online HMD questionaire –  quick score for depression – adjusted for layman

online HMD questionaire –  quick score for depression – classic printable version

Casablanca is a 1942 film – Captain Louis Renault
I am shocked — shocked— to find that gambling is going on in here!

Adverse side effects of ssris

14) Problems associated with long term treatment with selective serotonin reuptake inhibitors by Chantal Moret* and Mike Isaac*

Sexual dysfunction, weight gain and sleep disturbance are the most troubling adverse events seen during long-term SSRI therapy. The most common side effects associated with SSRIs such as nausea and headache, nervousness, insomnia and sexual dysfunction.

Other Blogs

15) Christopher Lane Ph.D. The Antidepressant Dilemma Psychology today Jan 09, 2010
antidepressants have limited-to-zero efficacy for those with mild depression. Yet the drugs have been prescribed to that population in very high numbers (in June 2005, as I’ve reported before, the International Review of Psychiatry estimated that the total amount prescribed in the U.S. alone has been to upwards of 67.5 million people, almost one quarter of the general population).

Antidepressants Don’t Help Mild Depression: Study By Ed Silverman // January 5th, 2010 // 4:06 pm

17)  deleted

Antidepressants Hardly Help By LAURA BLUE/LONDON Tuesday, Feb. 26, 2008 Time MAgazine

Antidepressant-Placebo Debate in the Media- Balanced Coverage or Placebo Hype?
A spate of articles has recently appeared in the popular media with such intriguing titles as “Maybe It’s All in Your Head,” “Make-Believe Medicine,” “New Study of Brain Illustrates the Power of Placebo,” “Antidepressants: Hype or Help?” and “Misguided Medicine: A Stunning Finding about Antidepressants Is Being Ignored,” to name but a few. Journalists have found a new public-interest story about mental health that readers seem to be hungry for-the antidepressant versus placebo controversy.

20) Gaudiano, B. A., & Herbert, J. D. (2003). Methodological issues in clinical trials of antidepressant medications: Perspectives from psychotherapy outcome research. Manuscript under review.

21) Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., et al. (1994). Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the national comorbidity survey. Archives of General Psychiatry, 51, 8-19.

22) Khan, A., Leventhal, R. M., Khan, S., & Brown, W. A. (2002). Severity of depression and response to antidepressants and placebo: An analysis of the Food and Drug Administration database. Journal of Clinical Psychopharmacology, 22, 40-45.

23) Kirsch, I., Moore, T. J., Scoboria, A., & Nicholls, S. S. (2002). The emperor’s new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment, 5, art. 23. Retrieved February 1, 2003, from

24) Kirsch, I., & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment, 1, art. 0002a. Retrieved February 1, 2003, from

25) Klein, D. F. (1998). Listening to meta-analysis but hearing bias. Prevention & Treatment, 1, art. 0006c. Retrieved February 1, 2003, from

26) Leber, P. (2000). The use of placebo control groups in the assessment of psychiatric drugs: An historical context. Biological Psychiatry, 47, 699-706.

27) Leuchter, A. F., Cook, I. A., Witte, E. A., Morgan, M., & Abrams, M. (2002). Changes in brain function of depressed subjects during treatment with placebo. American Journal of Psychiatry, 159, 122-129.

28) Lohr, J. M., Lilienfeld, S. O., Tolin, D. R., Herbert, J. D. (1999). Eye movement desensitization and reprocessing: An analysis of specific versus nonspecific treatment factors. Journal of Anxiety Disorder, 13, 185-207.

29) Mayberg, H. S., Silva, J. A., Brannan, S. K., Tekell, J. L., Mahurin, R. K., McGinnis, S., & Jerabek, P. A. (2002). The functional neuroanatomy of the placebo effect. American Journal of Psychiatry, 159, 728-737.

30) deleted

31) Moncrieff, J., Wessely, S., & Hardy, R. (2002). Active placebos versus antidepressants for depression (Cochrane Review). The Cochrane Library, 1. Oxford: Update Software.

32) Quitkin, F. M., Rabkin, J. G., Gerald, J., Davis, J. M., & Klein, D. F. (2000). Validity of clinical trials of antidepressants. American Journal of Psychiatry, 157, 327-337.

33) Rosenthal, R. (1979). The “file drawer problem” and tolerance for null results. Psychological Bulletin, 86, 638-641.

34) Vedantam, S. (2002, May 7). Against depression, a sugar pill is hard to beat. Washington Post, A01. Retrieved February 1, 2003, from

Suicide and the Military on SSRIs

America’s Medicated Army- By Mark Thompson Thursday, Jun. 05, 2008

36) R.D. Gibbons, C.H. Brown, K. Hur, S.M. Marcus, D.K. Bhaumik, and J.J.
Mann, “Relationship Between Antidepressants And Suicide Attempts: An Analysis of the Veterans Health Administration Data Sets,” American Journal of Psychiatry 164 (2007): 1044-1049.

37) Valenstein M, Kim HM, Ganoczy D, McCarthy JF, Zivin K, Austin KL, Hoggatt K, Eisenberg D, Piette JD, Blow FC, Olfson M. Higher-risk periods for suicide among VA patients receiving depression treatment: prioritizing suicide prevention efforts. Journal of Affective Disorders, 2009 Jan;112(1-3):50-8.

38) M. Raja, A. Azzoni, and A.E. Koukopoulos, “Psychopharmacological treatment before suicide attempt among patients admitted to a Psychiatric Intensive Care Unit,” Journal of Affective Disorders 113 (2009): 37-44.


39) Antidepressants Can Cause Long-Term Depression Dr. Peter Breggin
reform psychiatrist Huffington Post

40) Synapse. 1993 Aug;14(4):324-31. Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain: an autoradiographic study. Hrdina PD1, Vu TB.

This study was undertaken to investigate the effect of chronic treatment with fluoxetine, a selective serotonin uptake inhibitor used widely in the treatment of depression, on the distribution and density of 5-HT uptake sites, 5-HT2 receptors, and vesicular amine uptake sites in rat brain. Fluoxetine (10 mg/kg i.p.) was administered daily for 21 days. The density of 5-HT uptake sites labelled by [3H]paroxetine, 5-HT2 receptors labelled by [3H]ketanserin in presence of tetrabenazine and vesicular amine uptake sites labelled by [3H]ketanserin in the presence of mianserin were measured by quantitative autoradiography in 22 areas of rat brain, using coronal tissue sections. Chronic administration of fluoxetine produced significant increases in the density of 5-HT uptake sites in layers of frontoparietal cortex (by 32-43%), of striate cortex (by 55%), in CA1 field of hippocampus (by 111%) and in superior colliculus (by 20%). Fluoxetine treatment also resulted in upregulation of 5-HT2 receptors in layers of frontoparietal cortex (31-38%) and in CA2-3 fields of hippocampus (by 39%). The density of tetrabenazine-sensitive vesicular amine uptake sites in the caudate-putamen was also significantly increased (by 66%). The observed alterations in 5-HT uptake site and 5-HT2 receptor densities are likely a part of adaptive neuronal changes that occur after chronic administration of fluoxetine and may be related to the antidepressant effect of the drug.

41)  Benmansour, Saloua, et al. “Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level.” The Journal of neuroscience 19.23 (1999): 10494-10501.
SERT density in the CA3 region of the hippocampus of the same rats, assessed by quantitative autoradiography with tritiated cyanoimipramine ([3H]CN-IMI), was decreased by 80–90% in SSRI-treated rats but not in those treated with phenelzine or DMI. The serotonin content of the hippocampus was unaffected by paroxetine or sertraline treatment, ruling out neurotoxicity as a possible explanation for the SSRI-induced decrease in SERT binding and alteration in 5-HT clearance. Levels of mRNA for the SERT in the raphe nucleus were also unaltered by chronic paroxetine treatment. Based on these results, it appears that the SERT is downregulated by chronic administration of SSRIs but not other types of antidepressants;

42)   Hébert, Caroline, et al. “Effects of chronic antidepressant treatments on 5-HT and NA transporters in rat brain: an autoradiographic study.” Neurochemistry international 38.1 (2001): 63-74.

Also, densities of NA transporters decreased in temporal cortex, CA2 and nucleus raphe dorsalis in fluoxetine-treated rats as compared to the controls.

43)  Mol Psychiatry. 2000 Jul;5(4):378-88.  Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments.  Lammers CH1, Diaz J, Schwartz JC, Sokoloff P.

The mesolimbic dopaminergic system is a neuroanatomical key structure for reward and motivation upon which previous studies indicated that antidepressant drugs exert a stimulatory influence, via still unknown neurobiological mechanisms. Here we examined the effects of chronic administration of antidepressants of several classes (amitriptyline, desipramine, imipramine, fluoxetine and tranylcypromine) and repeated electroconvulsive shock treatments (ECT) on dopamine D3 receptor expression in the shell of the nucleus accumbens, a major projection area of the mesolimbic dopaminergic system. Short-term drug treatments had variable effects on D3 receptor mRNA expression. In contrast, treatments for 21 days (with all drugs except fluoxetine) significantly increased D3 receptor mRNA expression in the shell of nucleus accumbens; D3 receptor binding was also significantly increased by amitriptyline or fluoxetine after a 42-day treatment. ECT for 10 days increased D3 receptor mRNA and binding in the shell of nucleus accumbens. D1 receptor and D2 receptor mRNAs were increased by imipramine and amitriptyline, but not by the other treatments. The time-course of altered D3 receptor expression, in line with the delayed clinical efficiency of antidepressant treatment, and the fact that various antidepressant drugs and ECT treatments eventually produced the same effects, suggest that increased expression of the D3 receptor in the shell of nucleus accumbens is a common neurobiological mechanism of antidepressant treatments, resulting in enhanced responsiveness to the mesolimbic dopaminergic system.

44)  Maturitas. 1986 Oct;8(3):229-37.  Effects of different dopamine agonists and antagonists on post-menopausal hot flushes.  Zichella L, Falaschi P, Fioretti P, Melis GB, Cagnacci A, Gambacciani M, Mancini S.

The dopaminergic system seems to be involved in both pulsatile luteinizing hormone (LH) secretion and hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectiveness of dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessed scores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one of the following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergic agent, Liposom; the antidopaminergic drug, veralipride or the peripheral antidopaminergic agent, domperidone. All of these treatment regimens were effective in alleviating hot flushes, but the pharmacological agents proved to be more effective than the placebo. A direct dopaminergic action is hypothesized in the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through different indirect mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on tuberoinfundibular dopamine (TIDA) neurons with a secondary dopamine-like activity, or stimulation of the opioid system.

45)  Am J Obstet Gynecol. 1988 May;158(5):1107-15.
Veralipride: alternative antidopaminergic treatment for menopausal symptoms.
David A1, Don R, Tajchner G, Weissglas L.

The vasomotor hot flushes and increased perspiration symptomatic of the menopausal period reflect the adaptation of the body to the lowering of its preset basal temperature resulting from the interference of various central neurotransmitters of suprahypothalamohypophyseal origin. The present double-blind study was conducted to test the efficacy of veralipride, a synthetic antidopaminergic molecule, in eliminating the symptoms of menopause in 50 patients. Results indicated a total elimination of both hot flushes and excessive perspiration in 63% to 80% of the patients treated. The beneficial effects persisted up to 3 months of follow-up. Veralipride significantly increased dehydroepiandrosterone sulfate and estradiol levels. High values of prolactin were found, and some patients showed slight breast discharge; these changes disappeared 48 hours after the drug was stopped.

?????????????????????? Women report hot flashes worsened by requip

Patent Ropinirole controls menopausal hot flashes
Dopamine agonist with affinity to D2 D3 D4 receptors

46) Improved method and compound for treatment of menopausal symptoms
CA 2866494 A1

The subject invention describes a method of use of Ropinirole TM to alleviate and control menopausal symptoms in women, and in particular, hot flashes. The invention describes the use of Ropinirole as a dopamine agonist with affinity for the dopamine D2, D3, or D4 receptors. Ropinirole may also be used to treat menopausal symptoms in cojunction with TizanidineTM to further reduce the effects menopausal symptoms by providing a sedative and muscle relaxant effect which aids in sleep. The combination of Ropinirole and Tizanidine provides a useful new compounds for treatment of menopausal symptoms that are most disruptive to the functioning in activities of daily living.


47)   Pharmacopsychiatry. 1996 Jan;29(1):23-6.
Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression.
Skolnick P1, Layer RT, Popik P, Nowak G, Paul IA, Trullas R.

Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action.

48) Biol Psychiatry. 2013 Jun 15;73(12):1180-8. The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors.
Musazzi L1, Treccani G, Mallei A, Popoli M.

Recent compelling evidence has suggested that the glutamate system is a primary mediator of psychiatric pathology and also a target for rapid-acting antidepressants. Clinical research in mood and anxiety disorders has shown alterations in levels, clearance, and metabolism of glutamate and consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these as major factors in psychopathology. Enhancement of glutamate release/transmission, in turn induced by stress/glucocorticoids, seems crucial for structural/functional changes. Understanding mechanisms of maladaptive plasticity may allow identification of new targets for drugs and therapies. Interestingly, traditional monoaminergic-based antidepressants have been repeatedly shown to interfere with glutamate system function, starting with modulation of N-methyl-D-aspartate (NMDA) receptors. Subsequently, it has been shown that antidepressants reduce glutamate release and synaptic transmission; in particular, it was found antidepressants prevent the acute stress-induced enhancement of glutamate release. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression models. Finally, a number of studies over the years have shown that these drugs regulate glutamate receptors, reducing the function of NMDA receptors, potentiating the function of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, and, more recently, exerting variable effects on different subtypes of metabotropic glutamate receptors. The development of NMDA receptor antagonists has opened new avenues for glutamatergic, rapid acting, antidepressants, while additional targets in the glutamate synapse await development of new compounds for better, faster antidepressant action.

49)  Niciu, Mark J., et al. “Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder.” Journal of Neural Transmission 121.8 (2014): 907-924.

Next, N-acetylcysteine (NAC) is a potent anti-inflammatory/antioxidant via its cysteine moiety, which is the rate-limiting substrate for glutathione production in the mammalian brain (De Rosa et al. 2000; Dringen and Hirrlinger 2003). It generates cystine, which, via a specific exchanger on the surface of synaptically localized astrocytes, increases glutamate to act presynaptically on metabotropic glutamate receptor II/III suppressing glutamate secretion (Moran et al. 2005). NAC was an effective MDD augmentation strategy in two MDD patients (Carvalho et al. 2013).

50) Cipriani, Andrea, et al. “Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.” The Lancet (2016).

“When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents.”(compared with placebo)

51)  Preda, Adrian, Rebecca W. MacLean, and Malcolm B. Bowers. “Antidepressant-associated mania and psychosis resulting in psychiatric admissions.” The Journal of clinical psychiatry 62.1 (2001): 30-33.
The safety and tolerability of the selective serotonin reuptake inhibitors and the newer atypical agents have led to a significant increase in antidepressant use. These changes raise concern as to the likelihood of a corresponding increase in adverse behavioral reactions attributable to these drugs.
METHOD:All admissions to a university-based general hospital psychiatric unit during a 14-month period were reviewed.
RESULTS:Forty-three (8.1%) of 533 patients were found to have been admitted owing to antidepressant-associated mania or psychosis.
CONCLUSION:Despite the positive changes in the side effect profile of antidepressant drugs, the rate of admissions due to antidepressant-associated adverse behavioral effects remains significant.

52)  Patel, Rashmi, et al. “Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study.” BMJ open 5.12 (2015): e008341.

Objectives To investigate the association between antidepressant therapy and the later onset of mania/bipolar disorder. Design Retrospective cohort study using an anonymized electronic health record case register.Setting South London and Maudsley National Health Service (NHS) Trust (SLaM), a large provider of inpatient and community mental healthcare in the UK.

Participants 21 012 adults presenting to SLaM between 1 April 2006 and 31 March 2013 with unipolar depression.

Exposure Prior antidepressant therapy recorded in electronic health records.

Main outcome measure Time to subsequent diagnosis of mania or bipolar disorder from date of diagnosis of unipolar depression, censored at 31 March 2014. Methods Multivariable Cox regression analysis with age and gender as covariates.

Results The overall incidence rate of mania/bipolar disorder was 10.9 per 1000 person-years. The peak incidence of mania/bipolar disorder incidence was seen in patients aged between 26 and 35 years (12.3 per 1000 person-years). Prior antidepressant treatment was associated with an increased incidence of mania/bipolar disorder ranging from 13.1 to 19.1 per 1000 person-years. Multivariable analysis indicated a significant association with selective serotonin reuptake inhibitors (HR 1.34, 95% CI 1.18 to 1.52) and venlafaxine (1.35, 1.07 to 1.70).

Conclusions In people with unipolar depression, antidepressant treatment is associated with an increased risk of subsequent mania/bipolar disorder. These findings highlight the importance of considering risk factors for mania when treating people with depression.

53)  Antonuccio, David O., David D. Burns, and William G. Danton. “Antidepressants: A triumph of marketing over science?.” (2002): 25c.

54)   Arcand M, Hottin P. Le traitement de la dépression chez les personnes âgées. L’utilité des psychostimulants. Canadian Family Physician.1993;39:2420-2426.

55)  Candy, Bridget, et al. “Psychostimulants for depression.” The Cochrane Library (2008).
Three trials (62 participants) demonstrated that oral PS, as a monotherapy, significantly reduced short term depressive symptoms in comparison with placebo   CONCLUSIONS: There is some evidence that in the short-term, PS (Psycho-Stimulants) reduce symptoms of depression

Orr, K., and D. Taylor. “Psychostimulants in the treatment of depression: a review of the evidence.” CNS drugs 21.3 (2007): 239.

57)  Parker, G., and H. Brotchie. “Do the old psychostimulant drugs have a role in managing treatment-resistant depression?.” Acta psychiatrica Scandinavica 121.4 (2010): 308.

SSRI Benefit in Ischemic Stroke

58) Siepmann, Timo et al. “Selective Serotonin Reuptake Inhibitors to Improve Outcome in Acute Ischemic Stroke: Possible Mechanisms and Clinical Evidence.” Brain and Behavior 5.10 (2015): e00373. PMC. Web. 2 Aug. 2016.
Based on animal models, the mechanisms whereby SSRIs might ameliorate functional and structural ischemic‐brain damage were suggested to include stimulation of neurogenesis with migration of newly generated cells toward ischemic‐brain regions, anti‐inflammatory neuroprotection, improved regulation of cerebral blood flow, and modulation of the adrenergic neurohormonal system. However, to date, it remains speculative if and to what degree these mechanisms convert into humans and randomized controlled trials in large populations of stroke patients comparing different SSRIs are still lacking.
Possible mechanisms of action. The figure illustrates three possible mechanisms whereby SSRIs might improve structural‐brain tissue recovery from ischemia: stimulation of neurogenesis in the subependymal zone and hippocampal dentate gyrus, inhibition of microglia‐ and neutrophile‐induced inflammation mediated by cytotoxic inflammatory molecules, and improvement of cerebral vascular autoregulation (HO‐1, heme oxygenase‐1; VEGF, vascular endothelial growth factor).

59)  McCann, Sarah K., et al. “Efficacy of Antidepressants in Animal Models of Ischemic Stroke A Systematic Review and Meta-Analysis.” Stroke 45.10 (2014): 3055-3063.
In line with current clinical data and despite some limitations, antidepressant treatments seem to improve infarct volume and neurobehavioral outcome in animal models of ischemic stroke.

Lithium for Stroke Patients

60)  Clin Neuropharmacol. 2014 May-Jun;37(3):73-8. The effect of lithium in post-stroke motor recovery: a double-blind, placebo-controlled, randomized clinical trial.  Mohammadianinejad SE1, Majdinasab N, Sajedi SA, Abdollahi F, Moqaddam MM, Sadr F.
Evidences from cultured cells and animal models of ischemia suggest that lithium has neuroprotective and neurotrophic effects and may play a desirable role in reducing infarct volume and even improving the brain insults from stroke. The aim of this study was to evaluate the efficacy of lithium in early motor recovery of patients after ischemic stroke.
METHODS: Eighty patients with first ever stroke, allocated randomly in lithium, 300 mg twice daily, or placebo. Treatment was initiated 48 hours after stroke and continued for 30 days. Modified National Institute of Health Stroke Scale (mNIHSS) and hand subsection of Fugl-Meyer Assessment (hFMA) were used to evaluate impairment on the fifth and 30th day of treatment.
RESULTS: Sixty-six subjects (32 subjects in the lithium group and 34 subjects in the placebo group) completed the study. There were no significant differences in the improvement in mNIHSS (P=0.40) and hFMA (P=0.07) after 30 days. However, a subgroup analysis showed that patients with cortical strokes in the lithium group had significantly better improvement in both mNIHSS and hFMA in comparison to the placebo group (P=0.003). Approximately 44% (n=14) of patients in the lithium group, mainly from the cortical stroke subgroup, regained more than 25% of full function based on hFMA, whereas this rate in the placebo group was 14.7% (n=5; P=0.009).
CONCLUSION: The observed discrete difference between the lithium group and the placebo group in the cortical stroke subgroup may suggest an enhanced motor recovery after stroke by using an early treatment with a low dose of lithium carbonate. However, a larger trial with more patients with cortical stroke is needed to investigate this effect better.

61) Nonaka, Shigeyuki, and De-Maw Chuang. “Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats.” Neuroreport 9.9 (1998): 2081-2084.
We have recently shown that long-term, but not acute, treatment with lithium robustly protects cultured CNS neurons against excitotoxicity mediated by NMDA receptors. Since NMDA receptor over-excitation has been strongly implicated in the ischemic brain injury, we examined the effects of chronic lithium treatment on neurological deficit and brain infarct induced by occlusion of the left middle cerebral artery in rats. Subcutaneous injection of LiCl for 16 days significantly improved neurological deficits, including abnormal posture and hemiplegia, measured 24 h after artery occlusion. Importantly, the size of ischemic infarct was reduced by 56% after lithium pretreatment. These results raise the possibility that lithium may be useful for reducing focal ischemia-induced brain damage and neurological abnormalities.

62) Xu, Jihong, et al. “Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death.” Stroke 34.5 (2003): 1287-1292.
Conclusions— The present study demonstrates that chronic treatment with lithium at a low dose exhibits neuroprotection in transient focal cerebral ischemia. Antiapoptotic mechanisms are involved in the lithium-induced neuroprotective effects.

63) Curr Drug Targets. 2011 Feb;12(2):243-55.
Lithium and its neuroprotective and neurotrophic effects: potential treatment for post-ischemic stroke sequelae.  Gold AB1, Herrmann N, Lanctôt KL.
Post-stroke cognitive impairment has a high prevalence in stroke patients and is associated with poor short and long term outcomes, including a negative impact on functional recovery. There is evidence that post-stroke impairment is the direct result of stroke induced neurological injury. Gray matter atrophy has been implicated in the development of post-stroke cognitive impairment and is the result of a series of neurochemical processes that are activated by ischemia. Lithium, traditionally used as a mood stabilizer, has been recognized in the last 10 years for its robust neuroprotective and neurotrophic effects against diverse insults, such as ischemia, both in vitro and in vivo. This has generated several preclinical and clinical studies of lithium treatment for managing neurodegenerative diseases and cerebral ischemia. Evidence suggests that lithium may protect against the cerebral atrophy and neuronal degeneration induced by the neurochemical processes and pathways known to regulate cell death and atrophy after an ischemic event. Lithium-mediated neurotroprotective and neurotrophic effects involve mechanisms highly relevant to the post-stroke population including the increased expression of brain-derived neurotrophic factor (BDNF) and Bcl-2, and inhibition of GSK-3β. Lithium-induced increases in human gray matter have been reported and occur within a time frame consistent with the known effects of lithium through increased expression of BDNF, Bcl-2 and GSK-3β inhibition. This article reviews the evidence to support the use of lithium to reduce neuronal damage post-stroke through 1) mechanisms of excitotoxicity and post-ischemic inflammation; and 2) neurotrophic signaling cascades. Lithium’s relevant actions in preclinical and clinical studies will be reviewed and presented to support the neuroprotective and neurotrophic effects of lithium as well as other clinical considerations in using lithium in the post-ischemic stroke population.

SSRI Discontinuation Syndrome/Withdrawal Effects

64) Fava, Giovanni A., et al. “Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review.” Psychotherapy and psychosomatics 84.2 (2015): 72-81.
Conclusions: Clinicians need to add SSRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs. The term ‘discontinuation syndrome’ that is currently used minimizes the potential vulnerabilities induced by SSRI and should be replaced by ‘withdrawal syndrome’.

65) Renoir, Thibault. “Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved.” Frontiers in pharmacology 4 (2013): 45.
SSRI discontinuation syndrome include dizziness, lethargy, and sleep disturbances

66) Mental Health The Hidden Harm of Antidepressants
An in-depth analysis of clinical trials reveals widespread underreporting of negative side effects, including suicide attempts and aggressive behavior
By Diana Kwon on February 3, 2016 Scientific AMerican

Movement Disorder Induced by SSRI

67)  Gerber, Patricia E., and Larry D. Lynd. “Selective serotonin-reuptake inhibitor–induced movement disorders.” Annals of Pharmacotherapy 32.6 (1998): 692-698.

To compile and evaluate all available data suggesting an association between selective serotonin-reuptake inhibitor (SSRI) administration and the occurrence of movement disorders, and to characterize these reactions in terms of onset, duration, treatment and outcome, and potential predisposing factors.
METHODOLOGY:Reports of movement disorders were identified by conducting a comprehensive literature search that included tertiary adverse drug reaction resources, MEDLINE, EmBASE, Biological Abstracts, Current Contents, Reactions, ClinAlert, and International Pharmaceutical Abstracts. In addition, reports were solicited from the Canadian proprietary manufacturers of SSRIs, and from the Therapeutic Products Program of Health Canada. Each case was then classified according to the description of the movement disorder, based on predefined diagnostic criteria.
RESULTS:A total of 127 published reports of SSRI-induced movement disorders were identified involving akathisia (n = 30), dystonia (19), dyskinesia (12), tardive dyskinesia (6), parkinsonism (25), and 15 cases of mixed disorders. Ten isolated cases of bruxism were identified. Ten additional reports could not be classified. Manufacturers of SSRIs provided 49 reports of akathisia, 44 of dystonia, 208 of dyskinesia, 76 of tardive dyskinesia, 516 of parkinsonism, and 60 of bruxism. Treatment strategies included discontinuation of the SSRI; dosage reduction; or the addition of a benzodiazepine, beta-blocker, or anticholinergic agent.
CONCLUSIONS:SSRI use appears to be associated with the development of movement disorders, as either a direct result of the drug or exacerbation of an underlying condition. Predisposing factors may include the use of neuroleptics, existing neurologic diagnoses, or preexisting movement disorders. Clinicians should be cognizant of the potential for these reactions, as prompt recognition and management is essential in preventing potentially significant patient morbidity.

68)  Psychiatr Serv. 1996 Sep;47(9):991-3.
Tardive dyskinesia associated with fluoxetine.
Dubovsky SL1, Thomas M.
Three cases in which patients who were taking fluoxetine for relief of depression showed patterns of abnormal movements suggestive of tardive dyskinesia are presented. In the first case, abnormal facial movements began four weeks after fluoxetine was added to doxepin and lithium and remitted after fluoxetine was discontinued. In the second case, abnormal movements of the mouth and hands were noticed four years after the patient started taking fluoxetine and continued to be present a year after withdrawal of the medication. In the third case, orofacial dyskinesia that had remitted after withdrawal of sertraline and paroxetine and reappeared with fluoxetine was still present eight months after fluoxetine was withdrawn.

69)  Aust N Z J Psychiatry. 1994 Jun;28(2):328-30.
Fluoxetine induced dyskinesia.  Mander A1, McCausland M, Workman B, Flamer H, Christophidis N.
A case of fluoxetine induced dyskinesia in an elderly woman with previous use of low dose haloperidol is described. In contrast to neuroleptic induced tardive dyskinesia it was characterised by a rapid onset after commencing fluoxetine and rapid resolution on cessation. In the case discussion we describe other cases of fluoxetine induced extrapyramidal syndromes and possible mechanisms.

70)  Mov Disord. 1996 May;11(3):324-6.
Complex movement disorders induced by fluoxetine.
Bharucha KJ1, Sethi KD.
We report two cases of complex movement disorders induced by fluoxetine. A 72-year-old woman developed rhythmic palatal movements, myoclonus, chorea, and possibly dystonia after 2 years of therapy with fluoxetine. On withdrawal of fluoxetine, the movements abated after 5 days and did not recur. The second patient, a 58-year-old man, developed myoclonic jerking and rapid, stereotypic movements of his toes after a year of fluoxetine therapy. These complex movements have not been reported previously as an adverse effect of fluoxetine.

71) Fisher, Helen E., and J. A. Thomson. “Lust, romance, attachment: do the side effects of serotonin-enhancing antidepressants jeopardize romantic love, marriage, and fertility?.” Evolutionary cognitive neuroscience (2007): 245-283. Lust romance attachment SSRI serotonin antidepressants jeopardize romantic love marriage fertility Helen Fisher 2007

72)  Friedman, Richard A., and Andrew C. Leon. “Expanding the black box—depression, antidepressants, and the risk of suicide.” New England Journal of Medicine 356.23 (2007): 2343-2346.

Jeffrey Dach MD
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Davie, Florida 33314

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SSRI Antidepressants No Better Than Placebo Says JAMA
SSRI Antidepressants No Better Than Placebo Says JAMA
Jeffrey Dach MD