‘The Emperors New Drugs’ journal article pretty much substansiates what this scholar wrote over three years ago! http://www.seroxat.pwp.blueyonder.co.uk/namiscc.org_Research_2002_DrugEfficacy.pdf
It has been suggested that depression results from the depletion of certain brain neurotransmitters such as Norepinephrine for example, Richelson (1991). However biochemical theories of depression fail to account for environmental causes of depression which undoubtedly cause the illness in the majority of cases, the past experiences of the individual leading to lowered amounts of neurotransmitter and it can therefore be argued resulting in depression as a consequence perhaps as an evolutionary adaptation, Nesse (2000). Farvolden, Kennedy, & Lam (2003) suggest that effective treatments include the existing range of therapeutic drugs: SSRI (Selective Serotonin Reuptake Inhibitors), SNRI (Selective Norepinephrine Reuptake Inhibitors), MAOI’s (Monoamine Oxidase Inhibitors) and Tricyclic antidepressants. However there is significant evidence to suggest that such drugs rather than resulting in remission merely treat the symptoms rather than the cause, Farvolden et al (2003).
Indeed it has even be suggested that the aforementioned antidepressants are little better than placebos, any pill whether containing an inert substance such as talc or the active drug Paroxetine (Seroxat) one of the SSRI class of medications having pretty much the same therapeutic effect perhaps as a result of a release of neurotransmitters instituted by the brain in response to placebo, Kirsch, Moore, Scoboria, and Nicholls (2002).
To determine which biochemical theory of depression is most strongly supported by the available evidence the remainder of this essay will look at the current evidence, evaluating and interpreting the suggested causes of depression leading to a valid conclusion.
Before looking at the biochemical theories of depression it is important to look briefly at things that are known to cause depression in the first instance such as childhood anxiety disorders, Muris, Meesters, & Van Melick (2002). Muris et al (2002) carried out a study with children aged 9-12 years to compare the effectiveness of cognitive behavioural therapy with a psychological placebo such as emotional disclosure. Participants in the study were either assigned to cognitive behavioural therapy (a), emotional disclosure (placebo) (b), or (c) no treatment (control). The results of the study indicated that cognitive behavioural therapy (CBT) was superior to emotional disclosure, and the no treatment conditions. The researchers concluded from the results that only the CBT condition resulted in significant reductions in anxiety, trait anxiety and depression. It can easily be argued from the results of the Muris et al (2002) study that the cognitive behavioural therapy method of treatment caused a remission of psychiatric symptoms of the young participants in the study. However what is unclear is exactly what the method achieved, i.e. was it an increase in neurotransmitters or something else entirely?
Healy (2002) highlights that there exist two separate biochemical theories of endogenous depression: the amine, and catecholamine theories. Schildkraut (1965) proposed in the catecholamine hypothesis that depression resulted from a decrease in available Norepinephrine at central adrenergic receptor sites, Norepinephrine inhibitors such as Reserpine resulting in depression, and MAOI’s increasing levels of Norepinephrine, relieving depressive symptoms. Whereas in the Indoleamine hypothesis there exists evidence to suggest that there is an imbalance or disturbance in three main areas;
Amine metabolism, electrolyte distribution and, or hormonal function result in depression and other affective disorders, Toru, & Itokawa (2001).
There is a problem with the catecholamine hypothesis however. If depression resulted simply as a result of lowered catecholamine levels within the brain one would expect that alpha-methyl-paratyrosine would cause depression in humans as it inhibits the enzyme tyrosine hydroxylase limiting catecholamine synthesis, and the introduction of the chemical does not have that effect, Berman, Sanacora, Anand, Roach, Fasula, Finkelstein, Wachen, Oren, Heninger, and Charney (2002). Berman et al (2002) carried out a study to assess the integrated role of the monoamine system in depressed patients. It was decided that un-medicated depressed subjects would be asked to partake in a 2 week double blind, random ordered crossover study. Subjects were placed in active indoleamine (via tryptophan depletion the precursor of Serotonin) plus catecholamine (via alpha-methyl-paratyrosine administration) depletion and separately Indoleamine plus sham (via diphenhydramine administration) catecholamine depletion.
The results of the Berman et al (2002) study suggests that simultaneous disruptions of the indoleamine and catecholamine systems do not make depression worse in previously un-medicated subjects. This finding lends support to the theory that monoamines regulate mood by some as yet unknown indirect mechanism such as the suggestion that neurotransmitters interact with one another, and that imbalances of these neurotransmitter systems result in depression. The currently held hypothesis is that monoamine depletion results in depression, Leonard (2000). Leonard suggests that the monoamine hypothesis predicts that there is some form of impairment of the monoaminergic system with lower than normal levels of Norepinephrine, Serotonin or both. Depletion studies have indicated a correlation between such deficiencies and depression, researchers measuring the active neurotransmitters and their metabolites in cerebrospinal fluid and urine, Sobczak, Honig, Van Duinen, Riedel, (2002). This would suggest that no one neurotransmitter is implicated in isolation and that instead of proposing that there is an abnormality in a singular neurotransmitter system perhaps more than one of the neurotransmitters interacting together results in depression. There have been several attempts to propose such a biogenic hypothesis, Prange, Wilson, Lynn, Alltop, & Stikeleather (1974). Researchers have found that drugs that act by increasing the amount of neurotransmitter in the synaptic cleft take a number of weeks to take effect, and can in some cases result in increasingly severe depression and anxiety in the mean time before the drug becomes effective, Bourin, David, Jolliet, & Gardier (2002).
During Paroxetine withdrawal, patients are known to experience very severe symptoms including electric shock like sensations, mood instability, hypomania, suicide, paresthesia’s etc., Haddad, Devarajan, & Dursun (2001), again suggestive that a reduction in Paroxetine (Seroxat) results in not only a lowering of Serotonin but perhaps also in Dopamine causing coordination problems similar to those found in Parkinson’s disease. Haddad et al (2001) highlight that 2 patients presented with stroke like symptoms which were later attributed to withdrawal from Paroxetine. The manufacturer GlaxoSmithKline have recently been found guilty of homicide where a grandfather murdered his wife, daughter and baby granddaughter before committing suicide after only two days on Paxil (Seroxat) resulting in law suits in several countries including the United States and United Kingdom, patients claiming that the drug is addictive and causes a range of very unpleasant side effects and withdrawal symptoms including those already mentioned, Boseley (2001).
Since SSRI and SNRI medications do not elicit immediate improvements in depression despite evidence that such drugs stop Serotonin or Norepinephrine from being reabsorbed in the synaptic cleft almost immediately, resulting in more of the neurotransmitter becoming available. This would suggest that indeed neurotransmitters do interact with one another, the increase in Serotonin leading to increases or decreases in other neurotransmitters, and thus reductions in symptoms of depression. The antidepressant medication Venlafaxine has a clinical effect upon both Serotonin and Norepinephrine and has been shown to elicit a much quicker response rate in terms of action again supporting the notion that several neurotransmitters are implicated and perhaps interacting together, Artigas, Nutt, & Shelton (2002). There is some evidence to suggest that SSRI medications such as Prozac and Paroxetine for example result in emotional blunting, Opbroek, Delgado, Laukes, McGahuey, Katsanis, Moreno, & Manber, (2002). It can be argued therefore that this could lead to the individual prescribed such drugs losing interest and pleasure in pursuits that they previously found enjoyable for example sex. SSRI’s often result in loss of libido, Hsu, & Shen (1995).
It can be hypothesised that Paroxetine and other SSRI medications increase Serotonin but also interfere with the Dopamine system since it has been demonstrated that the neurotransmitter Dopamine is involved in sexual function, Giuliano, & Allard (2001), and pleasure, Davis, & Woodside (2002). Therefore based on this argument it is easy to see how a grandfather might murder his entire family before turning the gun upon him-self after a very short period of time taking an SSRI ‘supposed’ to treat depression, his emotions blunted by Paroxetine to such an extent that he no longer found any pleasure in life.
This hypothesis is consistent with there being an interaction between the neurotransmitters Serotonin, Norepinephrine, Dopamine and depressive illnesses.
As has been mentioned previously Kirsch, Moore, Scoboria, and Nicholls (2002) analysed the efficacy data submitted to the Food and Drugs Administration (FDA) for approval of the 6 most widely prescribed antidepressants: Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Venlafaxine (Effexor), Nefazodone (Serzone), and Citalopram (Celexa) between the years 1987 and 1999 respectively. The results of the study indicated that 80% of participant responses to the medications were as a result of a placebo effect. Based on this finding it can be argued that antidepressant medications are little more than expensive placebos that cause severe side effects and withdrawal symptoms. Indeed Kirsch et al (2002) discuss in detail that researchers and participants alike knew without a doubt when the active drug was being given because placebos do not produce such side effects since they are inert substances used as a control to highlight that it was the drug having the clinical effect rather than a non-drug.
Healy (2002) suggests that psychotropic drugs were placebo controlled from the 1960s to 1984, but that the majority of trials following this period were merely a comparison between old and new medications, and therefore it is impossible to determine whether or not such ‘new’ dugs are actually better, or indeed if they even have any clinical efficacy. This has allowed pharmaceutical companies to state that their products are superior ‘magic bullets’ that are effective over a range of psychiatric illnesses where Serotonin has been implicated such as social anxiety disorder and obsessive compulsive disorder, based on dubious clinical trials that indicate only modest effectiveness, Healy (2002).
Healy purports that, “The clinical trial results are not compatible with the idea of a Serotonin lesion or a magic bullet effect in any of these disorders.”
It can be suggested that pharmaceutical companies such as the aforementioned GlaxoSmithKline have purposefully kept clinical trial data confidential because the data from such studies doesn’t back up their claim that the drugs are as effective in the treatment of depression or any of the other disorders for which they have gained a license to treat. The Government licensing body, the Medicines Control Agency and their expert advisors the Committee on Safety of Medicines have shares and other financial interests in both the drugs and companies they license drugs on behalf of. Therefore it can be argued that Seroxat (Paroxetine) and other SSRI’s gained a license not because they were effective, but rather because members sitting on the licensing committee had a conflict of interest, and still do, Committee on Safety of Medicines (1999). This view is supported by a recent Guardian newspaper article where an expert review was invalidated by the Committee on Safety of Medicines members having undisclosed interests in the SSRI’s they were supposed to be conducting a safety review of, Boseley (2003).
Based on the available evidence it is clear that the neurotransmitters Serotonin, Norepinephrine and Dopamine are all implicated in depression supporting the Indoleamine theory of depression. It is far from clear however whether or not the current range of new antidepressants, i.e. the SSRI and SNRI class of medications have any conclusive evidence to support the view that they benefit patients to the levels purported by pharmaceutical companies.
Any effect during clinical trials could it can be argued be a result of a placebo effect, participants perhaps believing that because they are experiencing side effects that this will lead to remission or partial remission of their depressed condition the levels of neurotransmitters in turn increasing or normalising due to the placebo effect. The fact that SSRI and SNRI medications take a number of weeks to elicit any antidepressant effect despite evidence to suggest that they act almost immediately also supports the view that decreased levels of a specific neurotransmitter is not the cause of depression but rather merely one of the causes. The study conducted by Berman et al (2002) where catecholamines were ruled out as the cause of depression supports the hypothesis that Amines, and perhaps hormonal imbalances result in depression and disorders where Serotonin and Norepinephrine have been implicated, Healy (2002).
Further research is necessary to determine whether or not the current ‘wonder drugs’ such as Seroxat and Prozac are as effective at treating depression as their manufacturers claim, and perhaps more importantly to dispel patient anxiety as to whether or not the SSRI class, Paroxetine (Seroxat) in particular are drugs of dependence, and can cause serious adverse reactions including suicide. Another important suggestion might be for the Government to tighten the rules governing who can and cannot sit on drug licensing bodies, as it is clear that many of the current members of the Committee on Safety of Medicines have intolerable conflicts of interest and it can be argued licensed unsafe drugs for the treatment of depression during the late 1980s and early 1990s resulting in it can be argued innumerable deaths as a result of suicide and withdrawal symptoms caused by adverse reactions to the medications.
References
Artigas, F., Nutt, D. J., Shelton, R. (2002). Mechanism of action of antidepressants. Psychopharmacological Bulletin, 36, 2: 123-132. Abstract from Endnote, Pubmed.
Berman, R. M., Sanacora, G., Anand, A., Roach, L. M., Fasula, M. K., Finkelstein, C. O., Wachen, R. M., Oren, D. A., Heninger, G. R., & Charney, D. S. (2002). Monoamine depletion in un-medicated depressed subjects. Journal of Biological Psychiatry, 51, 6: 469-473.
Boseley, S. (2001). Four People Dead is Four too Many. Guardian Unlimited. Online Resource:
http://www.guardian.co.uk/health/story/0,3605,534058,00.html
Boseley, S. (2003). Drug review halted over company links. Guardian Unlimited. Online Resource:
http://www.guardian.co.uk/uk_news/story/0,3604,921855,00.html
Bourin, M., David, D. J., Jolliet, P., & Gardier, A. (2002). Mechanism of action of antidepressants and therapeutic perspectives. Therapie, 57, 4: 385 - 396. Abstract from Endnote, Pubmed.
Committee on Safety of Medicines, (1999). Market Towers, London. Online Resource:
http://www.mca.gov.uk/aboutagency/regframework/csm/csmdoi99.pdf
Davis, C., & Woodside, D. B. (2002). Sensitivity to the rewarding effects of food and exercise in the eating disorders. Journal of Comparative Psychiatry, 43, 3: 189-194. Abstract from Endnote, Pubmed
Farvolden, P., Kennedy, S. H., & Lam, R. W. (2003). Recent developments in the psychobiology and pharmacotherapy of depression: optimising existing treatments and novel approaches for the future. Expert Opinion Investigating Drugs, 12, 1: 65 – 86. Abstract from Endnote, Pubmed.
Giuliano, F., Allard, J. (2001). Dopamine and sexual function. International Journal of Impotence Research, 13, 3: 18-28. Abstract from Endnote, Pubmed.
Haddad, P. M., Devarajan, S., & Dursun, S. M. (2001). Antidepressant discontinuation (withdrawal) symptoms presenting as 'stroke'. Journal of Psychopharmacology, 15, 2: 139-142. Abstract from Endnote, Pubmed.
Healy, D. (2002). The Creation of Psychopharmacology. Harvard University Press, pp, 114, 143, 209, 290, 299, 307.
Hsu, J. H., & Shen, W. W. (1995). Male sexual side effects associated with antidepressants: a descriptive clinical study of 32 patients. International Journal of Psychiatry Medicine, 25, 2: 191 – 201.
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, Volume 5, Article 23. Online Resource:
http://journals.apa.org/prevention/volume5/pre0050023a.html
Leonard, B. E. (2000). Evidence for a biochemical lesion in depression. Journal of Clinical Psychiatry, 61, 6: 12-7. Abstract from Endnote, Pubmed.
Muris, P., Meesters, C., & Van Melick, M. (2002). Treatment of childhood anxiety disorders: a preliminary comparison between cognitive-behavioral group therapy and a psychological placebo intervention. Journal of Behavioural Therapy Experimental Psychiatry, 33, 3-4: 143-158. Abstract from Endnote, Pubmed.
Nesse, R. M. (2000). Is depression an adaptation? Archive of Gen Psychiatry, 57, 1: 14 – 20. Abstract from Endnote, Pubmed.
Opbroek, A., Delgado, P. L., Laukes, C., McGahuey, C., Katsanis, J., Moreno, F. A., Manber, R. (2002). Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRI’s inhibit emotional responses? International Journal of Psychopharmacology, 5, 2: 147-151. Abstract from Endnote, Pubmed.
Prange, A.J, Wilson, I.C, Lynn, C.W, Alltop, L.B, Stikeleather, R.A. (1974). L-tryptophan in mania: contribution to a permissive hypothesis of affective disorders. Archives of General Psychiatry, 30: 56–62. Abstract from Endnote, Pubmed.
Richelson, E. (1991). Biological basis of depression and therapeutic relevance. Journal of Clinical Psychiatry, 52: 4 – 10. Abstract from Endnote, Pubmed
Schildkraut, J. J. (1965). The catecholamine hypothesis of affective disorders: a review of supporting evidence. American Journal of Psychiatry, 122, 5: 509-522. Abstract from Endnote, Pubmed.
Sobczak, S., Honig, A., Van Duinen, M. A. Riedel, W. J. (2002). Serotonergic dysregulation in bipolar disorders: a literature review of serotonergic challenge studies. Journal of Bipolar Disorder, 4, 6: 347-356. Abstract from Endnote, Pubmed.
Toru, M, & Itokawa, M. (2001). A history of famous hypotheses and the future development of studies on affective disorders. Nippon Rinsho, 59, 8: 1437-1443. Abstract from Endnote, Pubmed.
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