Antidepressant Part 2

Antidepressant Receptor Affinity:

A number of antidepressants have been compared below:

Compound	SERT	NET	DAT	H1	M1-5	α1	α2	5-HT1A	5-HT2C	D2
Agomelatine	?	?	?	?	?	?	?	?	270	?
Amitriptyline	4.3	35	3250	0.95	9.6	24	690	450	18	1460
Amoxapine	58	16	4310	25	1000	50	2600	?	?	?
Atomoxetine	8.9	2.03	1080	5500	2060	3800	8800	10900	940	35000+
Bupropion	45026	1389	2784	11800	35000+	4200	35000+	35000+	35000+	35000+
Buspirone	?	?	?	?	?	138	?	5.7	174	362
Butriptyline	1360	5100	3940	?	?	?	?	?	?	?
Citalopram	1.38	5100	28000	380	1800	1550	?	?	?	?
Clomipramine	0.28	<1	2190	31	37	38	3200	?	?	?
Desipramine	17.6	0.83	3190	60	66	100	5500	6400	350	3500
Dosulepin	8.6	46	5310	?	?	?	?	?	?	?
Doxepin	68	29.5	12100	0.17	23	23.5	1270	276	27	360
Duloxetine	1.55	11.2	240	2300	3000	8300	?	?	?	?
Escitalopram	1.1	7840	10000	1970	1240	3870	?	?	?	?
Etoperidone	890	20000	52000	3100	35000+	38	570	85	36	2300
Femoxetine	11	760	2050	4200	184	650	1970	2285	130	590
Fluoxetine	0.81	240	3600	5400	590	3800	13900	32400	280	12000
Fluvoxamine	2.22	1300	9100	10000	240000	7700	?	?	?	?
Imipramine	1.4	37	8500	37	46	32	3100	5800	150	620
Lofepramine	70	5.4	18000	360	67	100	2700	4600	200	2000
Maprotiline	5800	11.1	1000	2	570	90	9400	?	?	?
Mazindol	100	1.4	11	?	?	?	?	?	?	?
Mianserin	4000	71	9400	?	?	?	?	?	?	?
Milnacipran	123	200	10000+	?	?	?	?	?	?	?
Mirtazapine	1500+	1250~	1500+	1~	1000~	500~	100~	1500+	10~	1500+
Nefazodone	200	360	360	24000	11000	48	640	80	26	910
Nisoxetine	383	5.1	477	?	?	?	?	?	?	?
Nomifensine	1010	15.6	56	?	?	?	?	?	?	?
Nortriptyline	18	4.37	1140	6.3	37	55	2030	294	41	2570
Oxaprotiline	3900	4.9	4340	?	?	?	?	?	?	?
Paroxetine	0.13	40	490	22000	108	4600	17000	35000+	19000	32000
Protriptyline	19.6	1.41	2100	25	25	130	6600	?	?	?
Reboxetine	58.5	7.14	11500	312	6700	11900	?	?	?	?
Sertraline	0.29	420	25	24000	630	380	4100	35000+	9900	10700
Trazodone	160	8500	7400	1100	35000+	42	320	96	25.0	35000+
Trimipramine	149	2450	3780	0.27	58	24	680	?	?	?
Venlafaxine	82	2480	7647	35000+	35000+	35000+	35000+	35000+	35000+	35000+
Viloxazine	17300	155	100000+	?	?	?	?	?	?	?
Zimelidine	152	9400	11700	?	?	?	?	?	?	?

The values above are expressed as equilibrium dissociation constants. It should be noted that smaller dissociation constant indicates more efficacy. SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors. Note that desmethylclomipramine, a metabolite of clomipramine, has a comparably high affinity for the NET as clomipramine has for the SERT.

• Anti-inflammatory and immunomodulation:

Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system.

Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes, may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones. SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties. These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

Therapeutic efficacy:

To establish efficacy, an antidepressant must show that it can produce a therapeutic effect for the condition for which it is taken. An antidepressant should be more efficacious than placebo to justify the risk associated with side effects. For depression, the Hamilton Depression Rating Scale (HAM-D) is often used to measure the severity of depression. The maximum score for the 17-item HAM-D questionnaire is 52; the higher the score, the more severe the depression. What constitute a sufficient response to a drug has not been well established, but total remission or virtual elimination of all depression symptoms is the goal, however, remission rates are rarely published. For placebo, the percentage of symptom reduction is approximately 31 to 38%, compared to 46 to 54% for antidepressants.

On the basis of 234 studies, no clinically relevant superiority of one antidepressant over another was detected for the treatment of acute, continuation, and maintenance phases of depression, taking into account age, sex, ethnicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of health-related quality of life.
The largest and most expensive study conducted to date, on the effectiveness of pharmacological treatment for depression, was commissioned by the National Institute of Mental Health. The study was dubbed "The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study.

The results are summarized here.

• After the first course of treatment, 27.5% of the 2,876 participants reached remission with a HAM-D score of 7 or less. 21% dropped out.
• After the second course of treatment, 21 to 30% of the remaining 1,439 participants remitted. Only 310 participants were willing or available to continue the study., Switching medications can achieve remission in about 25% of patients.
• After the third course of treatment, 17.8% of the remaining 310 participants remitted.
• After the fourth and last course of treatment, 10.1% of the remaining 109 participants remitted.
• After a one year follow-up, of the 1085 remitted participants, 93% participants had either relapsed or dropped out of the study.

There were no statistical or meaningful clinical differences in remission rates, response rates, or times to remission or response among any of the medications compared in this study. These included bupropion sustained release, bupropion, citalopram, lithium, mirtazapine, nortriptyline, sertraline, triiodothyronine, tranylcypromine, venlafaxine extended release.

A 2008 review of randomized controlled trials concluded that symptomatic improvement with SSRIs was greatest by the end of the first week of use, but that some improvement continued for at least 6 weeks.
A 2002 review concluded that there was no evidence that antidepressants reduce the risk of recurrence of depression when their use is terminated. The authors of this review advocated that antidepressants be combined with therapy, and pointed to Interpersonal Psychotherapy (IPT) and Cognitive Behavioral Therapy (CBT).

1)     Review studies:

Some clinical reviews include:

• (2007) A review of the use of antidepressants for childhood depression
• (2004) An assessment of antidepressants compared with an "active placebo"
• (2001) A comparison of the relative efficacy of different classes of antidepressants in different settings and in regard to different kinds of depression
• (1999) An assessment of the newer types of the MAOI class

2)     Clinical guidelines:

The UK National Institute for Clinical Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression, because the risk-benefit ratio is poor; that for moderate or severe depression an SSRI is more likely to be tolerated than a tricyclic; and that antidepressants for severe depression should be combined with a psychological treatment such as Cognitive Behavioural Therapy.

The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder indicates that, if preferred by the patient, antidepressant medications may be provided as an initial primary treatment for mild major depressive disorder; antidepressant medications should be provided for moderate to severe major depressive disorder unless electroconvulsive therapy is planned; and a combination of antipsychotic and antidepressant medications or electroconvulsive therapy should be used for psychotic depression. It states that efficacy is generally comparable between classes and within classes and that the initial selection will largely be based on the anticipated side-effects for an individual patient, patient preference, quantity and quality of clinical trial data regarding the medication, and its cost.

3)     Efficacy limitations and strategies:

Between 30% and 50% of individuals treated with a given antidepressant do not show a response.
Even where there has been a robust response, significant continuing depression and dysfunction is common, with relapse rates 3 to 6 times higher in such cases. In addition, antidepressant drugs tend to lose efficacy over the course of treatment. A number of strategies are used in clinical practice to try to overcome these limits and variations. They include switching medication, augmentation, and combination.

• "Trial and error" switching:

The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant. The remission rate reported by the STAR*D study was 21% using this method.

A 2006 meta-analysis review found wide variation in the findings of prior studies; for patients who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial. However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication; although 34% of treatment resistant patients responded when switched to the new drug, 40% responded without being switched. Thus, the clinical response to the new drug might be a placebo effect associated with the belief that one is receiving a different medication.

• Augmentation and combination:

For a partial response, the American Psychiatric Association guidelines suggest augmentation, or adding a drug from a different class. These include: lithium and thyroid augmentation, dopamine agonists, sex steroids, NRI's, glucocorticoid-specific agents, or the newer anticonvulsants The STAR*D project reported a remission rate of 30% with this method.
A combination strategy involves adding an additional antidepressant, usually from different class so as to have effect other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy. The STAR*D project reported similar remission rates as with augmentation strategy.
Opponents of switching, augmentation and combination argue that treatment may also propel the illness to a malignant and treatment-unresponsive course with iatrogenic psychiatric-like symptoms and treatment resistance or episode acceleration.

• Long-term use:

The therapeutic effects of antidepressants typically do not continue once the course of medication ends, resulting in a high rate of relapse. A recent meta-analysis of 31 placebo-controlled antidepressant trials, mostly limited to studies covering a period of one year, found that 18% of patients who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo. The American Psychiatric Association guidelines advise four to five months of continuation treatment on an antidepressant following the resolution of symptoms. For patients with a history of depressive episodes, the British Association for Psychopharmacology's 2000 Guidelines for Treating Depressive Disorders with Antidepressants advise remaining on an antidepressant for at least six months and as long as five years or indefinitely.

In a five-year follow up, relapse rates was 23% greater for users greater than one year, but not different for 6 or 12 months users. In addition, gradual loss of therapeutic benefit occurs during the course of treatment.A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.

• Antidepressant-induced Mania:

Another possible problem with antidepressants is the chance of antidepressant-induced mania in patients with bipolar depression or manic depression. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the patient can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20-40% of bipolar patients.

Controversy:

• Ghost writing of studies for industry-sponsored drug trials is common. Of all 44 trial which was approved between 1994 and 1995 by the ethics committees of Copenhagen and Frederiksberg in Denmark, up to 91%, that is 40 of the 44 trials, has some form of ghostwriting, and for the most part, the ghost was a statistician. Cases relating to gabapentin, paroxetine, sertraline, fenfluramine/phentermine (fen-phen) are well documented, while many others, relating to olanzapine, quetiapine,remain under seal by the courts.

• Publication bias. Trials for which results were unfavourable were less likely to be published. Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drug to treat depression in children and young people. Of 90 drugs approved by the FDA between 1998 and 2000,the trials which did not show statistically significant results were 34% less likely to have been published, on the other hand, positive results are often published more than once. Based on Healy's examination of the data produced from the Cochrane study of Olanzapine for schizophrenia, the four initial trials of Zyprexa gave rise to 234 publications, most of which were ghost written.

• Lack of access to raw data, data suppression, misrepresentation, and manipulation has eroded value of trial results. Demands on access to data has been met by resistance on the part of industry.

• A meta-analysis by UK, US and Canadian researchers was published in 2008, surveying all pharmaceutical-company-sponsored drug trials on the six most widely prescribed new-generation antidepressants submitted for approval to the FDA between 1987 and 1999. The results showed that the difference in efficacy between antidepressants and placebo was minimal, but that it increased from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression. The difference reached conventional criteria for clinical significance for patients at the upper end of the very severely depressed category, due to a reduction in the efficacy of placebo. The study received widespread media coverage in some countries, but was met with criticism from the professional community.

Eli Lilly and Company responded by highlighting that the study did not take into account more recent studies on its product, Prozac, and that it was proud of the difference Prozac has made to millions of people. GlaxoSmithKline warned that this one study should not be used to cause unnecessary alarm and concern for patients. Two leading UK psychiatrists/pharmacologists, with financial and professional links to pharmaceutical companies, argued that short-term approval trials are not very suitable for evaluating effectiveness, that the unpublished trials are of poorer quality, that the meta-analysis authors came from a "psychology background" rather than drug testing background, and that the media and "elements of the medico/scientific community [sic]" have "a down on antidepressants" and that the media do not appreciate the seriousness of depression and blame and stigmatize sufferers. Wyeth pointed out that the data were good enough for FDA approval of the drugs.

Controversy Regarding Placebo Effects and Efficacy in Mild Depression:

A review of antidepressant trials submitted to the U.S. FDA by the industry for drug approval revealed that when a trial was successful, the results of the trial was published 94% of the time, however, when the trial was not found to be more effective than placebo, it was only published 50% of the time. This demonstrated a measure of bias in reporting by industry. Combined, 51% of all studies showed efficacy. The difference in effect between active placebos and several anti-depressants appeared small and strongly affected by publication bias.

Controversy regarding the efficacy of antidepressants has arisen due to studies showing that antidepressants fail to provide significantly greater efficacy than placebo in some studies. A 2002 study claimed that the difference between antidepressants and placebo is close to negligible.
A study published in JAMA demonstrated that the magnitude of the placebo effect in clinical trials of depression have been growing over time, while the effect size of tested drugs has remained relatively constant. The authors suggest that one possible explanation for the growing placebo effect in clinical trials is the inclusion of larger number of participants with shorter term, mild, or spontaneously remitting depression as a result of decreasing stigma associated with antidepressant use.

An article in The Washington Post titled "Against Depression, a Sugar Pill Is Hard to Beat" stated,

"A new analysis has found that in the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as--or better than--antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval. What's more, the sugar pills, or placebos, cause profound changes in the same areas of the brain affected by the medicines, according to research published last week... the makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more... When Leuchter compared the brain changes in patients on placebos, he was amazed to find that many of them had changes in the same parts of the brain that are thought to control important facets of mood... Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated. People's belief in the power of antidepressants may explain why they do well on placebos..."

Through a Freedom of Information Act request, two psychologists obtained 47 studies used by the FDA for approval of the six antidepressants prescribed most widely between 1987-99. Overall, antidepressant pills worked 18% better than placebos, a statistically significant difference, "but not meaningful for people in clinical settings", says psychologist Irving Kirsch, lead author of the study. He and co-author Thomas Moore released their findings in "Prevention and Treatment", an e-journal of the American Psychological Association. In a later publication, Kirsch concluded that the overall effect of new-generation antidepressant medication is below recommended criteria for clinical significance.

Another study by psychologists at the University of Pennsylvania, Vanderbilt University, the University of Colorado, and the University of New Mexico also found that antidepressant drugs hardly have better effects than a placebo in those cases of mild or moderate depression. The study was published in the Journal of the American Medical Association. The study focused on paroxetine (Paxil) from GlaxoSmithKline and imipramine.

The Cochrane Collaboration recently performed a systematic review of clinical trials of the generic antidepressant amitriptyline. The study concluded that in spite of moderate evidence for publication bias, there is strong evidence that the efficacy of amitriptyline is superior to placebo.
A review commissioned by the National Institute for Clinical excellence concluded that there there is strong evidence that SSRIs have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression. The treatment guidelines developed in conjunction with this review suggest that antidepressants should be considered in patients with moderate to severe depression and those with mild depression that is persistent or resistant to other treatment modalities.

In 2005, anti-depressants became the most prescribed drug in the United States, causing more debate over the issue. Some doctors believe this is a positive sign that people are finally seeking help for their issues. Others disagree, saying that this shows that people are becoming too dependent on anti-depressants.
In 2012, Aimee Hunter and her team used EEG and showed that taking placebo decreased pre-frontal brain activity in those subjects who had prior use of an antidepressants, similar to the expected antidepressant response, but increased brain activity in antidepressant naive subjects. She attributes this antidepressant response of placebo, in repeat users, to a memory effect.

However, in the later experiment conducted by John H. Krystal at Yale University School of Medicine to assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression showed that Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients.

Antidepressant page 3

REFERENCE:
http://en.wikipedia.org/wiki/Antidepressant