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The main classes of antidepressants have similar efficacy, but the newer types are generally regarded to have a more benign side-effect profile and less risk of lethality if taken in overdose.
Contents |
History
Like many psychiatric drugs, antidepressants were discovered by accident. The first useful antidepressants belonged to a group called MAOIs (MonoAmine Oxidase Inhibitors) and were discovered in the early 1950s. The original member of this group was iproniazid, which was originally developed to treat tuberculosis.[1] The next group were the tricyclic antidepressants. The first was imipramine. They were effective and safer than the MAOI but still quite dangerous in overdose. They are still used today but have been largely replaced by another group: SSRIs (Selective Serotonin Reuptake Inhibitors). The first SSRI was Zimelidine. Drugs from all three groups have been found to improve the mood of depressed patients. The SSRI antidepressants were early examples of rational drug design.
Classes and members
| Antidepressants (ATC N06A) | ||
|---|---|---|
| Monoamine oxidase inhibitors (MAOI) | Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine | |
| Reversible inhibitor of monoamine oxidase A (RIMA) | Brofaromine, Moclobemide | |
| Dopamine reuptake inhibitor (DARI) | Amineptine, Phenmetrazine, Vanoxerine, Modafinil | |
| Norepinephrine-dopamine reuptake inhibitors | Bupropion | |
| Norepinephrine reuptake inhibitor (NRI) or (NARI) | Atomoxetine, Maprotiline, Reboxetine, Viloxazine | |
| Serotonin-norepinephrine reuptake inhibitor (SNRI) | Duloxetine, Milnacipran, Venlafaxine | |
| Selective serotonin reuptake inhibitor (SSRI) | Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine | |
| Selective serotonin reuptake enhancer (SSRE) | Tianeptine | |
| Tricyclic antidepressants (TCA) | Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine | |
| Tetracyclic antidepressants | Maprotiline, Mianserin, Nefazodone, Trazodone | |
| Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine | ||
Classes
- Monoamine oxidase inhibitors (MAOIs)
- Tricyclic antidepressants (TCAs)
- Selective serotonin reuptake inhibitors (SSRIs)
- Serotonin-norepinephrine reuptake inhibitors (SNRIs)
- Norepinephrine/noradrenaline reuptake inhibitors (NRIs aka NERIs/NARIs)
- Dopamine reuptake inhibitors (DRIs)
- Opioids
- Selective serotonin reuptake enhancers (SSREs)
- Novel antidepressants
- Tetracyclic antidepressants
Prominent members
Well-known antidepressants are:
- Fluoxetine - of the SSRI class (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan)
- Sertraline - of the SSRI class (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton)
- Venlafaxine - of the SSRI class (Effexor, Efexor)
- Citalopram - of the SSRI class (Celexa, Cipramil, Talohexane)
- Paroxetine - of the SSRI class (Paxil, Seroxat, Aropax)
- Escitalopram - of the SSRI class (Lexapro, Cipralex)
- Fluvoxamine - of the SSRI class (Luvox, Faverin)
- Duloxetine - of the SSRI class (Cymbalta)
- Bupropion - of the DRI and NRI classes (Wellbutrin, Zyban)
- Amitriptyline - of the TCA class (Elavil)
- Dothiepin (Dosulepin) - of the TCA class (Prothiaden, Dothapax)
Mechanism of action
The therapeutic effects of antidepressants are believed to be related to an effect on neurotransmitters, particularly by inhibiting the monoamine transporter proteins of serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) specifically prevent the reuptake of serotonin (thereby increasing the level of serotonin in synapses of the brain), whereas earlier monoamine oxidase inhibitors (MAOIs) blocked the destruction of neurotransmitters by enzymes which normally break them down. Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine. Although these drugs are clearly effective in treating depression, the current theory still leaves unanswered questions. For example, concentrations in the blood build to therapeutic levels in only a few days and begin affecting neurotransmitter activity immediately. Changes in mood, however, often take four weeks or more to appear. One explanation holds that the "down-regulation" of neurotransmitter receptors—an apparent consequence of excess signaling and a process that takes several weeks—is actually the mechanism responsible for the alleviation of depressive symptoms. Another theory, based on recent research published by the National Institutes of Health in the United States, suggests that antidepressants may derive their effects by promoting neurogenesis in the hippocampus.[2][3]. Recent research suggests that antidepressants act on transcription factors termed "clock genes" [4], which also are involved in actions of drugs of abuse and possibly in obesity [5][6].
Treatment strategies
On efficacy measures, a successful antidepressant trial involves at least 50% of the test subjects on the drug responding to the medication. "Response" signifies at least a 50% reduction in depression symptoms, as opposed to "remission," which indicates a virtual elimination of depression symptoms. A number of different treatment strategies, however, may produce better results.
Switching
The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder 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.
A series of open-label studies by Michael Thase MD of the University of Pittsburgh found that more than half the patients who failed on their initial antidepressant achieved a response on their second antidepressant from the same class. (Thase ME et al. "Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline." J Clin Psychiatry. 1997 Jan;58(1):16-21.)
A 2002 double-blind study by the same author found a positive benefit among treatment-resistant patients switching either from an SSRI to a tricyclic or from a tricyclic to an SSRI. (Thase ME et al. "Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression." Arch Gen Psychiatry. 2002 Mar;59(3):233-9.)
Augmentation and combination
For a partial response, the American Psychiatric Association advises augmenting an antidepressant with a different pharmaceutical agent. These agents may include lithium, thyroid supplementation, atypical antipsychotics, and dopamine agonists, among others. Symbyax, a combination olanzapine-fluoxetine (Zyprexa-Prozac) pill, is approved in the US for treating bipolar depression, and is being investigated for other depression indications. In general, however, there are no major augmentation studies to guide psychiatrists.
Combination strategy involves using two or more antidepressants from different classes to target more than one neurotransmitter in order to hopefully achieve a more beneficial result. Again, this is a little-studied area of antidepressant treatment. (See article.)
Combining with psychotherapy
A 2000 study found that those on nefazadone (Serzone) plus a form of short-term psychotherapy called Cognitive Behavioral Analysis System of Psychotherapy (CBASP) fared significantly better (85% response, 42% remission) than those on Serzone alone (55% response, 22% remission) or CBASP alone (52% response, 24% remission). (Keller MB et al. "A comparison of nefazadone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression." N Engl J Med. 2000 May 18;342(20):1462-70.)
Preventing relapse
A 2003 meta-analysis of 31 placebo-controlled antidepressant trials found that continuing with antidepressants reduced the risk of relapse by 70%. (Geddes JR et al. "Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review." Lancet. 2003 Feb 22;361(9358):653-61.)
The American Psychiatric Association advises 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 Evidence Based Guidelines for Treating Depressive Disorders with Antidepressants advises remaining on an antidepressant for at least six months and as long as five years or indefinitely.
Tolerance and dependence
Antidepressants are not thought to produce tolerance, although sudden withdrawal may produce adverse effects. Antidepressants create little if any immediate change in mood and require between several days and several weeks to take effect.
Antidepressants do not seem to have all of the same addictive qualities as other substances such as nicotine, caffeine, cocaine, or other stimulants. (There is, however, controversy on the definition of addiction.) Some argue that antidepressants do not meet the general requirements for the commonly-established view. While some antidepressants may cause dependence and withdrawal they do not seem to cause uncontrollable urges to increase the dose due to euphoria or pleasure. For example, if an SSRI medication is suddenly discontinued, it may produce both somatic and psychological withdrawal symptoms, a phenomenon known as "SSRI discontinuation syndrome" (Tamam & Ozpoyraz, 2002). When the decision is made to stop taking antidepressants it is common practice to "wean" off of them by slowly decreasing the dose over a period of several weeks.
It is generally not a good idea to take antidepressants without a prescription. The selection of an antidepressant and dosage suitable for a certain case and a certain person is a lengthy and complicated process, requiring the knowledge of a professional. Certain antidepressants can initially make depression worse, can induce anxiety, or can make a patient aggressive, dysphoric or acutely suicidal. In certain cases, an antidepressant can induce a switch from depression to mania or hypomania, can accelerate and shorten a manic cycle (i.e. promote a rapid-cycling pattern), or can induce the development of psychosis (or just the re-activation of latent psychosis) in a patient with depression who wasn't psychotic before the antidepressant.
Side effects
Antidepressants can often cause side effects, and an inability to tolerate these is the most common cause of discontinuing an otherwise working medication.
General
Although recent drugs may have fewer side effects, patients sometimes report severe side effects associated with their discontinuation, particularly with paroxetine and venlafaxine. Additionally, a certain percentage of patients do not respond to antidepressant drugs. Another advantage of some newer antidepressants is they can show effects within as few as five days, whereas most take four to six weeks to show a change in mood. However, some studies show that these medications might be even more likely to result in moderate to severe sexual dysfunction. However, there are medications in trials that appear to show an improved profile in regard to sexual dysfunction and other key side effects.
MAO inhibitors can produce a potentially lethal hypertensive reaction if taken with foods that contain high levels of tyramine, such as mature cheese, cured meats or yeast extracts. Likewise, lethal reactions to both prescription and over the counter medications have occurred. Any patient currently undergoing therapy with an MAO inhibiting medication should be monitored closely by the prescribing physician and always consulted before taking an over the counter or prescribed medication. Such patients should also inform emergency room personnel and information should be kept with one's identification indicating the fact that the holder is on MAO inhibiting medications. Some doctors even suggest the use of a medical alert ID bracelet. Although the reactions in question are dramatic when they happen, the total number of deaths due to interactions and dietary concerns are comparable to over-the-counter medications.
Antidepressants should be used with great care, usually in conjunction with mood stabilisers, in the treatment of bipolar disorder, as they can exacerbate symptoms of mania. They have also been known to trigger mania or hypomania in some patients with bipolar disorder and in a small percentage of patients with depression.[7] SSRIs are the antidepressants most frequently associated with this side effect.
Use of antidepressants should be monitored by a psychiatrist, but in countries such as New Zealand, the United Kingdom, and the United States, primary care physicians are able to prescribe antidepressants without consulting a psychiatrist. In particular, it has been noted that the most dangerous period for suicide in a patient with depression is immediately after treatment has commenced, as antidepressants may reduce the symptoms of depression such as psychomotor retardation or lack of motivation before mood starts to improve. Although this appears to be a paradox, studies indicate the suicidal ideation is a relatively common component of the initial phases of antidepressant therapy, and it may be even more prevalent in younger patients such as pre-adolescents and teenagers. It is strongly recommended that other family members and loved ones monitor the young patient's behavior, especially in the first eight weeks of therapy, for any signs of suicidal ideation or behaviors. Until the black box warnings on these drugs were issued by FDA as well as by agencies in other nations, side effects and alerting families to risk were largely ignored and downplayed by manufacturers and practitioners. This may have resulted in some deaths by suicide although direct proof for such a link is largely anecdotal. The higher incidence of suicide ideation reported in a number of studies has drawn attention and caution in how these drugs are used.
Sexual
Sexual dysfunction is a very common side effect, especially with SSRIs. Bupropion, a dual reuptake inhibitor (NE and DA), in many cases results in a moderately increased libido, due to increased dopamine activity. This effect is also seen with dopamine reuptake inhibitors, CNS stimulants and dopamine agonists, and is due to increases in testosterone production (due to inhibition of prolactin) and increased nitric oxide synthesis. Apomorphine, nefazodone and nitroglycerin have been shown to reverse some sexual dysfunction via increased nitric oxide activity. MAOIs are reported to have fewer negative effects on sexual function and libido, particularly moclobemide at a 1.9% rate of occurrence. Betanechol has been reported to reverse MAOI-induced sexual dysfunction via its cholinergic agonist properties (Gross 1982).
In order for the physician to select the appropriate response, the patient should provide the physician with information to distinguish between reduced libido (little or no desire for sex), reduced sexual function (impotence, vaginal dryness) and anorgasmia, as these have separate causes and prompt different treatment.
REM Sleep
It is well recognized that virtually all major antidepressant drugs suppress REM sleep and it has, in fact, been proposed that the clinical efficacy of these drugs largely derives from their suppressant effects on REM sleep. The three major classes of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep.[8] The MAOIs virtually completely abolish REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. Ironically, a common side effect of most antidepressants is an increase in vivid dreams, and nightmares are a common result of rapid withdrawal from MAOIs.
Opioids
Opium has long been known as an antidepressant.[9] Various Opiates were commonly used as antidepressants until the mid-1950s, when they fell out of favor with medical orthodoxy due to their addictive nature, the tolerance buildup issues and their side-effect profile.
Today the use of opioids in treating depression is a large taboo in the medical field due to associations with drug abuse; hence, research has proceeded at a very slow rate.
A small clinical trial conducted at Harvard Medical School in 1995[10], demonstrated that a majority of treatment-refractory, unipolar, non-psychotic, major depression patients could be successfully treated with an opioid medication called Buprenorphine, which is a partial mu agonist and potent kappa antagonist. The exact mechanism of its action in depression is not known, as kappa antagonists are antidepressants in their own right. After the release of this paper, use of buprenorphine against depression in the clinical setting has increased. The lack of large-scale clinical trials has been a deterrent to widespread use.
While opioids have been proven to substantially relieve symptoms of depression for a large class of patients, re-acceptance of this fact has been severely hampered by governmental narcotic prohibition efforts, and the (until buprenorphine) lack of alternatives with low risk of tolerance and addiction.
Buprenorphine is generally preferred as the first-line opiate in depression treatment, as managing the tolerance buildup of other opiates can be complicated.
Gamma-Hydroxybutyric acid
Gamma-Hydoxybutyric acid (GHB) has been used by some as an antidepressant. Claude Rifat, a French biologist, conducted some early research into GHB's antidepressant potential. Rifat noted that GHB did not cause the emotional blunting effects caused by conventional antidepressants, but instead intensified pleasurable and rewarding feelings in the user while powerfully suppressing depression.[11] Unfortunately, GHB has now been outlawed, except for use as a prescription treatment for narcolepsy.
Controversy
Several studies have stimulated doubt about the effectiveness of antidepressants. The studies cite that the difference between antidepressants and placebo is negligible (Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002a), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23[12]).
The paper in question has been severely criticized by independent researchers, however. One reason for this is that it deals almost exclusively with the SSRI class of medication. In leveling criticism against the efficacy of SSRIs, critics state, it is not the best paper, merely the most widely known one. Also, other classes of antidepressants have demonstrated superior efficacy, and it has been argued that this paper is "throwing the baby out with the bathwater", while its thrust should in fact be levelled at the serotonin hypothesis of depression.
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 University of Connecticut psychologist Irving Kirsch. He and co-author Thomas Moore released their findings in "Prevention and Treatment," an e-journal of the American Psychological Association.
More than half of the 47 studies found that patients on antidepressants improved no more than those on placebos, Kirsch says. "They should have told the American public about this. The drugs have been touted as much more effective than they are." He says studies finding no benefit have been mentioned only on labeling for Celexa, the most recently approved drug. The others included in his evaluation: Prozac, Paxil, Zoloft, Effexor and Serzone.
Additional papers have been published regarding the benefits of atypical vs. typical antidepressants. These are timely papers given the need for evidence based medicine, as well as the cost of health care. Discussion of a key paper reviewing this topic titled "Quantitative analysis of sponsorship bias in economic studies of antidepressants" can be found at an on-line journal club.
Peter Glenmullen, a Harvard psychiatrist, has written a book on the subject for the layperson; see link below.
Alternative medicines
Alternative treatments for depression such as the herbal remedy St John's wort and the amino acid derivative SAM-e have gained popularity in recent years. Clinical trials have shown the effect of acupuncture to be comparable with amitriptyline; in addition, acupuncture has been found to be more effective in depressive patients with decreased excretion of 3-methyl-4-hydroxy-phenylglycol (the principal metabolite of the central neurotransmitter norepinephrine), while amitriptyline is more effective for those with inhibition in the dexamethasone suppression test (World Health Organisation, Acupuncture: Review and Analysis of Reports on Controlled Clinical Trials, 2002). Acupuncture has also been proven to prompt the body to produce greater levels of endorphins.[13] Clinical trials have shown SAM-e to be as effective as standard antidepressant medication, with many fewer side effects (Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). Most studies conclude that St. John's wort is usually as effective against depressions as other modern medication, again with fewer side effects, and it is widely prescribed for depression in Europe. However, a recent study showed St. John's wort to be no more effective than a placebo in cases of severe depression (Hypericum Depression Trial Study Group, 2002). Tryptophan dietary supplements, although banned in many countries due to impurities that caused a blood disease, have also been used as natural antidepressants. Dietary supplements of 5-HTP, a chemical the body forms from tryptophan and uses to make serotonin, have shown some promising research results but need further study.
Developments
NMDA antagonists such as ketamine and dextromethorphan have recently gained some interest in this field as their apparent ability to reverse endogenous opioid tolerance can give fast-acting dramatic effects. However, their acute psychoactive effects have been a problem.[1]
Memantine, a moderate affinity NMDA antagonist, has been used to avoid tolerance buildup, and has seen use in opioid tolerance reversal. Proglumide is used to induce acute reversal of tolerance prior to this maintenance strategy; it does not work by itself in the long term, due to tolerance to its effects.
References
- Roberto Delle Chiaie, Paolo Pancheri and Pierluigi Scapicchio. (2002). Efficacy and tolerability of oral and intramuscular S-adenosyl- L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr, 76 (5): 1172S-1176S
- Mischoulon D, Fava M. (2002). Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr, 76 (5): 1158S-61S.
- Hypericum Depression Trial Study Group (2002). Effect of Hypericum perforatum (St John's Wort) in Major Depressive Disorder: A Randomized Controlled Clinical Trial. JAMA, 287 (14):1807-1814.
- Acupuncture: Review and Analysis of Reports on Controlled Clinical Trials, World Health Organisation (2002)
- David Healy, The Antidepressant Era, Paperback Edition, Harvard University Press 1999
- ^ "Drug 'treats depression in hours'", BBC, 2006-08-07. Retrieved on 2006-09-17.
External links
- Pharmacological treatment of Mood Disorder
- A brief history of depression - 1950s
- Treating depression - Antidepressant drugs
- Creation of New Neurons Critical to Antidepressant Action in Mice
- Do Antidepressants Cure or Create Abnormal Brain States? - Article by Joanna Moncrieff and David Cohen in PLoS Medicine.
- NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
- NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
- American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder
- Children and Medication - a multimodal presentation
- British Association for Psychopharmacology 2000 Evidence Based Guidelines for Treating Depressive Disorders with Antidepressants
- The Good Drug Guide: new mood-brighteners and antidepressants
- Review of "The Anti-depressant Solution" by Peter Glenmullen
- Video of Loren Mosher, M.D. (first Chief of Schizophrenia Studies at NIMH and founding editor of the Schizophrenia Bulletin) discussing the difficulties in giving true informed consent regarding the SSRI's and his belief that there is a link between school shooters, suicide, and the SSRI's
- The Antidepressant Web von Charles Medawar
- Joanna Moncrieff: Evidence base for older antidepressants is shaky too. BMJ 2005;330:420 (19 February)
- Introduction to Let Them Eat Prozac by David Healy
- An information leaflet from the Royal College of Psychiatrists
