Antidepressant Part 1

Antidepressant

Fluoxetine (Prozac), an SSRI

The chemical structure of venlafaxine (Effexor), an SNRI

Antidepressants are drugs used for the treatment of depression. Although these medications called antidepressant , they are often used to treat a wide range of other conditions such as:

• anxiety disorders
• obsessive compulsive disorder
• eating disorders
• chronic pain
• neuropathic pain
• some hormone-mediated disorders

They can be used both alone or combination with other medications. Most antidepressants have a delayed onset of action (2–6 weeks) but for those who respond well to a given drug, some degree of efficacy is often seen after one week.
Many off-label or recreational drugs can produce an antidepressant effect, but their use is controversial. Opioids were used to treat major depression until the late 1950s. Amphetamines were used until the mid-1960s. Scant research on the use of opioids limit their use for the treatment of depression, whereas amphetamines have found a thriving market for conditions as widely arrayed as attention deficit disorder, narcolepsy, and obesity, and continue to be studied for myriad applications.

Both opioids and amphetamines induce a therapeutic response very quickly, showing results within twenty-four to forty-eight hours; the therapeutic ratios for both opioids and amphetamines are greater than those of the tricyclic antidepressants. In a small study published in 1995, the opioid buprenorphine was shown to have potential for treating severe, treatment-resistant depression.The nutritional supplement tryptophan is also used in treating some forms of seasonal depression or in combination with use of bright light exposure.

Low dose antipsychotics are also sometimes used, and St John's wort. Benzodiazepines can improve the short-term response of antidepressants when used together, but also carry a risk of physical dependence with reduced effect over time as well as withdrawal symptoms. Antipsychotics can have severe long term negative effects, such as tardive dyskinesia, brain atrophy, and metabolic syndrome Inert placebos can also have significant antidepressant effects.
Non pharmaceutical approaches to the treatment of depression include psychotherapy, cognitive-behavioural therapy, electro-convulsive therapy, acupuncture, exercise, sleep deprivation, or bright light exposure.

History of Antidepressants:

St John's wort

Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Their use was later restricted due to their addictive nature and side-effects. Extracts from the herb St John's wort had been used as a "nerve tonic" to alleviate depression.

• Isoniazid, iproniazid, and imipramine:

In 1951, Irving Selikoff and Edward Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation... the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems." The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side-effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two thirds of their patients and coined the term antidepressant to describe its action.A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952, before Lurie and Salzer, Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid, although it remains a mainstay of tuberculosis treatment. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.

Selikoff and Robitzek also experimented with another anti-tuberculosis, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd, described the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid remained relatively obscure until Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer". Roche put a significant marketing effort behind iproniazid, including promoting its off-label use for depression. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

The antidepressant effect of a tricyclic, a three ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics.
Attempting to improve the effectiveness of chlorpromazine, Kuhn, in conjunction with the Geigy Pharmaceutical Company, discovered that compound "G 22355", later renamed imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a "thymoleptic" "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves" in 1955-56. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.

• Second generation antidepressants:

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 individuals per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of "reversible" forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.
By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the U.S. Food and Drug Administration (FDA) in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David Wong and others.
SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects.

St John's wort fell out of favor in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis. It remains an over-the-counter drug (OTC) supplement in most countries. Research continues to investigate its active component hyperforin and to elucidate its mode of action.

Classes of antidepressants:

1)     Selective serotonin reuptake inhibitors:

Selective serotonin reuptake inhibitors, SSRIs are thought to prevent the reuptake of serotonin (also known as 5-hydroxytryptamine, or 5-HT) by the presynaptic neuron, thus initially maintaining higher levels of 5-HT in the synapse. Like all anti-depressants their mechanism of action remains unknown.

SSRI antidepressants includes:

• Citalopram (Celexa)
• Escitalopram (Lexapro, Cipralex)
• Paroxetine (Paxil, Seroxat)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Sertraline (Zoloft, Lustral)

2)     Norepinephrine reuptake inhibitors:

Selective norepinephrine reuptake inhibitors (NRIs) inhibit the reuptake of norepinephrine.

The NRIs include:

• Atomoxetine (Strattera)
• Reboxetine (Edronax)
• Viloxazine (Vivalan)

3)     Noradrenergic and specific serotonergic antidepressants (NaSSA):

Noradrenergic and specific serotonergic antidepressants NaSSA inhibit reuptake of serotonin, and noradrenaline at the presynaptic alpha-2 adrenergic receptors.

Examples include:

• Mianserin (Tolvon)
• Mirtazapine (Remeron, Avanza, Zispin)

4)     Serotonin–norepinephrine reuptake inhibitors:

Serotonin–norepinephrine reuptake inhibitors (SNRIs) inhibit reuptake of serotonin and norepinephrine.

These include:

• Desvenlafaxine (Pristiq)
• Duloxetine (Cymbalta)
• Milnacipran (Ixel, Savella)
• Venlafaxine (Effexor)

5)     Serotonin antagonist and reuptake inhibitors:

The Serotonin antagonist and reuptake inhibitors (SARIs) include:

• Etoperidone (Axiomin, Etonin)
• Nefazodone (Serzone, Nefadar)
• Trazodone (Desyrel)

6)     Norepinephrine-dopamine reuptake inhibitors:

Norepinephrine-dopamine reuptake inhibitors inhibit the neuronal reuptake of dopamine and norepinephrine.

These include:

• Bupropion (Wellbutrin, Zyban)

7)     Selective serotonin reuptake enhancers:

• Tianeptine (Stablon, Coaxil, Tatinol)
• Amineptine

8)     Norepinephrine-dopamine disinhibitors:

Norepinephrine-dopamine disinhibitors (NDDIs) act by antagonizing the serotonin 5-HT2C receptor, which normally acts to inhibit norepinephrine and dopamine release, thereby promoting outflow of these neurotransmitters.

• Agomelatine (Valdoxan, Melitor, Thymanax)

9)     Tricyclic antidepressants:

Tricyclic antidepressants block the reuptake of norepinephrine and serotonin.

The tricyclics include:

• Tertiary amine tricyclic antidepressants:

• Amitriptyline (Elavil, Endep)
• Clomipramine (Anafranil)
• Doxepin (Adapin, Sinequan)
• Imipramine (Tofranil)
• Trimipramine (Surmontil)

• Secondary amine tricyclic antidepressants:

• Desipramine (Norpramin)
• Nortriptyline (Pamelor, Aventyl, Noritren)
• Protriptyline (Vivactil)

10)     Monoamine oxidase inhibitor:

Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme monoamine oxidase, which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine. There are two types with regard to the effect on the enzyme, the irreversible and the newer reversible inhibitors. As there are potentially fatal interactions between irreversible MAOIs and certain foods (particularly those containing tyramine), as well as certain drugs, classic irreversible MAOIs are rarely prescribed any more. However, this does not apply to Emsam and moclobemide, Ensam is the transdermal patch form of selegiline, which due to its bypassing of the stomach has a lesser propensity to induce such events, while moclobemide is a reversible inhibitor of monoamine oxidase A (RIMA), which does not require dietary restrictions.

• Irreversible monoamine oxidase inhibitors:

• Isocarboxazid (Marplan)
• Phenelzine (Nardil)
• Selegiline (Eldepryl, Emsam)
• Tranylcypromine (Parnate)

• Reversible monamine oxidase inhibitors:

• Moclobemide (Aurorix, Manerix)
• Pirlindole (Pirazidol)

11)     Nicotine:

Nicotine is believed to act as an antidepressant, by stimulating the release of dopamine and norepinephrine; additionally, nicotine is believed to exert an antidepressant effect due to the desensitisation of nicotinic receptors which occurs as a result of tolerance. Clinical trials have demonstrated nicotine (administered using a dermal nicotine patch) exerts an antidepressant effect in both depressed nonsmokers and smokers, and can be considered for treatment-resistant depression. The proposed mechanism of chronic nicotine causing desensitisation of nicotinic receptors, thereby leading to an antidepressant effect, is consistent with the theory first proposed over 30 years ago and subsequent research that confirmed excessive acetylcholine activity in the brain leads to depressive symptoms. Varenicline, a nicotinic receptor-acting drug used to wean people off of nicotine dependence has also demonstrated antidepressant properties.

12)     Caffeine:

Individuals who use caffeine, at moderate doses (fewer than 6 cups of coffee per day), have a reduced incidence of depressive symptoms and an overall reduced risk of suicide. Anxiety is an important side effect of caffeine which occurs more commonly in individuals who suffer from panic disorder or social phobia or when caffeine is taken in excessive amounts.

13)     Adjunct medication:

Other medications are used to "augment" the effect of antidepressants with mixed results.

Some of the drugs used include

• Psychostimulants such as:

• amphetamine (Adderall)
• methylphenidate (Ritalin)
• modafinil (Provigil, Alertec)

Modafinil is unique in its effect on sleep; it increases alertness and reduces drowsiness while the patient is active, but does not inhibit normal sleep. Extreme caution must be used, however, with certain populations. Stimulants are known to trigger manic episodes in people suffering from bipolar disorder. Close supervision of those with substance abuse disorders is urged. Emotionally labile patients should avoid stimulants, as they exacerbate mood shifting. A review article published in 2007 found psychostimulants "may" be effective in treatment-resistant depression with concomitant antidepressant therapy. A more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the "somewhat" contradictory nature of their results. However, the authors claim psychostimulants are likely to have a higher level of clinical effectiveness under circumstances in which the patient will probably die soon, so rapid relief is of great importance. In this situation, the patient is likely to die before dependence on, or tolerance of, the medication interferes with their care.

• nicotine:

Chronic nicotine intake via nicotine patches results in an increased response to standard antidepressants. Similarly varenicline has been shown to augment subtherapeutic dose levels of SSRIs to produce an antidepressant effect.

• lithium:

Lithium remains the standard treatment for bipolar disorder and is often used in conjunction with other medications. Lithium's potential side effects include thirst, tremors, light-headedness, nausea, diarrhea. Long term use is associated with kidney failure.

Anticonvulsants are also used, particularly in bipolar disorder.They include:

• carbamazepine (Tegretol)
• sodium valproate (Epilim, Depakote)
• lamotrigine (Lamictal)
• clonazepam (Klonopin)
• oxcarbazepine (Trileptal)

Benzodiazepines also play a prominent role in the treatment of bipolar disorder. The are used to counteract the often nervous or "jittery" effects of psychostimulant medications can produce. For example a common side effect of Prozac is insomnia thus a tranquilizer such as Valium maybe prescribe to offset this effect. Additionally, benzodiazepines have been proven to augment and compliment the effects of antidepressants giving the patient the optimum results of the drug. Due to their potential for dependency however most patients over the course of their treatment take benzodiazepines on an "as needed" (PRN) basis.

The most commonly used benzodiazepines are:

• diazepam (Valium)
• clonazepam (Klonopin)
• lorazepam (Ativan)
• alprazolam (Xanax)
• temazepam (Restoril)

14)     Alternative therapies:

• Herbalism:

St. John's wort is by far the most widely-used and well-studied herbal antidepressant. A number of other herbs have been used traditionally to treat depression and related ailments like anxiety, but the research on most of these treatments is sparse.
In a small (30-patient), double-blind, randomized clinical trial, saffron (Crocus sativus L.) was to be equally effective with imipramine for treating mild to moderate depression. However, no other researchers have confirmed these results, nor has a larger population study been published. Another small (40-patient), eight-week, double-blind, randomized trial found saffron to have a similar effect to fluoxetine (Prozac) in the treatment of mild to moderate depression, including a similar remission rate and similar rate of side effects. Neither study has been confirmed in larger trials at other centers.

Several plants in the Salvia genus have been studied for antidepressant properties, although most of the research conducted so far has only been from mice and rat studies. Salvia elegans, also known as pineapple sage, is widely used in Mexican traditional medicine, and has been found in single study in mice to have antidepressant and antianxiety properties. Salvia sclarea, also known as clary, is known to have an antidepressant-like effect in rats, which is thought to be explained by modulation of dopamine.

• Nutrition:

Poor nutrition has been proposed as a risk factor for developing depression. In a study of older adults, poor nutrition was a strong predictor of depressive symptoms.
Omega 3 fatty acids have been proposed as a treatment for depression, alone or in combination with other treatments. One small pilot study of childhood depression (ages six to 12) suggested omega 3 fatty acids may have therapeutic benefits for treating childhood depression. A 2005 review article included double-blind studies, randomized control trials, epidemiological studies linking omega 3 fatty acids consumption and depression found that low fish consumption (the primary source of omega 3 fatty acids) correlated to increased rates of depression, and case-control and cohort studies of unipolar and postpartum depression indicating low blood levels of omega-3 fatty acids in depressed patients.

A 2008 review of clinical studies of the effectiveness of omega-3 fatty acids on depression has shown somewhat inconsistent results: "Of the evaluated studies, 13 showed a significant positive association between omega-3 and depression, while six studies did not show a relationship between the referred variables." To be read with caution because of limited data, a 2008 Cochrane systematic review found in the one eligible study that omega 3 fatty acids are an effective adjunctive therapy for depressed but not manic symptoms in bipolar disorder. The authors found an "acute need" for more randomised, controlled trials.

Mechanisms of Action:

For depression, the mechanism of action of antidepressants is unknown.

• Neurogenic Adaptations:

The neurogenic hypothesis states that molecular and cellular mechanisms underlying the regulation of adult neurogenesis is required for remission from depression and that neurogenesis is mediated by the action of antidepressants. Chronic use of antidepressant increased neurogenesis in the hippocampus of rats.

Other animal research suggests that long term drug-induced antidepressants effects modulate the expression of genes mediated by clock genes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).

The delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs).

• Hypothalamic-Pituitary-Adrenal Axis:

One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not know whether this HPA axis disregulation is reactive or causative for depression. This briefing suggest that the mode of action of antidepressants may be in regulating HPA axis function.

• Monomine Hypothesis:

In 1965, Joseph Schildkraut postulated the Monoamine Hypothesis when he posited an association between low levels of neurotransmitters and depression. By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain.

To date, there is no evidence to support serotonin dysfunction in the pathophysiology of this disorder.

Serotonin levels in human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response. Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin level in the brain and symptoms of depression have not been linked

Although there is evidence that antidepressants inhibit the reuptake of serotonin, norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants, and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants.

While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2A receptors, suggesting it is too simplistic to say serotonin is a happy hormone.

In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.

Antidepressant Page 2

REFERENCE:

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