Prozac, a selective serotonin reuptake inhibitor (
SSRI)
Serotonin-norepinephrine reuptake inhibitor, Venlafaxine
An antidepressant, is a psychiatric medication or other substance
(nutrient or herb) used for alleviating depression or dysthymia ('milder' depression). Drug groups known as MAOIs, tricyclics and SSRIs are particularly associated with the term. These medications are now
amongst the drugs most commonly prescribed by psychiatrists and general practitioners, and their
effectiveness and adverse effects are
the subject of many studies and competing claims. An example of an herbal remedy that is an antidepressant is St John's Wort. Nutrients that are antidepressants include phenylalanine, tyrosine, tryptophan,
5-Hydroxytryptophan, and choline.
Most antidepressants have a delayed onset of action and are usually taken over the course of weeks, months or years. They are
generally considered distinct from stimulants, and drugs used for an immediate
euphoric effect only are not generally considered antidepressants. Despite the name,
antidepressants are often used in the treatment of other conditions, including anxiety
disorders, bipolar disorder, obsessive compulsive disorder, eating disorders
and chronic pain. Some have also become known as lifestyle
drugs or "mood brighteners". Other medications not known as antidepressants, including antipsychotics in low doses[1] and
benzodiazepines,[2]
are also widely used to manage depression.
The term antidepressant is sometimes applied to any therapy (e.g. psychotherapy,
electro-convulsive therapy, acupuncture)
or process (e.g. sleep disruption, increased light levels, regular exercise) found to improve clinically depressed mood. An inert
placebo tends to have a significant antidepressant effect, so establishing something as an
antidepressant in a clinical trial involves demonstrating a significant additional
effect.
History
Opium[3] and
St John's Wort[4]
(as a "nerve tonic") had long been used to alleviate depression (amongst many other things), but iproniazid was the first synthetic chemical compound generally accepted as an antidepressant. The chemical
from which it was derived, isoniazid was independently recognized as having clinically
significant effects on depression, in 1952 by Jean-Francois Buisson in France and Max Lurie in the United States, after it had come into widespread use as a treatment for tuberculosis.
Iproniazid was then then observed to have a greater "psychostimulant" effect and to
inhibit the enzyme Monoamine Oxidase. Nathan Kline and colleagues conducted the first clinical
trial to demonstrate a significant effect of iproniazid on depression in psychiatric patients. Kline approached Roche with what he called a "psychic energizer"[5] and the first Monoamine oxidase inhibitor (MAOI)
was introduced as Marsilid. Sales grew massively in the following years, and others of the class
were introduced by several drug companies, but adverse effects such as hypertension crisis
related to food amines, and acute hepatic necrosis, curtailed their use.
The discovery that a tricyclic ("three ringed") compound had a significant
antidepressant effect was also first made in the early 1950s, by Roland Kuhn in a Swiss
psychiatric hospital. By that time antihistamine derivatives were coming in to use to
treat surgical shock and then as psychiatric neuroleptics. Although, in 1955, reserpine was
indicated to be more effective than placebo in alleviating anxious depression, neuroleptics (literally "to seize the neuron")
were developing for use as sedatives and antipsychotics.
In attempting to improve the effectiveness of one of them, chlorpromazine, in
conjunction with the Geigy pharmaceutical
company, Kuhn discovered that compound "G 22355" (manufactured and patented in the US in 1951 by Häfliger and Schinder)
had a beneficial effect in patients with depression with mental and motor retardation.[6] He first reported his findings on what he called a "thymoleptic" (literally
"taking hold of the emotions", by contrast with neuroleptics, "taking hold of the nerves") in 1955/56 and they gradually became
established, resulting in the marketing of the first tricyclic antidepressant, imipramine,
soon followed by variants.
These new drug therapies became prescription-only medications in the 1950s. It
was estimated that no more than 50 to 100 people per million suffered from the kind of depression that these new drugs would
treat and pharmaceutical companies were not enthusiastic. Sales through the 1960s remained poor compared to the major tranquilizers (neuroleptics/antipsychotics) and minor
tranquilizers (such as benzodiazepines), which were being marketed for different uses.
The term antidepressant is reported to have been coined by Lurie and to not have been widely adopted until at least the
1960s.[7] Imipramine remained in common use and numerous
successors were introduced. The field of MAO inhibitors remained quiet for many years until "reversible" forms affecting only the
MAO-A subtype were introduced, avoiding some of the adverse effects.[8][9][10]
Most pharmacologists by the 1960s thought the main therapeutic action of tricyclics was to inhibit norepinephrine reuptake, but it was gradually observed that this action was associated with energizing
and motor stimulating effects whilst some antidepressant compounds appeared to have differing effects through action on
serotonin systems (notably proposed by Carlsson and Lindqvist (1969) and Lapin and Oxenkrug
(1969)).
Researchers began a process of rational drug design to isolate antihistamine-derived
compounds that would 'selectively' (specifically) target these systems. The first such compound to be patented, in 1971, was
zimelidine, whilst the first released clinically was indalpine. Fluoxetine (Prozac), FDA approved for commercial use in 1988,
became the first blockbuster SSRI. Fluoxetine was developed at Eli
Lilly in the early 1970s by Bryan Molloy, Ray Fuller, David Wong and others.[11][12]
While it had fallen out of favor in most countries through the 19th and 20th centuries, the herb St John's Wort had become increasingly popular in Germany where
Hypericum extracts eventually became licensed, packaged and prescribed by doctors. Small-scale
efficacy trials were carried out from the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis of these.[13] It
remained an over-the-counter drug (OTC) or supplement in most countries and
research continued to investigate its neurotransmitter effects and active components, particularly hyperforin[14][15]
SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and
NRIs with various different selective effects, such as
venlafaxine, duloxetine, nefazodone and mirtazapine[16]
Types of Antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
Selective serotonin reuptake inhibitors (SSRIs) are a
family of antidepressants considered to be the current standard of drug treatment. It is thought that one cause of depression is
an inadequate amount of serotonin, a chemical used in the brain to transmit signals between
neurons. SSRIs are said to work by preventing the reuptake of serotonin by the presynaptic nerve, thus maintaining higher levels
of 5-HT in the synapse. Recently, however, work by two researchers has called into question the link between serotonin deficiency
and symptoms of depression, noting that the efficacy of SSRIs as treatment does not in itself prove the link.[17] Recent research indicates that these drugs may interact with
transcription factors known as "clock genes",[18] which
may be important for the addictive properties of drugs of abuse, and possibly in obesity.[19][20]
Recent randomized controlled trials in Archives of General Psychiatry
showed that up to one-third of effects of SSRI Treatment can be seen in first week. Early effects also shown to have secondary
effect of reducing absolute reduction in HDRS score by 50%. Even more recent studies, published by the Archives of General
Psychiatry note that 25% of so-called clinical depression does not meet a disease criteria and should be considered to be
ordinary sadness and adjustment to the difficulties in life.
This family of drugs includes fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro, Esipram), citalopram (Celexa), and sertraline (Zoloft). These antidepressants
typically have fewer adverse side effects than the tricyclics or the MAOIs, although such effects as drowsiness, dry mouth,
nervousness, anxiety, insomnia, decreased appetite, and decreased ability to function sexually may occur. Some side effects may
decrease as a person adjusts to the drug, but other side effects may be persistent. Though safer than first generation
antidepressants, SSRI's may not work as often, suggesting the role of norepinephrine.
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Serotonin-norepinephrine reuptake inhibitors
(SNRIs) such as venlafaxine (Effexor) and duloxetine
(Cymbalta) are a newer form of antidepressant that works on both norepinephrine and 5-HT. They typically have similar side
effects to the SSRIs, although there may be a withdrawal syndrome on discontinuation that may necessitate dosage tapering.
Noradrenergic and specific serotonergic antidepressants (NASSAs)
Noradrenergic and specific serotonergic
antidepressants (NASSAs) form a newer class of antidepressants which purportedly work to increase norepinephrine
(noradrenaline) and serotonin neurotransmission by blocking presynaptic alpha-2
adrenergic receptors while at the same time minimizing serotonin related
side-effects by blocking certain serotonin receptors. The only example of this class in clinical use is mirtazapine (Avanza, Zispin, Remeron).
Norepinephrine (noradrenaline) reuptake inhibitors (NRIs)
Norepinephrine (noradrenaline) reuptake inhibitors (NRIs)
such as reboxetine (Edronax) act via norepinephrine (also known as noradrenaline).
NRIs are thought to have a positive effect on concentration and motivation in particular, though they have been known to increase
aggression.
Norepinephrine-dopamine reuptake inhibitors
Norepinephrine-dopamine reuptake inhibitors such as
bupropion (Wellbutrin, Zyban) inhibit the neuronal reuptake of dopamine and norepinephrine (noradrenaline).[21]
Tricyclic antidepressants (TCAs)
Tricyclic antidepressants are the oldest and include such medications
as amitriptyline and desipramine. Tricyclics block
the reuptake of certain neurotransmitters such as norepinephrine (noradrenaline) and serotonin. They are used less commonly now
due to the development of more selective and safer drugs. Several side effects include increased heart rate, drowsiness, dry mouth, constipation, urinary retention, blurred vision, dizziness, confusion, and
sexual dysfunction. Toxicity occurs at approximately ten times normal dosages. However, tricyclic antidepressants are still used
because of their high potency, especially in severe cases of clinical depression.
Monoamine oxidase inhibitor (MAOIs)
Monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil) may be used if other antidepressant medications are ineffective. Because there are
potentially fatal interactions between this class of medication and certain foods (particularly those containing Tyramine), as well as certain drugs, classic MAOIs are rarely prescribed anymore. MAOIs work by blocking the
enzyme monoamine oxidase which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). MAOIs
can be as effective as tricyclic antidepressants, although they can have a higher incidence of dangerous side effects (as a
result of inhibition of cytochrome P450 in the liver). A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible
inhibitor of monoamine oxidase A (RIMA), acts in a more short-lived and selective manner and does not require a special
diet. Additionally, (selegiline) marketed as Emsam in a
transdermal form is not a classic MAOI in that at moderate dosages it tends to effect MAO-B which does not require any dietary
restrictions.
Augmentor drugs
Some antidepressants have been found to work more effectively in some patients when used in combination with another drug.
Such "augmentor" drugs include tryptophan (Tryptan) and buspirone (Buspar).
Tranquillizers and sedatives, typically the
benzodiazepines, may be prescribed to ease anxiety and promote sleep. Because of their high potential for fostering dependence,
these medications are intended only for short-term or occasional use. Medications often are used not for their primary function
but to exploit what are normally side effects. Quetiapine fumarate (Seroquel) is designed primarily to treat schizophrenia and bipolar disorder, but a frequently reported side-effect is somnolence. Therefore, this drug can be used in place of an antianxiety agent such as clonazepam (Klonopin, Rivotril).
Antipsychotics such as risperidone
(Risperdal), olanzapine (Zyprexa), and Quetiapine
(Seroquel) are prescribed as mood stabilizers and are also effective in treating anxiety. Their use as mood stabilizers is a
recent phenomenon and is controversial with some patients. Antipsychotics (typical or atypical) may also be prescribed in an
attempt to augment an antidepressant, to make antidepressant blood concentration higher, or to relieve psychotic or paranoid symptoms often accompanying clinical depression.
However, they may have serious side effects, particularly at high dosages, which may include blurred vision, muscle spasms, restlessness, tardive dyskinesia,
and weight gain.
Antidepressants by their nature behave similarly to psychostimulants. Antianxiety medications by their nature are depressants.
Close medical supervision is critical to proper treatment if a patient presents with both illnesses because the medications tend
to work against each other.
Psycho-stimulants are sometimes added to an antidepressant regimen if the patient suffers from anhedonia, hypersomnia and/or excessive eating as well as low motivation.
These symptoms which are common in atypical depression can be quickly resolved with the addition of low to moderate dosages of
amphetamine or methylphenidate (brand names Adderall and Ritalin, respectively) as these chemicals enhance motivation and social
behavior, as well as suppress appetite and sleep. These chemicals are also known to restore sex drive. Extreme caution must be
used however with certain populations. Stimulants are known to trigger manic episodes in people suffering from bipolar disorder.
They are also easily abused as they are effective substitutes for Methamphetamine when
used recreationally. Close supervision of those with substance abuse disorders is urged. Emotionally labile patients should avoid
stimulants, as they exacerbate mood shifting.
Lithium remains the standard treatment for bipolar disorder and is often
used in conjunction with other medications, depending on whether mania or depression is being treated. Lithium's potential side
effects include thirst, tremors, light-headedness, and nausea or
diarrhea. Some of the anticonvulsants, such as
carbamazepine (Tegretol), sodium valproate
(Epilim), and lamotrigine (Lamictal), are also used as mood stabilizers, particularly in
bipolar disorder.
Prescription trends
In the United Kingdom the use of antidepressants increased by 234% in the 10 years up to 2002.[22] In the United States a 2005 independent report stated that 11% of women and 5%
of men in the non-Insitutionalised population (2002) now take antidepressants[23] A 1998 survey found that 67% of patients diagnosed with depression were prescribed an
antidepressant.[24] A 2007 study purports that 25% of
Americans were overdiagnosed with depression, regardless of any medical intervention.[25] the findings were based on a national survey of 8,098 people.
A 2002 survey found that about 3.5% of all people in France were being prescribed
antidepressants, compared to 1.7% in 1992, often for conditions other than depression and often not in line with authorizations
or guidelines[26] Between 1996 and 2004 in
British Columbia, antidepressant use increased from 3.4% to 7.2% of the
population[27] Data from the Netherlands indicated an increasing rate of prescriptions of SSRIs, and an increasing duration of
treatment.[28]
Surveys indicate that antidepressant use, particularly of SSRIs, has increased rapidly in most developed countries, driven by
an increased awareness of depression together with the availability and commercial promotion of new antidepressants.[29] Antidepressants are also increasingly used worldwide for
non-depressive patients as studies continue show the potential of immunomodulatory, analgesic and anti-inflammatory properties in
antidepressants.
The choice of particular antidepressant is reported to be based, in the absence of research evidence of differences in
efficacy, on seeking to avoid certain side effects, and taking into account comorbid (co-occurring) psychiatric disorders,
specific clinical symptoms and prior treatment history[30]
It is also reported that, despite unequivocal evidence of a significant difference in efficacy between older and newer
antidepressants, clinicians perceive the newer drugs, including SSRIs and SNRIs, to be more effective than the older drugs
(tricyclics and MAOIs).[31] A survey in the UK found that
male general physicians were more likely to prescribe antidepressants than female doctors.[32]
Most commonly prescribed antidepressants
Structural formula of the SSRI
escitalopram, in its free base form.
The most commonly prescribed antidepressants in the US in 2006 [13] were:
- Escitalopram - of the SSRI class (e.g. Lexapro, Cipralex)
- Sertraline - of the SSRI
class (e.g. Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton)
- Venlafaxine - of the SNRI class (e.g. Effexor XR,
Effexor)
- Bupropion - of the NDRI classes (e.g. Wellbutrin XR, Zyban)
- Duloxetine - of the SNRI class (e.g. Cymbalta)
- Paroxetine - of the SSRI
class (e.g. Paxil, Seroxat, Aropax)
The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) hypericum perforatum (St
John's Wort).[14] In the Netherlands, paroxetine, marketed as Seroxat® among generic preparations, is the most prescribed
antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine. [15]
Mechanisms of action
The therapeutic effects of antidepressants are believed to be related to their effects on neurotransmitters. Monoamine oxidase inhibitors
(MAOIs) block the break-down of monoamine neurotransmitters (serotonin and norepinephrine) by inhibiting the enzymes which oxidize them, thus
leaving higher levels still active in the brain (synaptic cleft).
Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters,
including serotonin, norepinephrine, and
dopamine. Selective serotonin reuptake
inhibitors (SSRIs) more specifically prevent the reuptake of serotonin (thereby increasing the level of active serotonin
in synapses of the brain). Other novel antidepressants
specifically affect serotonin and other neurotransmitters.
A theory centered on neurotransmitter effects appears to be incomplete, however. Neurotransmitter levels are altered as soon
as the antidepressant chemicals build up in the bloodstream, but effects on mood appear to occur several days or weeks later.
One explanation of this 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 hypothesis is that
antidepressants may have some longer-term effects due to the promotion of neurogenesis in
the hippocampus, an effect found in mice[33][34] Other animal research
suggests that antidepressants can also affect the expression of genes in brain cells, by influencing "clock genes".[35]
New research suggests that 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).[36] Data also suggest antidepressants to have the ability of modulating neural plasticity in longterm administration.[37]
Anti-inflammatory and immunomodulation
Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, and is possible that symptoms manifest in these psychiatric illnesses are being
attenuated by pharmacological affect of antidepressants on the immune system.[38][39][40][41][42]
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.[43] 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.[44][45][46][47][48]
Antidepressants, specifically TCAs and dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs (or SSRI-NRI
combinations), have also shown analgesic properties additionally.[49][50]
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.[51] 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.[52]
Therapeutic efficacy
There is a large amount of research evaluating the potential therapeutic effects of antidepressants, whether through efficacy
studies under experimental conditions (including randomized clinical trials) or through studies of "real world" effectiveness. A
sufficient response to a drug is often defined as at least a 50% reduction in self-reported or observed symptoms, with a
partial response often defined as at least a 25% reduction. The term remission indicates a virtual elimination of
depression symptoms, albeit with the risk of a recurrence of symptoms or complete relapse. Full remission or
recovery signifies a full sustained return to a "normal" psychological state with full functioning.
Review studies
Recent clinical reviews include:
- A comparison of the relative efficacy of different classes of antidepressants[53] in different settings[54]
and in regard to different kinds of depression[55]
- An assessment of antidepressants compared with an "active placebo"[56]
- An assessment of the newer types of the MAOI class[57]
- A meta-analysis of randomized trials of St John's Wort[58]
- A review of the use of antidepressants for childhood depression
