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 and benzodiazepines, 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
and St John's Wort (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 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" 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.
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.
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.
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.
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. 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.
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.
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. Recent
research indicates that these drugs may interact with transcription
factors known as "clock genes", which may be important
for the addictive properties of drugs, of abuse, and possibly
in obesity.
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 percent.
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).
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.
