Antidepressants are among the most widely prescribed medications and they are used for many purposes, not just for the treatment of depression, but there are many types of medications that are called “antidepressants.”
Moreover, antidepressants may not be very effective for certain kinds of depression, they may even make depression worse. It is helpful to consider that the phrase “antidepressant” does not describe with great accuracy the effects of these medications.
This is a summary of information about antidepressants derived from several sources, including Wikipedia, and is a work in progress.
This page uses the traditional scheme for classifying psychotropic medications. For information about the Neuroscience Based Nomenclature, an alternative system that is supported by a number of prestigious organizations click here.
Monoamine Neurotransmitters
Antidepressants largely appear to function as the result of their effects on a handful of neurotransmitters, known as monoamines. The monoamine neurotransmitters are –
- norepinephrine (noradrenaline)
- epinephrine (adrenaline)
- dopamine
- serotonin
The first three of these are also known as catecholamines and are all interrelated chemically. See the image to the right which shows how the catecholamines all derive from phenylalanine and tyrosine.
Serotonin is derived from the amino acid tryptophan and is chemically related to melatonin.
These four neurotransmitters seem to be affected by most of the medications that are effective treating depression. This has led to what has been called the monoamine hypothesis of depression which is the basis for the notion that depression is a disease or condition that reflects a lack of adequate amounts of brain chemicals – a deficiency of dopamine, epinephrine, norepinephrine or serotonin. The monoamine hypothesis has been extremely useful, but is equally clearly inadequate to explain depression (Hirschfeld, J Clinical Psychiatry, 2000).
This video is a pretty good overview of the current deficiency hypothesis which talks about some of the basics of brain neurotransmission.
Antidepressants and Monoamine Neurotransmitters
Almost all antidepressants are classified based on how they affect monoamine neurotransmission.
Most antidepressants increase levels of neurotransmitters in the gaps between brain cells (neurons) where brain signalling takes place. They do this mostly by interfering with the activity of what are called reuptake proteins.
In the very simplified drawing to the left you can see that when a signal comes to the top neuron that signal leads to the release of serotonin (transmitting the signal to the next brain cell or neuron). The signal ends when the serotonin is either taken back into the releasing neuron or is broken down by enzymes in the gap between the two neurons (the synaptic cleft).
Reuptake inhibitors interfere with the reuptake of the neurotransmitter and thus should lead to increased brain signalling.
This process occurs in the synapses of all of the monoamine neurotransmitters, so there can be agents that inhibit norepinephrine reuptake (norepinephrine reuptake inhibitors or NRIs), dopamine reuptake (DRIs), etcetera. However, it turns out that most of the medications we routinely use primarily affect serotonin.
One often useful way of thinking about these neurotransmitters is summarized in the picture to the right. In that image you can see that low levels of serotonin, norepinephrine and dopamine (depending on where they occur in the brain) can be associated with different symptoms of depression, and thus the selection of agent may usefully relate to the most predominant symptoms that someone is experiencing.
Low serotonin may be associated with obsessive thoughts and perhaps impulsiveness. Indeed, I often describe serotonin antidepressants as medications that are most especially useful for dealing with recurring worries… In depression this recurrent worry can take the form of a sense that something bad is about to happen… a kind of worried anticipation of disaster.
Low norepinephrine may be associated with poor concentration and reduced motivation. There are no norepinephrine medications that have been approved in this country as antidepressants, but one medication that is available in Europe (reboxetine) showed in clinical trials that it was associated with significant improvement in motivation and work and social functioning in people with depression, although it was not able to show that overall levels of depression improved.
Low dopamine has been associated with anhedonia, or a lack of pleasure, or reward and motivation. And low dopamine states can be very uncomfortable (they are associated with a lot of the craving seen in people who abuse cocaine and stimulants). There are no currently approved dopamine specific agents. Nomifensine was approved for the treatment of depression but was withdrawn because it was shown to be associated with rare but severe dysregulation of body temperature.
The most important classes of antidepressants are
- serotonin reuptake inhibitors (SRIs)
- serotonin–norepinephrine reuptake inhibitors (SNRIs)
- norepinephrine and dopamine reuptake inhibitors (NDRIs)
- norepinephrine reuptake inhibitors (NRIs)
There are also medications that affect serotonin alpha-two antagonists as serotonin – norepinephrine disinhibitors (SNDIs), serotonin antagonists and reuptake inhibitors (SARIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase A inhibitors (rMAO-A inhibitors), tetracyclic antidepressants (TeCAs), and noradrenergic and specific serotonergic antidepressant (NaSSAs).
Serotonin Reuptake Inhibitors (SRIs)
Serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitors (SRIs) increase the level of the neurotransmitter serotonin by limiting its reuptake into the firing neuron. “Selective” serotonin re-uptake inhibitors have only weak effects on two other kinds of neurons that have been implicated in depression norepinephrine and dopamine neurons.
SSRIs are the most widely prescribed antidepressants in many countries. The efficacy of SRIs in mild or moderate cases of depression has been disputed. They are clearly effective in moderate to severe depression.
Clinical Uses of SRI Antidepressants
SRIs seem to be effective for many conditions associated with recurrent worry or depressive thoughts. Their effects on depression seem to follow after they reduce the negative or catastrophic thoughts that often accompany depression (“something bad is going to happen”).
At high doses this can lead to apathy or emotional flatness, for people who have had this experience with the medications it can be important to carefully titrate the medications to a dose that treats the excessive worry thoughts but doesn’t lead to a lack of appropriate concern about things that need to be done.
Adverse Effects
SRIs can cause delayed or reduce orgasm in both men and women, diminished interest in sex (libido) particularly in women, and much less frequently erectile dysfunction and genital numbness.
SRIs interact with blood thinners, like Coumadin and Aspirin and anti-platelet agents. This results in an increased risk of GI bleeding, and post-operative bleeding. SRIs affect platelet function (an essential element of blood clotting). This risk is greater in those who are on more than one of these medications – anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs like Motrin), as well as in those with liver disease.
Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimize discontinuation-related symptoms which may include nausea, headache, dizziness, chills, body aches, tingling sensations, trouble sleeping and electric shock-like sensations.
Paroxetine seems to have the greatest risk of discontinuation syndromes and fluoxetine the least. Planned discontinuation can almost always be managed with minimal discomfort.
List of agents
Drugs in this class include:
- Citalopram (Celexa)
- Escitalopram (Lexapro)
- Fluoxetine (Prozac)
- Fluvoxamine (Luvox)
- Paroxetine (Paxil)
- Sertraline (Zoloft)
Doses
A recent study suggests that higher than usual doses may be more effective. See more information here.
Serotonin – Norepinephrine Reuptake Inhibitors (SNRI’s)
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depressive disorder (MDD) and other mood disorders. They are sometimes also used to treat anxiety disorders, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.
SNRIs are potent inhibitors of the reuptake of both serotonin and norepinephrine. SSRIs affect serotonin alone. There are also agents that primarily affect norepinephrine and dopamine systems. Some evidence suggests that when choosing between medications that only affect serotonin and medications that affect norepinephrine (with or without serotonin), a genetic test that identifies the gene for the norepinephrine transmitter may be helpful.
Where serotonin effects may reduce excessive worry or depressive thoughts, effects on norepinephrine seem to enhance motivation and focus. So for some patients a combined agent may be more effective, and generally that is what studies show.
On the other hand SNRIs may have a greater propensity for certain activation or jitteriness side effects early on in treatment and may be more likely to cause other energized or hypomanic states.
Serotonin: Norepinephrine Ratios
The serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 10:1, milnacipran = 1:3, and levomilnacipran = 1:2 (Sansone RA, 2014). The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear, but may include improved effectiveness, though also increased side effects.
List of Agents
- Venlafaxine (Effexor) – The first and most commonly used SNRI. The reuptake effects of venlafaxine are dose-dependent. At low doses (<150 mg/day), it acts only on serotonergic transmission. At moderate doses (>150 mg/day), it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day), it also affects dopaminergic neurotransmission. Of all of these medications venlafaxine is the best studied. This means that we have the most information about how dose affects response and therefore can titrate the medication most effectively to the optimal dose. On the other hand, it has a short half life which means that it has a higher risk of
discontinuation symptoms when it is abruptly stopped (so don’t do that…). See the chart to the right for information about how venlafaxine and desvenlafaxine are related to each other. People who have the “poor metabolizer” genotype of the cytochrome P4502D6 enzyme may do better taking desvenlafaxine. - Desvenlafaxine (Pristiq) – The active metabolite of venlafaxine. It is believed to work in a similar manner, though some evidence suggests lower response rates compared to venlafaxine and duloxetine. It was introduced by Wyeth in May 2008 and was then the third approved SNRI. It does not appear to have a dose response curve. The recommended desvenlafaxine dose is of 50 mg/day. Dosage forms include extended release tablets of 50 and 100 mg, but the initial clinical trials showed no evidence that doses greater than 50 mg/day confer any additional benefits… In clinical studies, doses of 50 mg to 400 mg per day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg per day and adverse reactions and discontinuations were more frequent at higher doses.
- Duloxetine (Cymbalta ) – Was the second SNRI, it was developed by Eli Lilly. Because of difficulty with early clinical trials it was almost not marketed, it was approved for the treatment of depression and neuropathic pain in August 2004. Duloxetine is contraindicated in patients with heavy alcohol use or chronic liver disease, as duloxetine can increase the levels of certain liver enzymes that can lead to acute hepatitis or other diseases in certain at risk patients. Duloxetine is approved for major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic neuropathy, chronic musculoskeletal pain, including chronic osteoarthritis pain and chronic low back pain (as of October, 2010), and is one of the only few medicines approved by the FDA for fibromyalgia. Whether there is any reason to believe that the medication is more effective for these indications than other SNRIs is not clear. There is some reason to think that the dose of duloxetine that was approved may be less effective than venlafaxine. The usual dose is 60 mg. It is approved at doses of 60 or 120 mg with a note that the clinical trials did not find a difference in effectiveness at the two doses, however those studies were small and under-powered to find differences, and there was a trend to more effectiveness at the higher doses.
- Milnacipran (Savella) – Shown to be significantly effective in the treatment of depression and fibromyalgia. The Food and Drug Administration (FDA) approved milnacipran for treatment of fibromyalgia in the United States of America in January 2009, but it is not approved for the treatment of depression. Milnacipran has been commercially available in Europe and Asia for several years.
- Levomilnacipran (Fetzima) – Levomilnacipran is the levo- enantiomer of milnacipran, and has similar effects and pharmacology, acting as a serotonin-norepinephrine reuptake inhibitor (SNRI).The FDA approved levomilnacipran in July 2013 based on the results of one 10-week phase II and four 8-week phase III clinical trials. Four of the five trials demonstrated a statistically significant superiority to placebo as measured by the Montgomery–Åsberg Depression Rating Scale. Superiority to placebo was also demonstrated by improvement in the Sheehan Disability Scale. The efficacy of extended-release levomilnacipran has been established (versus placebo) in doses ranging from 40 mg/day to 120 mg/day. Principal side effects in clinical trials include nausea, constipation, and sweating. Approximately 1%-3% of patients will report a significant increase in blood pressure and up to 6% will report a significant elevation of pulse. Like its racemate, levomilnacipran is neither a substrate for nor potent inhibitor of cytochrome P450 isoenzymes.
- Sibutramine (Meridia, Reductil) – An SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an appetite suppressant for weight loss purposes. Sibutramine was the first drug for the treatment of obesity to be approved in 30 years.
Side-effects
The most common side effects include loss of appetite, weight, and sleep. There may also be drowsiness, dizziness, fatigue, headache, a transient increase in suicidal thoughts (due to increased energy without improved mood), nausea/vomiting, sexual dysfunction, and urinary retention. There are two common sexual side-effects: diminished interest in sex (libido) and difficulty reaching climax (anorgasmia), which are usually somewhat milder with the SNRIs in comparison to the SSRIs. Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. People at risk for hypertension and heart disease should have their blood pressure monitored.
Discontinuation syndrome
As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or “discontinuation syndrome”, which could include states of anxiety and other symptoms. Therefore, it is recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be worse for venlafaxine when compared to other SNRIs. This is likely due to venlafaxine’s relatively short half-life and therefore rapid clearance upon discontinuation.
Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)
A norepinephrine-dopamine reuptake inhibitor (NDRI) is a drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.
Attempts to develop antidepressants that inhibit the reuptake of dopamine have not been as successful as efforts to develop norepinephrine or serotonin reuptake inhibitors. A number of agents have been developed but have not made it successfully to market either due to safety concerns or problems showing effectiveness.
The two agents listed below are very different.
List of NDRI’s
- Bupropion (Wellbutrin)
- Methylphenidate (Ritalin, Concerta, Metadate, Methylin, Rubifen, Stimdate)
Norepinephrine Reuptake Inhibitors (NRIs)
As noted above, there is no norepinephrine inhibitor that is currently approved for the treatment of depression in the United States. However there is one approved medication in this country and several approved agents in other countries.
- Atomoxetine (Strattera) is approved for the treatment of attention deficit with hyperactivity disorder (ADHD) in the US and is the only non-stimulant medication approved for that purpose, although bupropion is often also used for that indication. It is associated with side effects such as nausea (26%), dry mouth (20%), appetite loss (16%), insomnia (15%) and fatigue (10%). Usual doses in adults with ADHD are 40 – 80 mg and it may be increased up to 100 mg if those doses are not effective. It is a strong inhibitor of cytochrome P4502D6.
NRIs and SNRIs may have somewhat more of a tendency than SRIs to induce hypomania in people with bipolar depression, so caution is indicated.
Alpha 2 Antagonist and Serotonin Modulator
These are medications that block the alpha-2 adrenergic (norepinephrine) receptor. The alpha-2 receptor mostly functions as an auto-receptor. When the neurotransmitter is released by a neuron, auto-receptors function as the brakes to control the amount that is released. So by blocking the alpha-2 receptor you effectively remove this brake and increase release of norepinephrine.
In addition, these compounds block serotonin-2 receptors which can indirectly increase norepinephrine, dopamine and serotonin transmission.
Mirtazapine
In clinical studies, mirtazapine has been found to be an effective antidepressant with a generally tolerable side-effect profile relative to other antidepressants.
In a major meta-analysis published in 2009 that compared the efficacy and tolerability of 12 second-generation antidepressants, mirtazapine was found to be superior to all of the included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reboxetine and bupropion in terms of antidepressant efficacy, while it was average in regard to tolerability. However, its superior efficacy over the other medications in the top four (escitalopram, sertraline and venlafaxine) did not reach statistical significance.
Mechanism of Action
As mentioned above, this class of medications blocks the alpha-2 adrenergic (norepinephrine) autoreceptor and increases release of norepinephrine. Mirtazapine also is an inverse agonist (blocker) of the 5-HT2C (serotonin 2C) receptor which also boosts norepinephrine (and dopamine) in some parts of the brain. In addition, mirtazapine blocks 5-HT3 (serotonin 3) receptors which makes it an anti-nausea medication, and it is a powerful H1 (histamine 1) antagonist. This anti-histamine effect makes it a very sedating medication, and the combination of anti-histamine and 5-HT2C antagonism makes it a medication that increases appetite.
Side effects
Very common (≥10% incidence) adverse effects
- Constipation (13%)
- Dry mouth (25%)
- Increased appetite (17%)
- Somnolence (54%), sedation, sleepiness
- Weight gain (≥7% weight gain, only in pediatrics is this very common)
Although not common (about 3%) some people do have an increased heart rate with this medication. For someone who is basically healthy this is more an annoyance than anything else. It does point to the fact that this medication has sympathetic nervous system activation as an effect… and in keeping with that, it may, like NRI’s, have somewhat more of a tendency to induce hypomania in people with bipolar depression.
Serotonin Antagonist and Reuptake Inhibitor
Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α1-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
List of SARIs
- Nefazodone (Serzone)
- Trazodone (Desyrel)
Vilazodone is a related drug but does not fit into this class as it does not function as a serotonin antagonist, acting as a 5-HT1A receptor partial agonist
Serotonin Modulator and Stimulator
A serotonin modulator and stimulator (SMS), sometimes referred to more simply as a serotonin modulator, also known as serotonin partial agonist/reuptake inhibitor (SPARI) is a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine (Trintellix), which acts as a serotonin reuptake inhibitor (SRI), partial agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone (Viibryd), which acts as an SRI and 5-HT1A receptor partial agonist.
SMSs were developed because there are many different subtypes of serotonin receptors (at least 15 in total are currently known) and not all of these receptors appear to be involved in the antidepressant effects of SRIs. Some serotonin receptors seem to play a relatively neutral or insignificant role in the regulation of mood, but others, such as 5-HT1A autoreceptors and 5-HT7 receptors, appear to play an oppositional role in the efficacy of SRIs in treating depression. As such, a drug which combines the actions of, say, an SRI, 5-HT1A partial agonism (to desensitize 5-HT1A autoreceptors), and 5-HT7 receptor antagonism, could, in theory, have the potential to prove more effective than pure SRIs. Alternatively, antagonism of 5-HT3 – a receptor that is involved in the regulation of nausea, vomiting, and the gastrointestinal tract – could counteract the undesirable increase in activation of this receptor mediated by SRIs, thereby potentially improving tolerability.
Monoamine Oxidase Inhibitors (MAOIs)
Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression. They are also used in the treatment of Parkinson’s disease and several other disorders.
Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed. New research into MAOIs indicates that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite proven effectiveness of this class of drugs, it is underutilized and misunderstood in the medical profession. New research also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research.
Newer MAOIs such as selegiline (EmSam) (typically used in the treatment of Parkinson’s disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy.
MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.
MAOIs appear to be particularly indicated for outpatients with “neurotic depression” complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected.
Medications with Other Mechanisms of Action
NMDA Receptor Antagonists
A medication approved by the FDA in 2022 claims to be the first oral antidepressant that functions as an NMDA receptor antagonist. The NMDA receptor is one of two types of glutamate receptors in the brain. Glutamate is the most common excitatory neurotransmitter in the brain and is thus analogous to GABA, which is the most common inhibitory neurotransmitter in the brain.
The medication has the brand name of Auvelty and the generic name of dextromethorphan / bupropion. There are two published clinical trials looking at the effectiveness of the medication. Both show much faster response times (a significant difference compared to placebo by week 1) and higher remission rates (40% with Auvelty vs 17% with placebo) than are reported in most other clinical trials of antidepressants.
Clinical experience is limited and one question we don’t have enough information to judge is the duration of the effect and whether or not there are long term side effects.
Progesterone Related Allosteric Modifiers of GABA
Several medications recently approved for treatment of post-partum depression are similar structurally to the hormone progesterone and seem to function as allosteric modifiers of GABA. There is one oral medication that is being actively studied as a treatment for major depression that is not post-partum.
For More Information
How Long Should You Take Antidepressants
Antidepressant Selection Survey
Treatment Resistant or Chronic Depression
References
Iosifescu, Dan V. et al. “Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI).” The journal of clinical psychiatry 83.4 (2022): n. pag. Web.
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