Friday, 28 June 2013

Treatment-Resistant Depression: How is it Treated?

It might seem like quite the contradiction since I'm asking how a condition that is, by definition, treatment-resistant, treated but in psychiatry this question is perfectly valid. This is because the usual definition of treatment-resistance in the context of depression is usually an episode of depression that has failed to adequately respond to at least two adequate trials of two pharmacologically-distinct antidepressants.

I shall decipher this riddle: an adequate trial of an antidepressant is usually defined as one in of which an adequate dosage is given for an adequate period of time. Adequate dosages do, of course vary from person to person, but in the context of treatment-resistance usually this means that the prescribing physician has given the patient virtually every dosage they can within the standard dosage range for the antidepressant in question. An adequate period of time usually means that each dosage is tried for at least a few (≈1-3) months before the dosage is changed (usually increased). Pharmacologically-distinct antidepressants are basically antidepressants that work, or so we believe, via distinct mechanisms to achieve their antidepressant effects.
Normally the two pharmacologically-distinct classes of antidepressants tried first to treat depression before the depression is deemed treatment-resistant are the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). SSRIs work via preventing the “leakage” (reuptake) of serotonin from the synaptic cleft which is where it is used as a chemical messenger between neurons (the electrically-signalling cells of the brain, spinal cord and nerves) hence leading to an increase in serotonin-mediated signalling between neurons. The signalling that serotonin serves as a messenger in appears to, among other things, regulate mood, sleeping, temperature regulation, etc. SNRIs also prevent the “leakage” (reuptake) of serotonin from the synaptic cleft, but they additionally prevent the “leakage” (reuptake) of norepinephrine from the synaptic cleft. Norepinephrine signalling is also involved in mood regulation among other things.1
Other pharmacologically-distinct classes of antidepressants that are TGA and/or FDA approved include the monoamine oxidase inhibitors (MAOIs), the tricyclic antidepressants (TCAs), the noradrenergic (noradrenaline is a synonym for norepinephrine) and specific serotonergic antidepressants (NaSSAs), the serotonin antagonist and reuptake inhibitors (SARIs), the norepinephrine reuptake inhibitors (NRIs) and the norepinephrine-dopamine reuptake inhibitors (NDRIs).1
The MAOIs work by inhibiting the enzyme monoamine oxidase (MAO) that’s responsible for the degradation of monoamines which includes the monoamine neurotransmitters serotonin, norepinephrine and dopamine. Dopamine is another neurotransmitter that appears to be involved in mood regulation. This in turn allows monoamine neurotransmitter levels in the synaptic cleft to increase as less of these neurotransmitters is converted by monoamine oxidase to inactive compounds and this in turn leads to an increase in monoamine neurotransmission1. There are two types of MAO enzymes, MAOA and MAOB. MAOA degrades serotonin and norepinephrine whereas both MAOA and MAOB degrades dopamine equally. There are reversible and irreversible inhibitors of MAO too. Reversible inhibitors only inhibit MAO while they are present in the body whereas irreversible inhibitors form chemical bonds with the MAO enzyme thus permanently inactivating it and the body has to replace the enzyme in order to restore MAO activity to the level it was prior to the use of the drug. Irreversible MAOIs are subject to causing a potentially fatal interaction with tyramine-laced foods commonly referred to as the “Cheese effect”. Tyramine is found in cheese (especially aged cheeses), certain legumes, yeast extracts and liver products.
The NRIs work by inhibiting the reuptake (or “leakage”) of norepinephrine from the synaptic cleft, hence increasing neurotransmission mediated via norepinephrine. 1
The NDRIs work by inhibiting the reuptake of both norepinephrine and dopamine from the synaptic cleft, hence increasing neurotransmission mediated by both these neurotransmitters.1
The TCAs are a more diverse group of drugs that are not quite as homogenous as the others in their pharmacologic actions. This is because the term tricyclic refers to the chemical structure of TCAs, not specifically their pharmacologic targets. Most TCAs, however, serve as SNRIs but with some clinically-significant affinity for other biologic targets including the histamine (H1), muscarinic acetylcholine (M1-M5) and adrenergic1) receptors. These additional biologic targets of the TCAs are responsible, or so we believe, for many of the adverse effects of these drugs including1:
  • Sedation/drowsiness (involves mostly the histamine, H1 receptor)
  • Dry mouth (primarily involves the M1 receptor)
  • Constipation (M1)
  • Postural hypotension (“dizzy spells”, basically when upon standing up, that is, a change in posture, a person experiences a significant reduction in blood pressure resulting in dizziness and fainting spells; mostly adrenergic α1 receptor-mediated)
  • Confusion (M1)
  • Nasal congestion (α1)
  • Urinary retention (difficulty passing urine due to paralysis of the muscles involved in expelling urine; M1)
  • Weight gain (M3)
  • Blurred vision (M1)
The NaSSAs work by directly interacting with the receptors that serotonin and norepinephrine (or noradrenaline) bind to in order to elicit, among other effects, their mood-regulating effects. These drugs also tend to interact with the H­1, α1 and M1 receptors with particular preference for the H1 receptor.
The SARIs work by inhibiting the reuptake (or leakage) of serotonin from the reuptake cleft (albeit for them this is a relatively weak effect) and, primarily, by antagonising (blocking) the serotonin, 5-HT2A receptors. They also possess affinity for the α1 and H1 receptors.

Table 1: Dosing and other properties of Select Antidepressants2
Generic Name
Brand Name
Dosage rangea
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram is composed of two enantiomers (if you don’t understand this chemical term it basically means mirror images of the same molecule), the more active S-citalopram which is in its pure form in escitalopram, and the less active R-citalopram. Citalopram in its racemic form (form that contains both enantiomers) can cause potentially fatal side effects affecting the rhythm of the heart.

Citalopram is less effective in its racemic form than in its pure S-enantiomer form, or so says clinical trial data. The reason why is not entirely clear but we believe it might involve an inhibitory action of R-citalopram on the antidepressant efficacy of S-citalopram.
Clinical studies have demonstrated that escitalopram is possibly the most effective SSRI in the treatment of depression.4 These studies have also demonstrated that it is probably one of the most well tolerated (least in the severity and frequency of side effects) SSRIs. It does not seem to carry citalopram’s potential for causing heart arrhythmias (unusual heart rhythms).
Fluoxetine was the first FDA approved SSRI (receiving FDA approval in 1987) and hence the brand name Prozac makes more regular appearances in popular culture than the any other antidepressant.

Its active metabolite, norfluoxetine, allows it to be taken as rarely as once a week. In fact, it has been found that most patients on fluoxetine will not experience the symptoms characteristic of SSRI withdrawal even if they go off it cold turkey.1

It is also the most well studied of the SSRIs from what I can tell, probably due to how long it has been used in clinical practise.

It was recently discovered to have antiviral effects against the group of viruses known as the enteroviruses, which includes the polio virus.5-6

It has also been found to directly bind to two of the serotonin receptors (5-HT2A, 5-HT2C) where it seems to serve as an antagonist.7.8

Fluoxetine also appears to have the most stimulant (wakefulness-promoting; e.g. caffeine is a stimulant) of effects of the SSRIs.

It comes in a formulation containing the antipsychotic drug olanzapine that’s known by the trade name SYMBYAX and is frequently used in the treatment of treatment-resistant major depressive disorder and bipolar depression.
Fluvoxamine is the only SSRI that’s not FDA approved for depression. Rather it is FDA approved for obsessive-compulsive disorder. In the treatment of depression it appears to be the second least effective the second-generation antidepressants (after reboxetine).3 It has the highest affinity of all the SSRIs towards the σ1 receptor. The σ1 receptor is involved in mood regulation and memory and learning and hence fluvoxamine may possess some unique properties due to this action.

Eric Harris one of the adolescents involved in the Columbine High School massacre was on fluvoxamine at the time of his death, although it is believed he was discontinuing the drug at the time of his death.
Paroxetine is probably the only SSRI without any clinically-significant affinity for the muscarinic acetylcholine receptors and as of such it can possess some mild anticholinergic side effects such as dry mouth, constipation, urinary retention, etc. It has also been found to produce significant weight-gain, as opposed to the other SSRIs, sertraline and fluoxetine which caused no significant weight gain in the same study.4 It is also the SSRI that’s use is most contraindicated in pregnancy as it has been found to be associated with birth defects.1

Paroxetine is also the most prone of the SSRIs for causing withdrawal symptoms upon abrupt discontinuation or during large dose reductions.1
Sertraline, according to one meta-analysis (statistical analysis) of clinical study data is the 2nd most effective of the SSRIs in the treatment of major depressive disorder and it is also well-tolerated.3 It also modestly inhibits the reuptake of dopamine at therapeutic doses.10

Sertraline’s active metabolite, norsertraline, might also afford sertraline a lower (but not zero) propensity for causing withdrawal symptoms.

It has also been found to inhibit the growth of certain fungi.11
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Desvenlafaxine is a relatively newly marketed antidepressant and, as its name suggests, is the active metabolite of venlafaxine. It has a very high propensity for causing withdrawal symptoms.
Duloxetine is a fairly balanced inhibitor of serotonin and norepinephrine reuptake, as opposed to venlafaxine which has a clear preference for the inhibition of serotonin reuptake.13-14
Milnacipran is not FDA for the treatment of depression but it is FDA for the treatment of fibromyalgia – a chronic pain condition that causes non-painful stimuli (e.g. just being touched softly) are interpreted as being painful. It is a SNRI and hence it is reasonable to theorise that it might possess efficacy in the treatment of depression and some clinical trial data supports this use.
75-225 (outpatients)
75-375 (inpatients)
2-3 (IR), 1 (XR)
In outpatients venlafaxine’s maximum daily dose is usually limited to 225mg/day but for inpatients (i.e. patients receiving treatment in a hospital) the dose can be up to 375mg/day.2

Venlafaxine has been found to be associated with birth defects when taken in pregnancy and hence its use in pregnant women is contraindicated.1 It also appears to have the highest propensity of the second-generation (newer, this group includes all antidepressants that are newer than fluoxetine and fluoxetine) antidepressants for causing nausea and vomiting.2

In low doses (<150mg/day) venlafaxine acts as a relatively selective serotonin reuptake inhibitor but at higher dosages it acts on norepinephrine reuptake too.12

There has been some concern about whether it might cause or exacerbate gambling addiction in problem gamblers.15

Has a dose-dependent risk of causing hypertension (high blood pressure).

According to one meta-analysis it was the 3rd most effective second-generation antidepressant in the treatment of major depressive disorder.3
Norepinephrine Reuptake Inhibitors (NRIs)
Reboxetine is the only NRI that’s TGA approved for the treatment of depression. It is not FDA approved for depression and according to one meta-analysis it is also the least effective of the second-generation antidepressants in the treatment of depression.1
Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)
3 (IR)
1 (XR)
Usually doses are limited to ≤450mg/day due to a significant risk of seizures if these doses are exceeded.1

It is often also used to assist people who are attempting to quit smoking due to its additional effects on the nicotinic acetylcholine receptors that nicotine causes its effects by stimulating.

It is often also used as an adjunct (add on) to SSRI therapy in depression that hasn’t adequately responded to SSRIs.1
Noradrenaline and Specific Serotonergic Antidepressants (NaSSAs)
Largely replaced by mirtazapine in medicine and isn’t FDA approved but it is TGA approved. It can also cause agranulocytosis.
Mirtazapine, according to one meta-analysis is the most effective of the second-generation antidepressants in the treatment of major depressive disorder.3 It has a high affinity for the histamine H1 receptor (in fact it binds more strongly to this receptor than any other receptor type) and consequently is a potent sedative.1 It also has very potent appetite-stimulating and causes significant weight gain in a sizeable portion of patients.

Can cause agranulocytosis, but if prompt action is taken to treat said agranulocytosis (which includes the discontinuation of the drug) it is usually not fatal.
Serotonin antagonist and reuptake inhibitors (SARIs)
150-450 (outpatients)
150-600 (inpatients)
2-3 (IR)
1 (XR)
Normally used in the treatment of insomnia as it has prominent sedative effects. It is seldom used in the treatment of depression due to these prominent sedating effects, its comparatively low efficacy in the treatment of depression and the fact that it is known for causing weight-gain which is a common problem in depressed patients when used as a chronic treatment. Can also cause postural hypotension due to its α1 blocking effects.
Tricyclic Antidepressants (TCAs)
75-150 (outpatients)
100-300 (inpatient)
Received FDA approval in 1961 and hence is a very old antidepressant. It also is quite unique in that it directly activates the BDNF and NGF receptors as opposed to other antidepressants that seem to indirectly cause an increase in the expression of BDNF in the brain. Serves as a fairly balanced SNRI with prominent antihistamine (H1 blocking), anticholinergic (muscarinic acetylcholine receptor blocking) and α1 blocking effects. It also has some propensity for causing seizures in susceptible patients.1
120-400 (outpatients)
120-600 (inpatients)
Has a slight preference for inhibiting norepinephrine reuptake. It is the N-desmethyl metabolite of loxapine, a typical antipsychotic and may have antipsychotic activity in itself based on the receptors it binds to.
Has high selectivity for inhibiting the reuptake of serotonin over norepinephrine.
It is relatively selective for inhibiting the reuptake of norepinephrine over serotonin.
Fairly balance inhibitor of serotonin and norepinephrine reuptake.
50-150 (outpatients)
100-300 (inpatients)
First antidepressant to receive FDA approval. Fairly balanced SNRI.
75-225 (outpatients)
100-225 (inpatients)
Highly selective for inhibiting norepinephrine reuptake.
Somewhat selective for inhibiting norepinephrine reuptake.
Fairly selective for inhibiting norepinephrine reuptake.
75-200 (outpatients)
100-300 (inpatients)
Fairly balanced SNRI.
Monoamine Oxidase Inhibitors (MAOIs)
The least commonly used of the MAOIs
The only TGA approved reversible inhibitor of MAOA (RIMA). Not FDA approved.
The most commonly used irreversible MAOI.
Used as a transdermal patch and most commonly used treat Parkinson’s disease due to its high preference for MAOB over MAOA.
Has additional norepinephrine-dopamine releasing agent properties at approximately 1/10th the potency of amphetamine and hence has some prominent stimulant effects.
Works by activating the melatonin receptors (the neurotransmitter melatonin is involved in sleep primarily) and antagonising (blocking) the serotonin 5-HT2c receptors.
a – the dosage range is in mg/day and is for when the drug is taken orally by an otherwise healthy adult with major depressive disorder.s
b – “Dosing” in this context means the amount of times per day the drug usually needs to be taken. “XR” denotes extended-release formulations which are tablets designed to release the drug over an extended period of time. “SR” denotes sustained-release formulations which are tablets designed to release the drug a little faster than extended-release tablets. “IR” denotes immediate-release formulations which are just ordinary tablets that just release the drug immediately.
c – the percentages given are the percentage of patients that get these symptoms according to clinical study data available on Micromedex.

In cases of treatment-resistant depression, however, there are two approaches open to physicians: augmentation and drug switching. Augmentation involves the addition of a drug that normally doesn’t poses antidepressant effects by itself but is expected to improve responses to an existing treatment. Drug switching is exactly what it sounds like, it is the switching of a patient to another drug, usually of a pharmacologically-distinct class and waiting to see whether they respond more favourably than to their prior medications.

Augmentation can be done with a number of different drugs, including:
  • Bupropion
  • Vitamin C
  • Lithium
  • Thyroid hormone (T3)
  • Atypical antipsychotics
  • Buspirone (an anxiolytic [anti-anxiety] drug)
  • S-adenosylmethionine (SAMe)
  • Stimulant medications (e.g. dextroamphetamine, methylphenidate or modafinil)
  • Other antidepressants
  • Yohimbine

The evidence for bupropion, SAMe and stimulant medication augmentation is limited and hence will only be discussed briefly. Bupropion is believed to be of some benefit in patients on SSRI medications due to the fact the combination works on all three monoamine neurotransmitters instead of just one in the case of SSRIs. SAMe is a naturally occurring compound in the human body that’s the primary methyl donor in the body and hence it is used in the synthesis of the monoamine neurotransmitters. According to two studies I was able to dig up it appears to be an effective adjunct in treatment-resistant depression and patients that only achieve a partial response to treatment.16-17 Stimulant medications are often thought to be effective due to their effects on the release of the monoamine neurotransmitters but they are often avoided in practice due to their high potential for abuse.18-20

Yohimbine is normally used to treat erectile dysfunction but it can be helpful in augmenting fluvoxamine antidepressant therapy in the treatment of treatment-resistant cases of depression according to one placebo-controlled study.21 It probably works by antagonising the α2 adrenergic receptors which regulate the release of norepinephrine and dopamine in the brain and by serving as a partial agonist (less potent activator than serotonin) at the 5-HT1A receptor which has two actions, first it regulates the release of serotonin (i.e. the inhibits the release of the neurotransmitter that activates it) and second it directly regulates mood. Since it serves as a partial agonist at this receptor it both antagonises the receptor in the presence of serotonin since it produces a smaller effect than what would otherwise be expected by the serotonin activating it and it also activates receptors that are not already occupied by serotonin thus both decreasing and increasing signalling via the receptor depending on the environment.  

Buspirone is another partial agonist at the 5-HT1A receptor. According to one well-designed clinical trial it appears to improve responses in treatment-resistant cases.22 Vitamin C has been tried as an adjunct in major depressive disorder (albeit in this study the depression wasn’t treatment-resistant) with success.23 It’s believed that this is due to the fact that oxidative stress from free radicals appears to contribute to depression and hence, vitamin C, an antioxidant is capable of reducing this oxidative stress and hence ameliorates the symptoms of depression.

Lithium also appears to be a useful adjunct in the treatment of depression probably due to fact it enhances the release of serotonin and has neuroprotective effects which are known to be involved in antidepressant action. It is amongst the best studied of adjuncts in treatment-resistant depression and appears effective in placebo-controlled trials.24

Atypical antipsychotics are perhaps the best studied adjuncts in the treatment of treatment-resistant depression, in fact there’s a capsule sold under the brand name Symbyax specifically for the treatment of bipolar and treatment-resistant unipolar depression (which are the two indications for which it has FDA approval) that contains the atypical antipsychotic olanzapine and the SSRI antidepressant fluoxetine. The best studied of antipsychotics in the treatment of treatment-resistant depression (TRD) include:
  • Aripiprazole (ABILIFY)25-27
  • Olanzapine (SYMBYAX when with fluoxetine and ZYPREXA when alone)28-31
  • Quetiapine (SEROQUEL)32

The mechanism of action of atypical antipsychotics in augmenting responses to antidepressants in major depressive disorder is probably related to their antagonistic effects on the 5-HT2A receptor and their partial agonist effects at the 5-HT1A receptor. 

Additionally there are a few experimental treatments in development including two drugs that have been used in medicine for decades but only recently been discovered to have antidepressant effects. These drugs include scopolamine (hyoscine) which is commonly used in the treatment of motion sickness and ketamine which is often used as an anaesthetic.


Agranulocytosis – a rapid and life-threatening drop in white blood cell (which are the immune cells of the body) count thus leaving patients wide open to infection.
Antipsychotics – drugs that are used to treat psychosis. Psychosis is a psychological state that presents with hallucinations, delusions and problems with thought processes. Antipsychotics are often used in the treatment of the psychiatric illness schizophrenia but they can also be used in the treatment of other psychiatric illnesses such as bipolar disorder, schizoaffective disorder, major depressive disorder with psychotic features and treatment-resistant depression. Atypical antipsychotics are antipsychotics that are newer (received FDA approval since 1990) and have less severe extrapyramidal side effects (side effects that closely resemble Parkinson’s disease and involve tremor, trouble initiating movement and stopping movement and controlling movements with precision, etc.).
BDNF – Brain-derived neurotrophic factor. BDNF is a protein that serves to promote the formation of new brain cells and the protection of existing brain cells by activating its receptor.
Bipolar disorder – a psychiatric disorder characterised by manic episodes, hypomanic episodes, depressive episodes along with euthymic episodes.
Dysthymia – a chronic (long-term) mild depression.
Hypomania – a less severe form of mania. Usually without psychotic features.
Major Depressive Disorder – a psychiatric disorder characterised by frequent major depressive episodes (periods of moderate-severe depression).
Mania – a psychological state in of which people often experience elated mood and may report feeling “high”, happy and full of energy. People with mania often eat less and sleep less as part of being full of energy and they often think and talk rapidly – sometimes to the point of being incoherent. They may be grandiose (thinking that they are unusually talented, special or have friends in power) and even psychotic (i.e. experience hallucinations and delusions). Manic individuals are often reckless and impulsive, and may engage in risky behaviour and, often, go out on shopping sprees spending money they do not have. Manic individuals are also often easily distracted. They can also become agitated and may act out violent if they are.
NGF – Nerve growth factor. NGF is a protein that serves to promote the formation of new nerve cells and the protection of existing nerve cells by means of activating a receptor specifically designed for it.
Placebo-controlled trial – a clinical trial in of which patients are given either a placebo or the drug being tested and then the two groups of patients are compared to see if there is any discernible benefit of the drug in the treatment of whatever condition is being treated.

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