Combining antidepressants to address treatment-resistant depression

Financial disclosures

As discussed in Chapter 1 , it is helpful to define treatment-resistant depression (TRD). Although one defines treatment resistance, it is clear that this is a very significant clinical problem. We now know from multiple randomized controlled clinical trials and years of clinical experience that only a minority of patients are able to attain remission after treatment with an adequate dose of an antidepressant ( ).

Definitions of treatment resistance range from inadequate response to at least one antidepressant trial of adequate doses and duration, to failure to respond to a minimum of four different antidepressant treatments, including medications, evidence-based psychotherapy, or electroconvulsive therapy, administered at adequate doses and duration during the episode. Response has traditionally been defined as a 50% improvement on a dimensional rating scale of depressive symptoms such as the Hamilton Rating Scale for Depression (HAM-D) or the Montgomery-Asberg Depression Rating Scale (MADRS). However, the holy grail of depression treatment is remission, defined as a complete return to premorbid functioning arbitrarily defined as a HAM-D of 7 or less or an MADRS score of 10 or less. One might argue that even these are too liberal definitions of remission as those cutoffs would include patients with considerable morbidity ( ; ).

Reasons for why the remission rates in major depressive disorder (MDD) range from 28% in STAR*D ( ) to 50% in the PReDICT study of never-treated depressed patients remain obscure except the most obvious explanation, as recently reviewed by Nemeroff, is our very poor understanding of the pathophysiology of this serious and common psychiatric disorder ( ). Be that as it may, clinicians have a variety of evidence-based treatments to choose from when presented with a clear antidepressant monotherapy failure. These evidence-based strategies comprise a substantial portion of this volume. There are also exciting new developments in terms of novel treatments including theta burst accelerated TMS and novel antidepressants ( ).

Conceptualization of treatment resistance and modeling the approach, as addressed in 2, 6 respectively, are first steps to aid the clinician in achieving the goal of remission. There are multiple facets to creating a person-centered approach and our subspecialty of medicine allows us a very open-ended journey to knowing and helping patients as individuals. An optimal treatment plan combines the complex matrices of the person and the treatments. Other chapters provide in depth discussions of subtype of depression (unipolar, bipolar, psychotic); the macro- and microtime dimensions (child and adolescent, geriatric, pregnancy and postpartum, chronotherapeutics), the more common comorbidities (anxiety disorders, personality disorders, substance abuse, and chronic pain), and the potential role of pharmacogenomics, the latter clearly not realized. Faced with the many evidence-based treatments for patients who have failed antidepressant monotherapy, the clinician has little to guide him/her as there are no validated predictors of treatment response. Thus lithium, T3, pramipexole, a variety of atypical antipsychotics and several neuromodulation modalities are all available, many FDA approved.

In this chapter, we focus on the extant data concerning the use of combination antidepressant therapy.

Brief overview of antidepressants

Tricyclic antidepressants and monoamine oxidase inhibitors were developed in the 1950s and were the first FDA-approved antidepressants. They have continued utility in the treatment of MDD (see 9, 10 respectively) and in combination therapy. Antidepressants are typically categorized by their purported mechanism of action, namely their affinity for neurotransmitter receptors and transporters.. The main systems with which the existing antidepressant armamentarium interacts are serotonin, norepinephrine, dopamine, glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and histamine neural circuits. The first three systems are believed to represent the predominant sites that mediate their therapeutic effects, while the latter two are viewed as mediating side effects.

Within this classification system are selective serotonin reuptake inhibitors (SSRIs), serotonin agonist/antagonist reuptake inhibitors (SARIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), selective norepinephrine reuptake inhibitors (NRIs) and other miscellaneous agents such as bupropion and trazodone. Not surprisingly the strategies for combining antidepressants is largely based on the notion that combining antidepressants with distinctly different mechanisms of action will result in a more powerful antidepressant effect. To that end, understanding the pharmacological difference among antidepressants in their affinity for receptors and transporters may be helpful in developing a rational combination therapy strategy.

Limits of the monoamine hypothesis are the comparable efficacies of antidepressants despite widely varying potencies for monoaminergic effects and disparate mechanisms of action. Multiple monoamines may influence final common pathways relevant to depression. Additionally, the precise role of glutamate and GABA neural circuits as well as others, such as the corticotropin-releasing hormone and brain derived neurotropic factor, remain obscure.

Below are tables with comparable receptor affinities and monoamine oxidase inhibitor comparisons ( Table 12.1 ).

Table 12.1

Antidepressants and relative affinities (Ki) for monoamine transporters ( ; ; ; ; ).

Drug	Serotonin transporter (nM)	Norepinephrine transporter (nM)	Dopamine transporter (nM)	Notes
Fluoxetine	1	660	4180	Active metabolite, long half-lives; P450 inhibition
Sertraline	0.29	420	25	Some dopaminergic activity
Paroxetine	0.07–0.2	40–85	490	1st trimester risks; discontinuation syndrome; K _iM ₁: 72 nM
Citalopram	1.6	6190	–	QTc prolongation risk
Escitalopram	80	6190	–	QTc prolongation risk
Fluvoxamine	2.5	1427	–	Short half-life; P450 inhibition; not FDA approved for MDD
Venlafaxine	7.8	1920	–	Discontinuation syndrome; serotonin: norepinephrine 30:1
Desvenlafaxine	115	3152	–	Serotonin: norepinephrine 14:1
Duloxetine	0.8	7.5	240	Serotonin: norepinephrine 10:1
Milnacipran	8.44	22	–	Serotonin: norepinephrine 2:1
Levomilnacipran	11.2	99.2	–	NMDA K _i: 1.7 μM serotonin: norepinephrine 1:3
Trazodone	69	30,751	–	5HT ₂antagonist; mCPP metabolite
Nefazodone	549	713	–	5HT ₂antagonist; no histamine activity; mCPP metabolite; cases of liver failure
Vilazodone	0.1	56	37	Food
Vortioxetine	1.6	113	–	5HT _1aagonism; 5HT _3,7antagonism
Atomoxetine	77	5	1451	Cardiovascular effects; not FDA approved for MDD
Bupropion	28.69 μM	1.37 μM	526	Active metabolites, possible VMAT activity
Imipramine	1.4	37	8500	D ₂antagonism; shortens delta wave stage sleep
Desipramine	17.6	3.5	3190	Relatively selective for norepinephrine transporter; mACh K _i: 66–198
Amitriptyline	2.8–4.3	19–35	320	mACh K _i: 9.6
Nortriptyline	15–18	1.8–4.4	1140	Relatively selective for norepinephrine transporter; mACh K _i: 37
Mirtazapine	> 10 K	4600	> 10 K	a2 K _i:18 nM

The monoamine oxidase inhibitors are broad-acting via enzyme inhibition, blocking breakdown of norepinephrine, serotonin and dopamine. Their use requires dietary restrictions and drug interaction monitoring. The members of this class all have relatively short half-lives, affecting dosing frequency and side effects. However, irreversible inhibition of enzymes lasts 2 weeks ( Table 12.2 ).

Table 12.2

MAOIs.

Phenelzine	May need divided daily dosing, pyridoxine supplementation
Tranylcypromine	Amphetamine structure
Isocarboxazid	Twice a day dosing
Selegiline	Transdermal patch avoids MAO-B inhibition in GI tract; loses MAO-B selectivity at higher doses

Receptor overview

The complexity of receptors may hold future promise in guiding the decision process of choosing antidepressant therapy. Research areas include allosteric and orthosteric binding site modulation. Below, we review monoamine receptor structures and activity. Serotonin receptors are found in both the central and peripheral nervous systems as well as in platelets and the gastrointestinal tract. They are divided into 7 families of G protein-coupled receptors except for the 5-HT3 receptor, a ligand-gated ion channel, which activates an intracellular second messenger cascade to produce an excitatory or inhibitory response. As illustrated in Tables 12.3 and 12.4 , serotonergic circuits have broad physiological and behavioral effects, including several (mood, appetite, sleep) that are part and parcel of the MDD syndrome.

Table 12.3

Serotonin receptors.

Family	Type	Mechanism	Potential
5-HT1	Gi/Go-protein coupled	Decreasing levels of cAMP	Inhibitory
5-HT2	Gq/G1-protein coupled	Increasing levels of IP3 & DAG	Excitatory
5-HT3	Ligand-gated Na ⁺and K ⁺cation channel	Depolarizing plasma membrane	Excitatory
5-HT4	Gs-protein coupled	Increasing levels of cAMP	Excitatory
5-HT5	Gi/Go-protein coupled	Decreasing levels of cAMP	Inhibitory
5-HT6	Gs-protein coupled	Increasing levels of cAMP	Excitatory
5-HT7	Gs-protein coupled	Increasing levels of cAMP	Excitatory

cAMP , cyclic adenosine monophosphate; IP3 , inositol triphosphate; DAG , diacylglycerol.

Table 12.4

Serotonin receptor subtypes.

Receptor	Function	CNS	Blood vessels	Platelets	PNS	Smooth muscle	GI
5HT1A	Mood	Y	Y	N	N	N	N
	Anxiety
	Appetite
	Nausea
	Sleep
	Memory
	Penile erection
	Sexual behavior
	Sociability
	Impulsivity
	Addiction
	Aggression
	Cardiovascular function
	Pupil dilation
	Nociception
	Thermoregulation
5HT1B	Anxiety	Y	Y	N	N	N	N
	Learning/memory
	Penile erection
	Addiction
	Aggression
	Vasoconstriction
5HT1D	Anxiety	Y	Y	N	N	N	N
	Locomotion
	Vasoconstriction
5HT1E	Unknown	Y	Y	N	N	N	N
5HT1F	Migraine	Y	N	N	N	N	N
5HT2A	Mood	Y	Y	Y	Y	Y	Y
	Anxiety
	Appetite
	Sleep
	Cognition
	Learning/memory
	Perception
	Imagination
	Sexual behavior
	Addiction
	Thermoregulation
	Vasoconstriction
5HT2B	Anxiety	Y	Y	Y	Y	Y	Y
	Appetite
	GI motility
	Sleep
	Cardiovascular function
	Vasoconstriction
5HT2C	Mood	Y	Y	Y	Y	Y	Y
	Anxiety
	Appetite
	GI motility
	Sleep
	Penile erection
	Sexual behavior
	Addiction
	Thermoregulation
	Vasoconstriction
5HT3 (A-E)	Anxiety	Y	N	N	Y	N	Y
	GI motility
	Emesis
	Nausea
	Learning/memory
	Addiction
5HT4	Mood	Y	N	N	Y	N	Y
	Anxiety
	Appetite
	GI motility
	Learning/memory
	Respiration
5HT5A	Sleep	Y	N	N	N	N	N
5HT6	Mood	Y	N	N	N	N	N
	Anxiety
	Cognition
	Learning/memory
5HT7	Mood	Y	Y	N	N	N	Y
	Anxiety
	Sleep
	Memory
	Thermoregulation
	vasoconstriction
	Respiration