Depression Symptoms Treatment

The use of antidepressants in the treatment of depression remains the best-understood use of these medications; however, there is a growing list of other indications for antidepressants, including panic disorder (PD), obsessive-compulsive disorder (OCD), bulimia and posttraumatic stress disorder (PTSD). Many of these illnesses respond best to combination treatment modalities that include medication and various forms of psychotherapy.

The first antidepressant was the monoamine oxidase inhibitor (MAOI), iproniazid, initially licensed as an antituberculosis drug. This was soon followed by the tricyclic antidepressant (TCA), imipramine. Although both were developed in the early 1950s, they represented different paths of discovery: iproniazid was the result of clinical and laboratory collaboration, whereas imipramine’s introduction was largely based on clinical observation.

Within the past 25 years, similarly efficacious tricyclic and heterocyclic antidepressants have been developed but with varying side-effect profiles. A new direction in antidepressant pharmacology began in 1987 with the discovery and marketing of fluoxetine, the first antidepressant selective for serotonin reuptake blockade. Beyond selective serotonin reuptake inhibitors (SSRIs), the latest offerings in antidepressant pharmacology include agents that act at multiple neurotransmitter levels.

In evaluations of the many antidepressants available, the focus has generally been on the agent’s side-effect profile and ease of administration. Despite many efforts in this area, there is no conclusive evidence to demonstrate the clinical superiority of any one group of agents.

Mechanisms of Action

All known antidepressants affect monoamine neurotransmission.

Monoamine oxidase inhibitors (MAOIs) inhibit the activity of monoamine oxidase, resulting in a decrease in the breakdown of dopamine, serotonin, and norepinephrine in the synapse, thus increasing the amount of these neurotransmitters available for release and synaptic transmission. MAOIs are highly effective antidepressants and anxiolytics but are rarely used due to dietary restrictions that must be adhered to in order to avoid tyramine-induced hypertensive crises.

Tricyclic antidepressants (TCAs) block presynaptic reuptake of norepinephrine and serotonin to various degrees. Several are related by metabolism, thus the tertiary amines amitriptyline and imipramine are metabolized to the secondary amines nortriptyline and desipramine respectively. All act through reuptake inhibition and are generally selective for the norepinephrine transporter; several, however, have equal or greater affinity for the serotonin transporter. The TCAs were the drugs of choice for depression through the 1980s. Though effective, their nonselective actions on cholinergic, histaminergic, and presynaptic adrenergic receptors resulted in a number of side effects.

Selective serotonin reuptake inhibitors (SSRIs) were first introduced in the late 1980s, and rapidly eclipsed the tricyclic antidepressants (TCAs) as the drugs of choice for depression. There are subtle differences between compounds, mainly in terms of their half-life, their potency for reuptake inhibition, and their affinity for some other receptors. As SSRIs more selectively affect reuptake, with few effects on the adrenergic, histaminergic, and cholinergic systems, side effects have been reduced.

The selective norepinephrine reuptake inhibitors (NRIs) such as reboxetine (not available in the US) or atomoxetine share a similar mechanism with the SSRIs, but act on the norepinephrine transporter and have little affinity for the serotonin transporter.

Several other second-generation agents, sometimes referred to as “atypical antidepressants”, were introduced during the same period as the selective serotonin reuptake inhibitors (SSRIs). These include bupropion, which seems to exert primarily a dopaminergic effect, and trazodone, which is structurally related to the tricyclic antidepressants (TCAs) but has a primary serotonergic mechanism.

Of the serotonin receptors, 5-hydroxytryptamine type 1A (5-HT_1A) appears most related to the therapeutic effects of antidepressants, and this receptor influences norepinephrine, dopamine, acetylcholine, neuropeptides, other serotonin receptors, and probably beta-receptor downregulation.

The so-called third-generation antidepressants include serotonin-norepinephrine reuptake inhibitors (SNRIs — venlafaxine, milnacipran and duloxetine), mixed serotonin antagonist/reuptake inhibitors (nefazodone and trazodone) and the mixed serotonin/noradrenaline antagonist mirtazapine. SNRIs have equal affinity for the norepinephrine and serotonin transporter. Though, like several of the TCAs, venlafaxine has multiple receptor effects, it is relatively free of the anticholinergic and antihistaminic side effects that are common with the tricyclic antidepressants (TCAs).

Mixed serotonin antagonist/reuptake inhibitors such as nefazodone have multiple mechanisms of action, with both serotonin (as well as norepinephrine) transporter inhibition as well as antagonism of 5-HT_2A and alpha-₁-receptors. Trazodone is similar; however, its effects are somewhat less specific.

The mixed serotonin/noradrenaline antagonist mirtazapine is unique in that it appears to work primarily through specific receptor blockade of the alpha-₂-autoreceptors on presynaptic noradrenergic neurons, enhancing noradrenergic output. This class may exert a similar effect toward autoreceptors on serotonin neurons. Antagonism of 5-HT₂ and 5-HT₃ receptors may also concentrate the effect of serotonin on 5-HT_1A receptors. The antidepressants available in the US, their class, and relative costs are listed in Table Table: Antidepressants available in the United States.

Table: Antidepressants available in the United States

Class	Name	Generic	How supplied	Recommended dose per day*	Price index**
TCAs	Amitriptyline	Y	Tablets (mg): 10, 25, 50, 75, 100, 150 Oral solution: 10 mg/5 mL IM: 10 mg/mL	150 mg	0.26
	Imipramine	Y	Tablets (mg): 10, 25, 50 Capsules (mg): 75, 100, 125, 150	150 mg	3.65
	Nortriptyline	Y	Oral solution: 10 mg/5 mL Capsules (mg): 10, 25, 50, 75	75 mg	2.66
	Desipramine	Y	Tablets (mg): 10, 25, 50, 75, 100, 150	150 mg	2.18
	Amoxapine	Y	Tablets (mg): 25, 50, 100, 150	300 mg	5.00
	Doxepin	Y	Oral solution: 10 mg/mL Capsules (mg): 10, 25, 50, 75, 100, 150	150 mg	1.66
	Protriptyline	N	Tablets (mg): 5, 10	45 mg	7.99
	Trimipramine	N	Tablets (mg): 25, 50, 100	150 mg	5.00
	Clomipramine	Y	Tablets (mg): 25, 50, 75	150 mg	3.03
	Maprotiline	Y	Tablets (mg): 25, 50, 75	150 mg	1.86
MAOIs	Isocarboxazid	N	Tablets: 10 mg	30 mg	2.45
	Phenelzine	N	Tablets: 15 mg	60 mg	2.64
	Tranylcypromine	N	Tablets: 10 mg	40 mg	3.94
SSRIs	Fluoxetine	Y	Oral solution: 20 mg/5 mL Tablets (mg): 10, 20, 40 Delayed release capsules: 90 mg (“Prozac Weekly”)	60 mg	1.10
	Sertraline	N	Oral solution: 20 mg/mL Tablets (mg): 25, 50, 100	100 mg	3.02
	Paroxetine	Y	Oral solution: 10 mg/5 mL Tablets (mg): 10, 20, 30, 40	40 mg	2.97
	Paroxetine controlled release		Controlled release tablets (mg): 12.5,25, 37.5	40 mg	3.39
	Fluvoxamine	Y	Tablets (mg): 25, 50, 100	200 mg	5.25
	Citalopram	Y	Oral solution: 10 mg/5 mL Tablets (mg): 10, 20, 40	40 mg	2.65
	Escitalopram	N	Oral solution: 1 mg/1 mL Tablets (mg): 5, 10, 20	20 mg	2.65
Atypical antidepressants	Bupropion	Y	Tablets (mg): 75, 100	300 mg	2.88
	Bupropion sustained release	Y	Sustained release (mg): 100, 150	300 mg	3.87
	Bupropion extended release	N	Extended release (mg): 150, 300	300 mg	4.84
	Trazodone	Y	Tablets (mg): 50, 100, 150, 300	100 mg	0.22
SNRI	Venlafaxine	N	Tablets (mg): 25, 37.5, 50, 75, 100 Extended release (mg): 37.5, 75, 150	225 mg 225 mg	4.30 3.77
	Duloxetine	N	Tablets (mg): 20, 30, 60	60 mg	3.64
Mixed serotonin antagonist/ reuptake inhibitors	Nefazodone	Y	Tablets (mg): 50, 100, 150, 200, 250	300 mg	3.14
Mixed serotonin/ noradrenaline antagonists	Mirtazapine	Y	Tablets (mg): 15, 30, 45 Dissolvable tablets (mg): 15, 30, 45	45 mg	0.81

* Recommended dose derived from Lexi-comp online.

** Price index: (dollar cost of average dose/d) The price index is a rough calculation, assuming an average recommended dose for the treatment of major depression, and assuming that the most efficient dosing regimen, and least expensive tablet choice, is prescribed. When available, generic prices are used. Prices were derived from 2006 Cardinal Health wholesale price guide provided by the Pharmacy Department of the New York State Institute.

Pharmacokinetics

The pharmacokinetics of tricyclic antidepressants (TCAs) are complex, as reflected in the diversity of half-lives (10 to 40 hours). TCAs are primarily absorbed in the small intestine, reaching peak plasma levels two to six hours after oral administration. Absorption can be affected by changes in gut motility. The drugs are extensively metabolized in the liver on first pass through the portal system. They are lipophilic, have a large volume of distribution, and are highly protein-bound (85-95%). TCAs are metabolized to active metabolites in the liver by hepatic microsomal enzymes and excreted by the kidneys. The rate of metabolism can vary genetically; 7 to 9% of the white population are slow hydroxylators. There is a large range of elimination half-lives.

Tricyclic antidepressants as a class have a relatively narrow therapeutic index; there is a significant risk of toxicity with blood levels of only two to six times the therapeutic level. A 1-week supply can be fatal in overdose, as blood concentrations of greater than 1000 ng/dl are correlated with prolongation of the QRS complex and arrhythmias. TCAs are commonly ingested agents by which patients successfully commit suicide by overdose.

Monoamine oxidase inhibitors (MAOIs) are also well absorbed from the gastrointestinal tract. Their short half-life of one to two hours is not particularly relevant as they bind irreversibly with MAO. Thus, the activity of these drugs depends less on pharmacokinetics and more on the synthesis of new MAO to restore normal enzyme activity. This synthesis requires approximately two weeks. This class of drugs is little used due to their potentially dangerous interactions with sympathomimetics and foods containing tyramine.

Each of the six SSRI agents (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and its S-enantiomer escitalopram) selectively block the reuptake of serotonin presynaptically, though each drug differs structurally from the others. As a result, these agents differ in their pharmacokinetic profiles. Many selective serotonin reuptake inhibitors (SSRIs) are, like the tricyclic antidepressants (TCAs), highly protein bound though the proportions of citalopram and escitalopram that are protein-bound are 80 and 56% respectively. In contrast, however, they have varying half-lives ranging from approximately 24 hours to several days.

All SSRIs are well absorbed and not generally affected by food administration, though sertraline is an exception to this rule — its blood level may be increased by food. All have large volumes of distribution and are extensively protein-bound. They are metabolized by hepatic microsomal enzymes and are potent inhibitors of these enzymes. The only serotonin reuptake inhibitor with an active metabolite is fluoxetine, whose metabolite norfluoxetine has a half-life of 7 to 15 days. Thus, it may take several months to achieve steady state with this agent. This is considerably longer than citalopram (half-life 1.5 days) or sertraline and paroxetine (half-lives 24 hours).

There is no correlation between half-life and time to onset. Drugs with shorter half-lives have an advantage in cases where rapid elimination is desired (e.g., in the case of an allergic reaction). Drugs with a longer half-life may also have advantages: fluoxetine, for example, has been successfully given in a once-weekly dosing during the continuation phase of treatment and a once-weekly formulation of this drug is currently available. All serotonin reuptake inhibitors are eliminated in the urine as inactive metabolites. Both fluoxetine and paroxetine are capable of inhibiting their own clearance at clinically relevant doses. As such, they have nonlinear pharmacokinetics: changes in dose can produce proportionately large plasma levels.

Citalopram and its S-enantiomer escitalopram are the most recent selective serotonin reuptake inhibitors (SSRIs) to be introduced in the Untied States; The Food and Drug Administration (FDA) approved citalopram in 1998 and escitalopram in 2002. Of the available SSRIs, these are the most selective for serotonin receptor blockade; escitalopram is 100 times more potent than the R-enantiomer.

As with most other antidepressants, bupropion undergoes extensive first pass metabolism in the liver. The parent compound has a half-life of 10 to 12 hours, but has three active metabolites. One, threohydrobupropion, has a half-life of 35 hours and is relatively free in plasma (it is only 50% protein-bound). There is considerable individual variability in the levels of bupropion and its metabolites. Trazodone has a relatively short half-life of three to nine hours; as a result of this and its apparent lack of active metabolites plasma levels of trazodone can be quite variable, requiring divided dosing.

Venlafaxine has a short half-life (4 hours); however, it is available in an extended release formulation that allows once-daily dosing. It appears to have a dual effect, in which at lower doses it primarily acts on the serotonin transporter, and clinically significant norepinephrine reuptake inhibition is not seen until higher doses are used (150 mg/day and above).

Nefazodone has relatively low bioavailability, and a short half-life (2-8 hours), and thus it is usually given in twice-daily doses. Mirtazapine has a half-life of 13 to 34 hours.

Duloxetine is the second selective inhibitor of norepinephrine and serotonin to be introduced in the United States. Compared with venlafaxine it has relatively greater effect on 5-HT reuptake in vitro but the clinical significance of this difference is unclear. The half-life of duloxetine is 8-17 hours (mean 12 hours).

The selective serotonin reuptake inhibitors (SSRIs) are also, to varying degrees, potent inhibitors of the P450 hepatic enzyme system. The result is increased blood levels of concomitant agents that are also metabolized by this enzymatic system. Switching from an SSRI to another antide-pressant group illustrates the clinical relevance. For example, when a patient changes from fluoxetine to venlafaxine, the inhibition of the P450 2D6 isozyme will reduce venlafaxine metabolism for several weeks. The resulting increase in the venlafaxine blood level can hasten the development of side effects. The aware clinician can avoid this by starting with a lower than usual initial dose and titrating upward slowly.