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Tailoring Antidepressant Treatment

In ADHD, ADHD Adult, ADHD child/adolescent, Anxiety, Medication, Psychiatry, Psychopharmacology on Monday, 24 September 2012 at 07:13

Tailoring Antidepressant Treatment: Factors to Individualize Medication Selection Thomas L. Schwartz, MD; Daniel Uderitz, MD

In the realm of psychopharmacology, we often declare medications within their respective therapeutic classes as being equal. This is a byproduct related to the way medications achieve their indications for treatment for specific psychiatric disorders. In the case of antidepressant treatments, the US Food and Drug Administration (FDA) indicates that if a study can obtain a majority of patients improved by 50% compared with placebo, then a drug may become an antidepressant treatment. There are no standards for differentiating antidepressant treatments beyond this. Clinicians often note that all antidepressant treatments are not created equal, especially when applied to clinical situations and patients who are often complex and have comorbid conditions. The goal of this article is to sort out regimens that may convey certain advantages during the treatment in an individualized manner. This involves conceptualizing and utilizing monotherapies, combination therapies, and adjunctive treatments.

Monotherapies

The first-line treatment of patients with major depressive disorder (MDD) should start with an aggressive monotherapy. This occurs in clinical practice and is supported by many guidelines and reviews. The various antidepressant medications have unique properties that can be used to individualize treatments. Most psychiatrists can easily name their “favorite” antidepressant to use in certain situations. This is sometimes based on a simple bias, but often has evidence to back up clinical practice. Let us start with the mechanistically simple and move toward more complex ways to think about these medications. This includes thinking about FDA approvals, available guidelines, comorbidities, side effects, and more complex pharmacodynamic receptor-based neuropsychiatry.

A patient rarely comes to a psychiatrist without having a combination of psychiatric symptoms. Typically, clinicians screen patients and find that they often meet criteria for more than 1 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-Text Revision (DSM IV-TR) criteria.[1] At a minimum, the individual patient raises suspicion for various problem areas, even if they do not meet criteria for a specific disorder. In reviewing FDA guidelines, clinicians may quickly make simple decisions regarding treatment regimens that are more individualized based on these comorbidities and predominant symptoms. Of note, additional FDA approval or lack of approval for various indications does not necessarily mean that evidence does not support efficacy for other disorders. For example, the manufacturer may not have pursued FDA approval for other indications, or may have decided not to support randomized controlled trials to study another indication.

Single Indication

The first group of antidepressants approved by the FDA for the single indication of MDD include amitriptyline, citalopram, desipramine, desvenlafaxine, mirtazipine, nortriptyline, protriptyline, trazodone, trimipramine, vilazodone, and the monoamine oxidase inhibitor (MAOI) class.[2-4] Clinicians should know that these medications have only the 1 indication, and this clearly supports their use in MDD. However, many practitioners recognize that there are multiple other factors that allow these medications to be used in an off-label manner for various individuals. In a pure model, these antidepressants have regulatory data suggesting use only in patients with MDD but, as discussed, a lack of approval for other indications does not necessarily indicate a lack of supportive data or lack of efficacy.

Multiple Indications

Unlike those listed above, many antidepressants have other labeled or approved indications. These span a variety of comorbidities including anxiety disorders, seasonal affective disorder, sleep disorders, pain disorders, premenstrual dysphoric disorder, bulimia nervosa, and other miscellaneous indications. Given this, and assuming MDD is often complicated by comorbidity, let us evaluate a few comorbidities where data-driven decisions may help in individualizing treatments in patients who are depressed and simultaneously experience other psychiatric conditions.

Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder often have comorbid depression. Only 2 antidepressants, the selective serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, are approved for this indication.[2] Multiple other medications have been recognized as effective off-label treatments for posttraumatic stress disorder, however; these include amitriptyline, fluoxetine, fluvoxamine, imipramine, and venlafaxine.[5-7] If a patient presents with MDD and posttraumatic stress disorder, these antidepressants may be considered if necessary to achieve efficacy for both conditions.

Obsessive-Compulsive Disorder

Several medications are approved for obsessive-compulsive disorder, including the tricyclic antidepressant clomipramine, and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[2] Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),[8] and the SSRI citalopram have shown some promise in obsessive compulsive disorder,[9] but have not yet received that indication from the FDA.

Panic Disorder

The SSRIs fluoxetine, paroxetine, and sertraline are approved for treatment of panic disorder, as is the SNRI venlafaxine.[2,10] Other antidepressants with an evidence base for use that are not approved include the TCAs clomipramine and imipramine, and the SSRI fluvoxamine.[6]

Anxiety Disorders

Social anxiety disorder. The SSRIs paroxetine and sertraline, and the SNRI, venlafaxine extended-release (ER) have been approved for the treatment of social anxiety disorder.[2] The SSRI fluoxetine is sometimes used for treatment of social anxiety disorder.

Generalized anxiety disorder. Four antidepressants have been indicated for the treatment of generalized anxiety disorder. These include the SSRI escitalopram and paroxetine, and the SNRI duloxetine and venlafaxine ER.[2,11]

Insomnia

Although sleep difficulties are a nearly universal symptom of depression, few antidepressants have an official indication for insomnia. Doxepin, a TCA, is the sole antidepressant labeled with this indication, when it is used at subtherapeutic antidepressant doses of 3 to 6 mg per day.[12] However, clinicians often use sedating antidepressants to induce sleep in those patients with MDD and insomnia (Schwartz TL. Novel hypnotics: moving beyond positive allosteric modulation of the GABA-A receptor. Manuscript submitted). These medications include the TCA amitriptyline, the tetracyclic mirtazapine, and the serotonin modulator trazodone.

Pain Syndromes

Duloxetine, an SNRI, is the only antidepressant medication that has official indications for treatment of pain syndromes.[2,10] These include chronic musculoskeletal pain, neuropathic pain (diabetic neuropathy in particular), and fibromyalgia. Alternatively, many of the TCAs, as well as other SNRI, have been studied for the treatment of pain syndromes, primarily involving neuropathic or chronic pain conditions.[13,14] Amitriptyline also is often used for migraine headaches. Unfortunately these other medications have not received official indications for these psychosomatic comorbidities.

Attention-Deficit/Hyperactivity Disorder

Some antidepressants have shown promise for the treatment of attention-deficit/hyperactivity disorder, but not enough to warrant a specific FDA indication. Nonetheless, these medications are used for the treatment of attention-deficit/hyperactivity disorder, particularly in patients with substance use disorder. Bupropion, desipramine, imipramine, nortriptyline, and venlafaxine have some evidence base to support their use.[15-19]

Other Comorbid Considerations

Premenstrual dysphoric disorder. The SSRI fluoxetine, paroxetine, and sertraline have been FDA approved for the treatment of premenstrual dysphoric disorder.[2]

Smoking cessation. Many patients who receive mental health treatment are also addicted to nicotine. Bupropion SR has received the indication for nicotine addiction.[2] Nortriptyline also has been shown to be helpful for smoking cessation efforts, but has not received an official indication.[20]

Miscellaneous. Bupropion XL carries a specific indication for prophylaxis of seasonal affective disorder and often is used off-label for the treatment of bipolar depression.[19,21,22] Fluoxetine is indicated for treatment of bulimia nervosa and sometimes is used for the treatment of Raynaud’ phenomenon.[2,19,23] Venlafaxine and paroxetine have data supporting use for the treatment of vasomotor hot flashes.[24,25] Finally, imipramine may be used in the treatment of enuresis.[26]

Take-Home Point

Clinicians should be aware of FDA approvals and the evidence base supporting the use of antidepressants in patients with MDD, who are often complex and suffering with other medical and psychiatric comorbidities. Choosing agents with indications that match the patient’s comorbid symptoms is one way to tailor and individualize treatment to each patient.

Beyond the simplistic but labor-intensive role of delineating specific comorbidities and focusing on antidepressant indications, is the imperative to develop a more complex individualized antidepressant treatment plan. If it were as simple as following the FDA labels and simple algorithms to make decisions, then much psychiatric education could be eliminated. A review of antidepressant mechanisms of action will allow us to further distinguish these medications, thus allowing more individualized treatments for MDD.

SSRI Class

The first and most commonly prescribed class of antidepressant is the SSRI. At the most basic understanding, these medications increase serotonin in the synapse and function ultimately to down-regulate serotonin receptors. However, as the science behind these medications is further explored, there is much more to these agents. When looking at the SSRI class as a whole, and in comparison with other antidepressant classes, a few general characteristics can be considered. The SSRI medications as a group are thought of as having fewer side effects than most other classes of antidepressants, and particularly the older classes of drugs. The most common and clinically relevant consideration for these medications is the development of gastrointestinal upset, sexual side effects, and weight gain.[27] The following delineates some of the subtle differences for each medication in this class and describes the benefits and drawbacks of treatment with each to help refine treatment selection.

Citalopram. Citalopram is one of the most widely used antidepressants today, and has a few properties that make it desirable. The medication has a long half-life of 23-45 hours, second only to fluoxetine,[2] and it is typically well tolerated in medically ill patients and the elderly.[19,28] Citalopram has weak H1 receptor antihistamine properties, and these properties provide anxiolytic and positively sedating effects.[27] Citalopram is made up of 2 mirror image enantiomers, each of which have different properties [27] that may lead to some inconsistencies in the property or function of the medication at lower doses. Citalopram is a weak inhibitor of CYP 2D6, with minimal drug-drug interactions.[30] Finally, recent FDA warnings have changed prescribing practices of this medication because of potential QTc prolongation at daily doses higher than 40 mg[29]; daily doses of 60 mg should no longer be used.

Benefits.Citalopram is a well-tolerated medication with mild antihistamine effects that may help with insomnia or mild anxieties. The longer half-life results in less withdrawal or discontinuation side effects.[31]

Drawbacks.Structural enantiomers result in this medication having less predictable effects at lower doses, and higher doses are contrary to FDA recommendations related to the potential for QTc prolongation. It has fewer FDA approvals for comorbid psychiatric disorders than other drugs in the SSRI class; as discussed earlier, this may simply reflect the manufacturer’s failure to seek approval for other indications.

Escitalopram. In contrast to the parent drug citalopram, escitalopram is separated and includes only the left enantiomer.[27] This results in the removal of much of the antihistamine and CYP 2D6 inhibitory properties.[19,27] It also results in more effective and predictable dose responses of the medication at the lower doses.

Benefits.Escitalopram has the benefit of better tolerability with less drug interactions. It may have less sedating effects, and is approved for generalized anxiety disorder as well as MDD.[2]

Drawbacks.Currently this is the only SSRI still on patent, and is thus more expensive than other, generic SSRI.

Fluoxetine. The first member of the SSRI class, fluoxetine has a few characteristics that make it desirable. Fluoxetine has mild serotonin 2C receptor antagonistic actions. This may result in the disinhibition of dopamine and norepinephrine release to the prefrontal cortex, which likely helps to improve concentration, energy, and executive functioning.[19,27] Furthermore, the serotonin 2C effects of this medication may contribute to the initial anorexic and ongoing anti-bulimic effects of this medication.[27] More recently, the effects of fluoxetine on the serotonin system have been combined with those of olanzapine, a second-generation antipsychotic, for the treatment of depression in patients with bipolar disorder and for treatment resistant unipolar depression.[19,27] Fluoxetine also may be a mild norepinephrine reuptake inhibitor, particularly at higher doses.

Fluoxetine significantly affects CYP 2D6 and 3A4 inhibition, and thus is highly likely to interact with other medications.[19,27] Finally, this medication has the longest half-life of the SSRIs, at 2-3 days, with an active metabolite that exists for 2 weeks.[2]

Benefits.Fluoxetine has action at the serotonin 2C receptor, and may affect norepinephrine levels at higher doses. The drug has the longest half-life among the SSRI, making it least likely to cause withdrawal. It is available as a once weekly dosing formulation and is approved for MDD, panic disorder, premenstrual dysphoric disorder, obsessive compulsive disorder, and bulimia nervosa.[2] It also has positive combination effects with the second generation antipsychotic olanzapine, and a combination formulation has been approved by the FDA for treating treatment-resistant and bipolar depression.*[19]

Drawbacks.The medication is likely to be activating in some patients, making it a more difficult option for those with insomnia, agitation, and intense anxiety.[19,27] Slower dose titration is warranted in these cases. Fluoxetine has a high degree of CYP 2D6 inhibition, resulting in significant drug-drug interactions.[19]

*Multiple trials of other second generation antipsychotics combined with various antidepressants including SSRI and SNRI have shown antidepressant efficacy for these combinations in patients with refractory depression.[32]

Paroxetine. The action of paroxetine is more complex than the previously described SSRI medications. In addition to serotonin reuptake inhibition, paroxetine functions with mild anticholinergic properties, mild norepinephrine reuptake inhibition (NRI), inhibition of nitric oxide synthetase, and potent inhibition of CYP 2D6 (similar to fluoxetine).[19,27] It has anticholinergic and antihistaminergic properties that may lend to its being calming and sedating, but also may increase dry mouth, blurred vision, and short term memory problems.[19,27] The NRI effects of the medication may contribute to clinical effectiveness. The effects on nitric oxide synthetase may cause sexual dysfunction.

Benefits.In addition to major depression, paroxetine is approved for various anxiety disorders, with possible calming/sedating effects. It is available in immediate- and slow-release preparations.

Drawbacks.Paroxetine has the potential for anticholinergic side effects[31] Its shorter half-life may result in more and more severe withdrawal side effects than other SSRI; paroxetine is also most strongly associated with weight changes, compared with other SSRI.[2] This medication also has a higher drug-drug interaction probability.

Sertraline. This SSRI may have dual mechanisms that distinguish it from other SSRIs. At higher doses, it acts as both a dopamine transporter inhibitor and a sigma 1 receptor binder.[27] The effects of dopamine transporter inhibition may result in improved energy, motivation, and concentration. Sigma 1 implications are not yet well understood, but some hypothetical benefit is attributed to their mild anxiolytic effects in psychotic and delusional depressions.[27]

Benefits.Sertraline is approved for MDD, many anxiety disorders, eating disorders, and premenstrual dysphoric disorder.[2] This medication has very little CYP 2D6 inhibition and therefore few drug-drug interactions.[19] It has a moderate half-life and thus the possibility of some withdrawal symptoms.

Drawbacks.Sertraline can be activating in patients with anxiety disorders, which may require slowly titrating doses; it is often associated with gastrointestinal distress.

Take-Home Point

The SSRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. However, a pharmacodynamic look into their wider mechanisms of action may suggest that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

SNRI Class

The next most common class of medications used for the treatment of MDD is the SNRI. This group of medications has a dual mechanism of action, increasing synaptic norepinephrine as well as serotonin.[19,27] In addition to increasing norepinephrine and serotonin levels throughout the brain, these medications may also boost dopamine in the prefrontal cortex, resulting in additional benefits.[27] In the prefrontal cortex, no dopamine transporters are there to recycle dopamine out of the synapse. Typically norepinephrine transporters remove dopamine in these areas, but with the inhibition of these, the dopamine effect in the dorsal lateral prefrontal cortex is more robust.[27] This activation in the brain has been correlated with antidepressant effects.

On the other hand, as the additional norepinephrine boost is added to the brain, it is not contained there. Norepinephrine effects are seen throughout the body, including the spinal cord, peripheral autonomic nervous system, heart, and bladder.[19,27] In the spinal cord this may reduce pain, but may also lead to side effects such as tremor, motor activation, and increased blood pressure and heart rate.[27] Also, these effects may allow a pseudo-anticholinergic effect resulting in such things as dry mouth, constipation, and urinary retention. However, these norepinephrine-related side effects do not rival those of the tricyclic antidepressant class.[31] Generally, the SNRIs are well tolerated, but the subtle increase in side effect burden needs to be considered.

Venlafaxine. Venlafaxine was the first SNRI and was initially approved in an immediate-release preparation. This medication is a substrate of CYP 2D6, and is converted into desvenlafaxine, an SNRI that was developed subsequently.[19,27] Unfortunately, the absorption of immediate-release venlafaxine is rapid, affording it remarkable side effects; this has been mitigated with an extended-release formulation that appears to be much better tolerated in practice. The medication also has a unique character, causing a varying ratio of serotonin to norepinephrine effects.[19,27] At low doses, there are fewer NRI properties (and more SRI properties) available and only at higher doses do the norepinephrine transporter inhibition properties increase more robustly.

Benefits.Compared with the SSRI, this medication has effects at both serotonin and norepinephrine receptors leading to its antidepressant effectiveness. The medication is very effective in the treatment of anxiety disorders, with multiple approved uses, likely comparable to sertraline and paroxetine.[2]

Drawbacks.The norepinephrine effects of the medication are much more robust only at higher doses and must be titrated. The medication has a short half-life resulting in many withdrawal side effects. There may be higher rates of nausea and dry mouth in comparison to some other antidepressants.[31] This medication may cause hypertension in some patients, and thus, blood pressure should be monitored.[19]

Desvenlafaxine. Desvenlafaxine is the active metabolite of venlafaxine,[19] and has the added benefit of a greater effect on norepinephrine transporter inhibition than its precursor at the initial dose levels. However, the effects on norepinephrine are less than those on serotonin.[27] Because it is the active metabolite of venlafaxine, it is less subjected to the genetic and drug-induced differences of CYP 2D6, which allows more consistent plasma levels of the medication.[27] It may be one of the “cleanest” antidepressant medications, given its extremely low vulnerability to cytochrome P450 metabolism, renal excretion, and low protein binding. The role of desvenlafaxine in the regulation of vasomotor symptoms (night sweats, hot flashes, insomnia, and related depression) in perimenopausal women is being investigated.[27]

Benefits.Although similar to extended-release venlafaxine, desvenlafaxine has a more balanced ratio of norepinephrine/serotonin properties, and it has one of the most favorable drug-drug interaction profiles.

Drawbacks.This medication has a short half-life and significant withdrawal side effects.[31]

Duloxetine. Duloxetine is unique among the SNRI class of drugs because, in addition to MDD, it is approved for treating a variety of pain syndromes.[2] This is related to the SNRI effect on the descending spinal norepinephrine pathways that reduce afferent pain fiber activity.[27] The increase in norepinephrine activity in spinal areas results in less thalamic input to the sensory cortex and therefore less perceived pain. The norepinephrine-facilitating effects in the prefrontal cortex also may show some benefit in treatment of cognitive symptoms prevalent in geriatric depression.[27]. Compared with venlafaxine, duloxetine has a lower incidence of treatment-related hypertension and milder withdrawal reactions. It is approved for MDD, generalized anxiety disorder, musculoskeletal pain, neuropathic pain, and fibromyalgia-related pain.[2]

Benefits.One of the only antidepressants approved for management of pain syndromes, duloxetine also has a more balanced norepinephrine to serotonin ratio at its initial doses.[28]

Drawbacks.Duloxetine is a mild to moderate CYP 2D6 inhibitor, which results in some drug-drug interactions.[19] In addition, it should not be used in alcoholic patients or those with renal and/or liver impairment.

Take-Home Point

The SNRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. As with the SSRI, a pharmacodynamic look into their wider mechanisms of action suggests that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This is clear when one considers the diverse FDA approvals for each and different potencies related to facilitating distinct ratios of serotonin to norepinephrine transporter inhibition. Again, this type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

TCA Class

This class is one of the oldest and still highly utilized classes of antidepressant in the history of psychopharmacology, and includes amitriptyline, imipramine, clomipramine, desipramine, trimipramine, and nortriptyline. The TCAs are often overlooked because of their relatively high level of side effects when compared with other classes of antidepressant, and because of high lethality in overdose. The TCAs have significant effects on the norepinephrine, serotonin, and to some extent dopamine activity in the brain.[19,27] The higher incidence of side effects are likely mediated through blockade of anticholinergic receptors (M1/M3), histamine receptors (H1), alpha 1 adrenergic receptors, and voltage-sensitive sodium channels.[19,27] Histamine blockade causes sedation and weight gain. Muscarinic blockade causes dry mouth, blurred vision, urinary retention, and constipation. Alpha 1 blockade causes orthostatic hypotension and dizziness. Sodium channel blockade affects the heart significantly, resulting in arrhythmias and conduction changes at higher doses.[27] This latter side effect results in significant risk of successful suicide with overdose, and renders TCAs difficult to use in medically comorbid patients.

Benefits.Overall, TCAs are very effective antidepressants. Indeed, early studies comparing TCA with SSRI medications found significantly higher remission rates with TCA than with SSRI in depressed, endogenous and inpatients samples.[33-36] However, in less severely depressed patients, there is not conclusive evidence of benefit of either class of antidepressant over another. Off-label, the use of TCAs in the treatment of pain, enuresis, and insomnia is widespread.[19] Availability of plasma level monitoring helps to guarantee therapeutic trials while minimizing toxicity.

Drawbacks.The significant adverse event profile causes an array of side effects that are often poorly tolerated and lead to medication noncompliance. Because of cardiac side effects, TCAs carry significant risk of death with overdose.

MAOI Class

This class of antidepressants has its own unique mechanism of action. MAOI has fallen into the realm of rarely used antidepressants in modern day psychopharmacology. This is related to the risks and side effects inherent to MAOI use. On the other hand, MAOI are among the most clinically powerful classes of antidepressant treatments. This class interferes with MAO enzyme subtypes A and B. The inhibition of these enzymes results in higher levels of serotonin and norepinephrine due to reduced catabolism of these neurotransmitters.[27] Moreover, by specifically lowering MAO-B activity, dopamine levels in the brain increase as well. Thus, all 3 monoamine neurotransmitter levels are robustly increased, which, in turn, affects a broad array of depressive symptoms.

The use of these medications may come at the cost of difficulty in using them. The most well-known drawback is that patients need to maintain a specific diet that is free of high tyramine foods, or risk the likelihood of hypertensive crisis related to the acute elevation of systemic norepinephrine, which also may result in stroke.[19,27] Foods to be avoided include tap beers, smoked meat or fish, fava beans, aged cheeses, sauerkraut, and soy. However, certain beers, wines, and cheeses are not contraindicated. These items need to be researched and discussed prior to starting a patient on the medication.

Drug-drug interactions are plentiful; combining an MAOI with other norepinephrine medications may increase blood pressure, and combining with a serotonin-based medication can cause serotonin syndrome.[19,27] Patients are also advised to avoid decongestants, stimulants, antidepressants, certain opioids, and appetite suppressants.[19,27]

The MAOI tranylcypromine may act similarly to an amphetamine in the frontal cortex, affording it some additional benefits.[27] Likewise, selegiline also involves breakdown into an amphetamine metabolite. Selegiline is more often used for Parkinson disease than depression.

Benefits.MAOIs are recognized as among the most potent of antidepressants in monotherapy, with effects on serotonin, dopamine, and norepinephrine. This class of antidepressant is often used for the patient who is refractory to other antidepressant trials.

Drawbacks.The MAOIs are associated with risks of hypertensive crisis and serotonin syndrome. There is a need to maintain a tyramine free diet except when using the low dose transdermal selegiline. Because of potential for drug-drug interactions, careful, ongoing monitoring of all additional medications (including over-the-counter medications) is essential.

Miscellaneous Antidepressants

Several other well-known antidepressant medications do not fit discretely into the 4 main antidepressant classes. Each has unique mechanisms that will be discussed similarly below.

Bupropion. This norepinephrine-dopamine receptor inhibitor (NDRI) medication is of particular use in a few subsets of patients. As the class name indicates, bupropion facilitates effects on norepinephrine and dopamine, blocking norepinephrine transporter and dopamine transporter activity at a moderate level, likely in the frontal cortex.[27] The unique properties of bupropion as an antidepressant may be related to its lack of serotonin activity. It is approved for smoking cessation and is used off-label to reduce craving for substances of abuse. Clinicians contend that the dopamine actions of this medication help to improve the loss of positive affect in MDD. Thus, it effectively increases joy, interest, pleasure, energy, enthusiasm, alertness, and self-confidence.[27] The norepinephrine and dopamine facilitation helps patients with attention-deficit/hyperactivity disorder as well.[19]

Several cases of psychosis and paranoia have been reported in patients taking bupropion, likely related to the dopamine effects of the drug.[37] Limited data suggest that this medication, like all antidepressants, may activate depressed patients with bipolar disorder, causing manic episodes. However, it is widely accepted that bupropion and the SSRI class may be less likely to activate mania compared with the TCA class of medications. Because it does not act on serotonin, this is one of the few antidepressants that does not cause sexual side effects or weight gain.[19,27] The medication is uniquely approved for the treatment of seasonal affective disorder.[2]

Benefits.Bupropion is indicated for the treatment of MDD, seasonal affective disorder, and nicotine dependence. It has very low sexual and weight gain side effect liability.

Drawbacks.There is limited serotonin activity with bupropion and less evidence for the treatment of anxiety. Bupropion lowers the seizure threshold in patients predisposed to these events (including patients with eating disorders and those with epilepsy).

Trazodone. Trazodone is a serotonin antagonist/reuptake inhibitor (SARI). It blocks serotonin 2A and 2C receptors and also acts as a mild serotonin reuptake inhibitor.[19,27] This medication typically is used at lower doses because of its properties as a strong antihistamine (H1) and alpha-1 adrenergic blocking medication. The blockade of these receptors causes significant sedation, which may help with insomnia, but may cause excessive somnolence and dizziness in the daytime. The blockade of serotonin also may explain trazodone’s properties as a hypnotic, providing more efficient sleep.[27] Although higher doses of this medication provide excellent benefit related to the synergistic effects of blocking serotonin 2A and 2C and by acting as a serotonin reuptake inhibitor, this medication is not typically given in full divided doses because of excessive side effects.[19,27] A new slow-release preparation has been approved to allow a better tolerated, full dose range.

Benefits.Trazodone is often called a sedating antidepressant. It helps insomnia, improves sleep efficiency, and has its action even at low doses. Sexual side effects and activating side effects are low.[19,27]

Drawbacks. Significant sedation may limit its use.

Mirtazapine. This medication is also considered to be sedating and is typically either avoided or sought because of its side effect profile. Side effects include sedation/hypnotic effects and appetite stimulation, but not sexual side effects. The lack of sexual side effects is again related to serotonin in that mirtazapine is not a serotonin reuptake inhibitor, but in this case acts as a serotonin 2A/2C receptor antagonist.[19,27] The blockade of these receptors may result in more dopamine and norepinephrine release in the prefrontal cortex. The histamine blockade (H1) results in sedation, anxiolytic/hypnotic effects, and weight gain.[19,27] Mirtazapine also acts as a 5HT3 receptor antagonist, resulting in reduction of gastrointestinal problems.[19,27] The primary mechanism of antidepressant action is through alpha 2/norepinephrine receptor antagonism. Through this antagonism, inhibition of norepinephrine is disinhibited through auto receptor blockade. This allows downstream effects on several pathways and may result in overall release of serotonin and norepinephrine. This effect can often be combined with an SNRI to obtain synergistic effects.[27]

Benefits.Mirtazapine has many unique mechanisms of actions that make it beneficial in particular populations. It lacks sexual side effects, reduces gastrointestinal upset, and is not activating. The sedating qualities of this medication are typically used to the medication’s and the patient’s benefit.

Drawbacks.Mirtazapine has significant weight gain/appetite stimulation effects, which could lead to metabolic disorders.

This review is both practical and factual. Clinicians ideally should be aware of regulatory approvals and appropriate use of them in certain patient populations. When used this way, clinicians may expect results comparable to those noted in the evidence base of regulatory trials. However, those who treat patients understand that not all are identical to those enrolled in research trials. What follows will provide some practical clinical approaches when responses do not meet expectations.

As noted, only one third of patients will fully remit on their first antidepressant trial.[38] These numbers hold true for patients who are fully treated with moderate to high dose SSRI for as long as 12 weeks. In clinical practice, patients may not even have such a rigorous dosing profile and failure rates are likely higher. What approaches should be taken when a patient is not responding to treatment?

Adherence and Dosing

First, ask and attempt to ensure adherence to the antidepressant treatment. This questioning should be nonjudgmental and empathic, as most patients will likely say they are compliant even when they are not. Oftentimes suggesting that most people tend to naturally miss a few doses and that you as the clinician are just checking up will diffuse the situation. As dosing becomes divided throughout the day and polypharmacy increases, compliance usually diminishes, making assessment for compliance and adherence to medical regimens even more important.

Tolerability

An important area to address to improve adherence to a regimen relates to side effects and antidepressant tolerability. Sometimes patients cease taking their antidepressant or fail to escalate the dose as advised when adverse effects are not well tolerated. Many mild side effects will dissipate over time and this should be discussed directly with the patient.[39] Patients should be instructed to inform prescribers of any moderate to severe side effects and the drug can then be safely stopped. Patients should also be told that there are many antidepressants, and these have different side effects.[2,39] For example, SSRI, SNRI, and NDRI may be activating, and thus cause insomnia or nervousness upon initiation of treatment. Patients may be switched to a less activating SARI or noradrenergic antagonist-selective serotonin antagonist mechanism-based product, as these tend to be less activating and more sedating.[2]

Some patients may experience drug-drug interactions depending upon their genetic make-up.[2] Switching away from hepatic inhibiting medications towards medications that are less likely to interact with other drugs may be warranted. Typical side effects of headaches, stomachaches, or even insomnia often can be treated very effectively with over the counter or prescription medications. Later onset side effects such as weight gain or sexual dysfunction may be more difficult to mitigate or treat. Open discussions with patients about these longer term risks are warranted because patients often have to stay on their antidepressants for a year or more to maintain remission and avoid a depressive relapse.[38] Because certain antidepressants may have a more, or less favorable weight or sexual side effect profile, they should be chosen based on a discussion about patient preference when possible.

Assuming adherence is adequate, the next step is to confirm that the antidepressant dose was at the moderate to high end of the approved range and has been taken for at least 4 to 6 weeks. If dosing is confirmed to be reasonable, consider a final maximization of dose or switch to a new antidepressant monotherapy.[39]

Switching Monotherapies

If it is necessary to consider switching monotherapies, no clear benefit has been attributed to any particular strategy.[38] Many experts agree, however, that a switch away from an SSRI is warranted if the fully dosed SSRI therapy has failed to improve the patient’s symptoms.[27,39] The theoretical implication is that the patient’s current depressive symptoms have been treated with aggressive serotonergic facilitation and that repeating this mechanism may not be fruitful. This suggests that, pharmacodynamically, the depression may not be entirely serotonin-based in regards to its etiology.[27,39] Given this, a cross titration on to an SNRI such as venlafaxine XR or duloxetine, a NDRI such as bupropion XL, a noradrenergic antagonist-selective serotonin antagonist such as mirtazapine, or a more aggressive serotonergic facilitating agent like a SARI such as trazodone ER or a serotonin partial agonist-reuptake inhibitor such as vilazodone theoretically may be warranted.[2]

One final concern regarding switching involves the use of generic vs brand-name drugs. The FDA ensures that the bioavailability between a brand name and its generic counterpart is approximately between 20% weaker and 20% stronger.[40,41] Most generics are highly comparable, but occasionally when a patient actually changes from one generic to another, the bioavailability could change from a 20% stronger to a 20% weaker generic drug and symptom relapse may occur. By contrast, going from a weaker to a stronger generic might actually improve depression outcomes but may also create new-onset side effects after months of stable treatment as the newer generic preparation is more potent, raising blood levels higher than previously. These types of events should be monitored and dosing adjusted as needed.

Finally, a generic drug may possess a different slow-release mechanism compared with the parent brand-name drug. Oftentimes the generic, despite being a slow-release drug itself may actually release active drug more quickly than the original brand’s slow-release technology. There may be no evidence of a clinical problem; however, some patients may develop side effects when taking the faster release preparation. In this case, the dose may need to be lowered while monitoring for relapse or a switch back to the brand-name slow-release product may be warranted.

In conclusion, this article seeks to identify treatments that match patients with MDD and their common comorbidities, as a first line approach to MDD management. Secondarily and more theoretically, patients’ MDD symptoms may be effectively treated if clinicians are aware of the neurotransmitters and receptors that each antidepressant modulates. Finally, patients may suffer issues with nonefficacy, noncompliance, and tolerability. Each patient is unique and these clinical situations may interfere with optimal depression outcomes. Each patient must be educated and given informed consent about the myriad effective antidepressant treatment options available.

Supported by an independent educational grant from Valeant Pharmaceuticals.

References:

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Retrieved from:

Tailoring Antidepressant Treatment: Factors to Individualize Medication Selection Thomas L. Schwartz, MD; Daniel Uderitz, MD

In the realm of psychopharmacology, we often declare medications within their respective therapeutic classes as being equal. This is a byproduct related to the way medications achieve their indications for treatment for specific psychiatric disorders. In the case of antidepressant treatments, the US Food and Drug Administration (FDA) indicates that if a study can obtain a majority of patients improved by 50% compared with placebo, then a drug may become an antidepressant treatment. There are no standards for differentiating antidepressant treatments beyond this. Clinicians often note that all antidepressant treatments are not created equal, especially when applied to clinical situations and patients who are often complex and have comorbid conditions. The goal of this article is to sort out regimens that may convey certain advantages during the treatment in an individualized manner. This involves conceptualizing and utilizing monotherapies, combination therapies, and adjunctive treatments.

Monotherapies

The first-line treatment of patients with major depressive disorder (MDD) should start with an aggressive monotherapy. This occurs in clinical practice and is supported by many guidelines and reviews. The various antidepressant medications have unique properties that can be used to individualize treatments. Most psychiatrists can easily name their “favorite” antidepressant to use in certain situations. This is sometimes based on a simple bias, but often has evidence to back up clinical practice. Let us start with the mechanistically simple and move toward more complex ways to think about these medications. This includes thinking about FDA approvals, available guidelines, comorbidities, side effects, and more complex pharmacodynamic receptor-based neuropsychiatry.

A patient rarely comes to a psychiatrist without having a combination of psychiatric symptoms. Typically, clinicians screen patients and find that they often meet criteria for more than 1 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-Text Revision (DSM IV-TR) criteria.[1] At a minimum, the individual patient raises suspicion for various problem areas, even if they do not meet criteria for a specific disorder. In reviewing FDA guidelines, clinicians may quickly make simple decisions regarding treatment regimens that are more individualized based on these comorbidities and predominant symptoms. Of note, additional FDA approval or lack of approval for various indications does not necessarily mean that evidence does not support efficacy for other disorders. For example, the manufacturer may not have pursued FDA approval for other indications, or may have decided not to support randomized controlled trials to study another indication.

Single Indication

The first group of antidepressants approved by the FDA for the single indication of MDD include amitriptyline, citalopram, desipramine, desvenlafaxine, mirtazipine, nortriptyline, protriptyline, trazodone, trimipramine, vilazodone, and the monoamine oxidase inhibitor (MAOI) class.[2-4] Clinicians should know that these medications have only the 1 indication, and this clearly supports their use in MDD. However, many practitioners recognize that there are multiple other factors that allow these medications to be used in an off-label manner for various individuals. In a pure model, these antidepressants have regulatory data suggesting use only in patients with MDD but, as discussed, a lack of approval for other indications does not necessarily indicate a lack of supportive data or lack of efficacy.

Multiple Indications

Unlike those listed above, many antidepressants have other labeled or approved indications. These span a variety of comorbidities including anxiety disorders, seasonal affective disorder, sleep disorders, pain disorders, premenstrual dysphoric disorder, bulimia nervosa, and other miscellaneous indications. Given this, and assuming MDD is often complicated by comorbidity, let us evaluate a few comorbidities where data-driven decisions may help in individualizing treatments in patients who are depressed and simultaneously experience other psychiatric conditions.

Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder often have comorbid depression. Only 2 antidepressants, the selective serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, are approved for this indication.[2] Multiple other medications have been recognized as effective off-label treatments for posttraumatic stress disorder, however; these include amitriptyline, fluoxetine, fluvoxamine, imipramine, and venlafaxine.[5-7] If a patient presents with MDD and posttraumatic stress disorder, these antidepressants may be considered if necessary to achieve efficacy for both conditions.

Obsessive-Compulsive Disorder

Several medications are approved for obsessive-compulsive disorder, including the tricyclic antidepressant clomipramine, and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[2] Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),[8] and the SSRI citalopram have shown some promise in obsessive compulsive disorder,[9] but have not yet received that indication from the FDA.

Panic Disorder

The SSRIs fluoxetine, paroxetine, and sertraline are approved for treatment of panic disorder, as is the SNRI venlafaxine.[2,10] Other antidepressants with an evidence base for use that are not approved include the TCAs clomipramine and imipramine, and the SSRI fluvoxamine.[6]

Anxiety Disorders

Social anxiety disorder. The SSRIs paroxetine and sertraline, and the SNRI, venlafaxine extended-release (ER) have been approved for the treatment of social anxiety disorder.[2] The SSRI fluoxetine is sometimes used for treatment of social anxiety disorder.

Generalized anxiety disorder. Four antidepressants have been indicated for the treatment of generalized anxiety disorder. These include the SSRI escitalopram and paroxetine, and the SNRI duloxetine and venlafaxine ER.[2,11]

Insomnia

Although sleep difficulties are a nearly universal symptom of depression, few antidepressants have an official indication for insomnia. Doxepin, a TCA, is the sole antidepressant labeled with this indication, when it is used at subtherapeutic antidepressant doses of 3 to 6 mg per day.[12] However, clinicians often use sedating antidepressants to induce sleep in those patients with MDD and insomnia (Schwartz TL. Novel hypnotics: moving beyond positive allosteric modulation of the GABA-A receptor. Manuscript submitted). These medications include the TCA amitriptyline, the tetracyclic mirtazapine, and the serotonin modulator trazodone.

Pain Syndromes

Duloxetine, an SNRI, is the only antidepressant medication that has official indications for treatment of pain syndromes.[2,10] These include chronic musculoskeletal pain, neuropathic pain (diabetic neuropathy in particular), and fibromyalgia. Alternatively, many of the TCAs, as well as other SNRI, have been studied for the treatment of pain syndromes, primarily involving neuropathic or chronic pain conditions.[13,14] Amitriptyline also is often used for migraine headaches. Unfortunately these other medications have not received official indications for these psychosomatic comorbidities.

Attention-Deficit/Hyperactivity Disorder

Some antidepressants have shown promise for the treatment of attention-deficit/hyperactivity disorder, but not enough to warrant a specific FDA indication. Nonetheless, these medications are used for the treatment of attention-deficit/hyperactivity disorder, particularly in patients with substance use disorder. Bupropion, desipramine, imipramine, nortriptyline, and venlafaxine have some evidence base to support their use.[15-19]

Other Comorbid Considerations

Premenstrual dysphoric disorder. The SSRI fluoxetine, paroxetine, and sertraline have been FDA approved for the treatment of premenstrual dysphoric disorder.[2]

Smoking cessation. Many patients who receive mental health treatment are also addicted to nicotine. Bupropion SR has received the indication for nicotine addiction.[2] Nortriptyline also has been shown to be helpful for smoking cessation efforts, but has not received an official indication.[20]

Miscellaneous. Bupropion XL carries a specific indication for prophylaxis of seasonal affective disorder and often is used off-label for the treatment of bipolar depression.[19,21,22] Fluoxetine is indicated for treatment of bulimia nervosa and sometimes is used for the treatment of Raynaud’ phenomenon.[2,19,23] Venlafaxine and paroxetine have data supporting use for the treatment of vasomotor hot flashes.[24,25] Finally, imipramine may be used in the treatment of enuresis.[26]

Take-Home Point

Clinicians should be aware of FDA approvals and the evidence base supporting the use of antidepressants in patients with MDD, who are often complex and suffering with other medical and psychiatric comorbidities. Choosing agents with indications that match the patient’s comorbid symptoms is one way to tailor and individualize treatment to each patient.

Beyond the simplistic but labor-intensive role of delineating specific comorbidities and focusing on antidepressant indications, is the imperative to develop a more complex individualized antidepressant treatment plan. If it were as simple as following the FDA labels and simple algorithms to make decisions, then much psychiatric education could be eliminated. A review of antidepressant mechanisms of action will allow us to further distinguish these medications, thus allowing more individualized treatments for MDD.

SSRI Class

The first and most commonly prescribed class of antidepressant is the SSRI. At the most basic understanding, these medications increase serotonin in the synapse and function ultimately to down-regulate serotonin receptors. However, as the science behind these medications is further explored, there is much more to these agents. When looking at the SSRI class as a whole, and in comparison with other antidepressant classes, a few general characteristics can be considered. The SSRI medications as a group are thought of as having fewer side effects than most other classes of antidepressants, and particularly the older classes of drugs. The most common and clinically relevant consideration for these medications is the development of gastrointestinal upset, sexual side effects, and weight gain.[27] The following delineates some of the subtle differences for each medication in this class and describes the benefits and drawbacks of treatment with each to help refine treatment selection.

Citalopram. Citalopram is one of the most widely used antidepressants today, and has a few properties that make it desirable. The medication has a long half-life of 23-45 hours, second only to fluoxetine,[2] and it is typically well tolerated in medically ill patients and the elderly.[19,28] Citalopram has weak H1 receptor antihistamine properties, and these properties provide anxiolytic and positively sedating effects.[27] Citalopram is made up of 2 mirror image enantiomers, each of which have different properties [27] that may lead to some inconsistencies in the property or function of the medication at lower doses. Citalopram is a weak inhibitor of CYP 2D6, with minimal drug-drug interactions.[30] Finally, recent FDA warnings have changed prescribing practices of this medication because of potential QTc prolongation at daily doses higher than 40 mg[29]; daily doses of 60 mg should no longer be used.

Benefits.Citalopram is a well-tolerated medication with mild antihistamine effects that may help with insomnia or mild anxieties. The longer half-life results in less withdrawal or discontinuation side effects.[31]

Drawbacks.Structural enantiomers result in this medication having less predictable effects at lower doses, and higher doses are contrary to FDA recommendations related to the potential for QTc prolongation. It has fewer FDA approvals for comorbid psychiatric disorders than other drugs in the SSRI class; as discussed earlier, this may simply reflect the manufacturer’s failure to seek approval for other indications.

Escitalopram. In contrast to the parent drug citalopram, escitalopram is separated and includes only the left enantiomer.[27] This results in the removal of much of the antihistamine and CYP 2D6 inhibitory properties.[19,27] It also results in more effective and predictable dose responses of the medication at the lower doses.

Benefits.Escitalopram has the benefit of better tolerability with less drug interactions. It may have less sedating effects, and is approved for generalized anxiety disorder as well as MDD.[2]

Drawbacks.Currently this is the only SSRI still on patent, and is thus more expensive than other, generic SSRI.

Fluoxetine. The first member of the SSRI class, fluoxetine has a few characteristics that make it desirable. Fluoxetine has mild serotonin 2C receptor antagonistic actions. This may result in the disinhibition of dopamine and norepinephrine release to the prefrontal cortex, which likely helps to improve concentration, energy, and executive functioning.[19,27] Furthermore, the serotonin 2C effects of this medication may contribute to the initial anorexic and ongoing anti-bulimic effects of this medication.[27] More recently, the effects of fluoxetine on the serotonin system have been combined with those of olanzapine, a second-generation antipsychotic, for the treatment of depression in patients with bipolar disorder and for treatment resistant unipolar depression.[19,27] Fluoxetine also may be a mild norepinephrine reuptake inhibitor, particularly at higher doses.

Fluoxetine significantly affects CYP 2D6 and 3A4 inhibition, and thus is highly likely to interact with other medications.[19,27] Finally, this medication has the longest half-life of the SSRIs, at 2-3 days, with an active metabolite that exists for 2 weeks.[2]

Benefits.Fluoxetine has action at the serotonin 2C receptor, and may affect norepinephrine levels at higher doses. The drug has the longest half-life among the SSRI, making it least likely to cause withdrawal. It is available as a once weekly dosing formulation and is approved for MDD, panic disorder, premenstrual dysphoric disorder, obsessive compulsive disorder, and bulimia nervosa.[2] It also has positive combination effects with the second generation antipsychotic olanzapine, and a combination formulation has been approved by the FDA for treating treatment-resistant and bipolar depression.*[19]

Drawbacks.The medication is likely to be activating in some patients, making it a more difficult option for those with insomnia, agitation, and intense anxiety.[19,27] Slower dose titration is warranted in these cases. Fluoxetine has a high degree of CYP 2D6 inhibition, resulting in significant drug-drug interactions.[19]

*Multiple trials of other second generation antipsychotics combined with various antidepressants including SSRI and SNRI have shown antidepressant efficacy for these combinations in patients with refractory depression.[32]

Paroxetine. The action of paroxetine is more complex than the previously described SSRI medications. In addition to serotonin reuptake inhibition, paroxetine functions with mild anticholinergic properties, mild norepinephrine reuptake inhibition (NRI), inhibition of nitric oxide synthetase, and potent inhibition of CYP 2D6 (similar to fluoxetine).[19,27] It has anticholinergic and antihistaminergic properties that may lend to its being calming and sedating, but also may increase dry mouth, blurred vision, and short term memory problems.[19,27] The NRI effects of the medication may contribute to clinical effectiveness. The effects on nitric oxide synthetase may cause sexual dysfunction.

Benefits.In addition to major depression, paroxetine is approved for various anxiety disorders, with possible calming/sedating effects. It is available in immediate- and slow-release preparations.

Drawbacks.Paroxetine has the potential for anticholinergic side effects[31] Its shorter half-life may result in more and more severe withdrawal side effects than other SSRI; paroxetine is also most strongly associated with weight changes, compared with other SSRI.[2] This medication also has a higher drug-drug interaction probability.

Sertraline. This SSRI may have dual mechanisms that distinguish it from other SSRIs. At higher doses, it acts as both a dopamine transporter inhibitor and a sigma 1 receptor binder.[27] The effects of dopamine transporter inhibition may result in improved energy, motivation, and concentration. Sigma 1 implications are not yet well understood, but some hypothetical benefit is attributed to their mild anxiolytic effects in psychotic and delusional depressions.[27]

Benefits.Sertraline is approved for MDD, many anxiety disorders, eating disorders, and premenstrual dysphoric disorder.[2] This medication has very little CYP 2D6 inhibition and therefore few drug-drug interactions.[19] It has a moderate half-life and thus the possibility of some withdrawal symptoms.

Drawbacks.Sertraline can be activating in patients with anxiety disorders, which may require slowly titrating doses; it is often associated with gastrointestinal distress.

Take-Home Point

The SSRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. However, a pharmacodynamic look into their wider mechanisms of action may suggest that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

SNRI Class

The next most common class of medications used for the treatment of MDD is the SNRI. This group of medications has a dual mechanism of action, increasing synaptic norepinephrine as well as serotonin.[19,27] In addition to increasing norepinephrine and serotonin levels throughout the brain, these medications may also boost dopamine in the prefrontal cortex, resulting in additional benefits.[27] In the prefrontal cortex, no dopamine transporters are there to recycle dopamine out of the synapse. Typically norepinephrine transporters remove dopamine in these areas, but with the inhibition of these, the dopamine effect in the dorsal lateral prefrontal cortex is more robust.[27] This activation in the brain has been correlated with antidepressant effects.

On the other hand, as the additional norepinephrine boost is added to the brain, it is not contained there. Norepinephrine effects are seen throughout the body, including the spinal cord, peripheral autonomic nervous system, heart, and bladder.[19,27] In the spinal cord this may reduce pain, but may also lead to side effects such as tremor, motor activation, and increased blood pressure and heart rate.[27] Also, these effects may allow a pseudo-anticholinergic effect resulting in such things as dry mouth, constipation, and urinary retention. However, these norepinephrine-related side effects do not rival those of the tricyclic antidepressant class.[31] Generally, the SNRIs are well tolerated, but the subtle increase in side effect burden needs to be considered.

Venlafaxine. Venlafaxine was the first SNRI and was initially approved in an immediate-release preparation. This medication is a substrate of CYP 2D6, and is converted into desvenlafaxine, an SNRI that was developed subsequently.[19,27] Unfortunately, the absorption of immediate-release venlafaxine is rapid, affording it remarkable side effects; this has been mitigated with an extended-release formulation that appears to be much better tolerated in practice. The medication also has a unique character, causing a varying ratio of serotonin to norepinephrine effects.[19,27] At low doses, there are fewer NRI properties (and more SRI properties) available and only at higher doses do the norepinephrine transporter inhibition properties increase more robustly.

Benefits.Compared with the SSRI, this medication has effects at both serotonin and norepinephrine receptors leading to its antidepressant effectiveness. The medication is very effective in the treatment of anxiety disorders, with multiple approved uses, likely comparable to sertraline and paroxetine.[2]

Drawbacks.The norepinephrine effects of the medication are much more robust only at higher doses and must be titrated. The medication has a short half-life resulting in many withdrawal side effects. There may be higher rates of nausea and dry mouth in comparison to some other antidepressants.[31] This medication may cause hypertension in some patients, and thus, blood pressure should be monitored.[19]

Desvenlafaxine. Desvenlafaxine is the active metabolite of venlafaxine,[19] and has the added benefit of a greater effect on norepinephrine transporter inhibition than its precursor at the initial dose levels. However, the effects on norepinephrine are less than those on serotonin.[27] Because it is the active metabolite of venlafaxine, it is less subjected to the genetic and drug-induced differences of CYP 2D6, which allows more consistent plasma levels of the medication.[27] It may be one of the “cleanest” antidepressant medications, given its extremely low vulnerability to cytochrome P450 metabolism, renal excretion, and low protein binding. The role of desvenlafaxine in the regulation of vasomotor symptoms (night sweats, hot flashes, insomnia, and related depression) in perimenopausal women is being investigated.[27]

Benefits.Although similar to extended-release venlafaxine, desvenlafaxine has a more balanced ratio of norepinephrine/serotonin properties, and it has one of the most favorable drug-drug interaction profiles.

Drawbacks.This medication has a short half-life and significant withdrawal side effects.[31]

Duloxetine. Duloxetine is unique among the SNRI class of drugs because, in addition to MDD, it is approved for treating a variety of pain syndromes.[2] This is related to the SNRI effect on the descending spinal norepinephrine pathways that reduce afferent pain fiber activity.[27] The increase in norepinephrine activity in spinal areas results in less thalamic input to the sensory cortex and therefore less perceived pain. The norepinephrine-facilitating effects in the prefrontal cortex also may show some benefit in treatment of cognitive symptoms prevalent in geriatric depression.[27]. Compared with venlafaxine, duloxetine has a lower incidence of treatment-related hypertension and milder withdrawal reactions. It is approved for MDD, generalized anxiety disorder, musculoskeletal pain, neuropathic pain, and fibromyalgia-related pain.[2]

Benefits.One of the only antidepressants approved for management of pain syndromes, duloxetine also has a more balanced norepinephrine to serotonin ratio at its initial doses.[28]

Drawbacks.Duloxetine is a mild to moderate CYP 2D6 inhibitor, which results in some drug-drug interactions.[19] In addition, it should not be used in alcoholic patients or those with renal and/or liver impairment.

Take-Home Point

The SNRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. As with the SSRI, a pharmacodynamic look into their wider mechanisms of action suggests that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This is clear when one considers the diverse FDA approvals for each and different potencies related to facilitating distinct ratios of serotonin to norepinephrine transporter inhibition. Again, this type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

TCA Class

This class is one of the oldest and still highly utilized classes of antidepressant in the history of psychopharmacology, and includes amitriptyline, imipramine, clomipramine, desipramine, trimipramine, and nortriptyline. The TCAs are often overlooked because of their relatively high level of side effects when compared with other classes of antidepressant, and because of high lethality in overdose. The TCAs have significant effects on the norepinephrine, serotonin, and to some extent dopamine activity in the brain.[19,27] The higher incidence of side effects are likely mediated through blockade of anticholinergic receptors (M1/M3), histamine receptors (H1), alpha 1 adrenergic receptors, and voltage-sensitive sodium channels.[19,27] Histamine blockade causes sedation and weight gain. Muscarinic blockade causes dry mouth, blurred vision, urinary retention, and constipation. Alpha 1 blockade causes orthostatic hypotension and dizziness. Sodium channel blockade affects the heart significantly, resulting in arrhythmias and conduction changes at higher doses.[27] This latter side effect results in significant risk of successful suicide with overdose, and renders TCAs difficult to use in medically comorbid patients.

Benefits.Overall, TCAs are very effective antidepressants. Indeed, early studies comparing TCA with SSRI medications found significantly higher remission rates with TCA than with SSRI in depressed, endogenous and inpatients samples.[33-36] However, in less severely depressed patients, there is not conclusive evidence of benefit of either class of antidepressant over another. Off-label, the use of TCAs in the treatment of pain, enuresis, and insomnia is widespread.[19] Availability of plasma level monitoring helps to guarantee therapeutic trials while minimizing toxicity.

Drawbacks.The significant adverse event profile causes an array of side effects that are often poorly tolerated and lead to medication noncompliance. Because of cardiac side effects, TCAs carry significant risk of death with overdose.

MAOI Class

This class of antidepressants has its own unique mechanism of action. MAOI has fallen into the realm of rarely used antidepressants in modern day psychopharmacology. This is related to the risks and side effects inherent to MAOI use. On the other hand, MAOI are among the most clinically powerful classes of antidepressant treatments. This class interferes with MAO enzyme subtypes A and B. The inhibition of these enzymes results in higher levels of serotonin and norepinephrine due to reduced catabolism of these neurotransmitters.[27] Moreover, by specifically lowering MAO-B activity, dopamine levels in the brain increase as well. Thus, all 3 monoamine neurotransmitter levels are robustly increased, which, in turn, affects a broad array of depressive symptoms.

The use of these medications may come at the cost of difficulty in using them. The most well-known drawback is that patients need to maintain a specific diet that is free of high tyramine foods, or risk the likelihood of hypertensive crisis related to the acute elevation of systemic norepinephrine, which also may result in stroke.[19,27] Foods to be avoided include tap beers, smoked meat or fish, fava beans, aged cheeses, sauerkraut, and soy. However, certain beers, wines, and cheeses are not contraindicated. These items need to be researched and discussed prior to starting a patient on the medication.

Drug-drug interactions are plentiful; combining an MAOI with other norepinephrine medications may increase blood pressure, and combining with a serotonin-based medication can cause serotonin syndrome.[19,27] Patients are also advised to avoid decongestants, stimulants, antidepressants, certain opioids, and appetite suppressants.[19,27]

The MAOI tranylcypromine may act similarly to an amphetamine in the frontal cortex, affording it some additional benefits.[27] Likewise, selegiline also involves breakdown into an amphetamine metabolite. Selegiline is more often used for Parkinson disease than depression.

Benefits.MAOIs are recognized as among the most potent of antidepressants in monotherapy, with effects on serotonin, dopamine, and norepinephrine. This class of antidepressant is often used for the patient who is refractory to other antidepressant trials.

Drawbacks.The MAOIs are associated with risks of hypertensive crisis and serotonin syndrome. There is a need to maintain a tyramine free diet except when using the low dose transdermal selegiline. Because of potential for drug-drug interactions, careful, ongoing monitoring of all additional medications (including over-the-counter medications) is essential.

Miscellaneous Antidepressants

Several other well-known antidepressant medications do not fit discretely into the 4 main antidepressant classes. Each has unique mechanisms that will be discussed similarly below.

Bupropion. This norepinephrine-dopamine receptor inhibitor (NDRI) medication is of particular use in a few subsets of patients. As the class name indicates, bupropion facilitates effects on norepinephrine and dopamine, blocking norepinephrine transporter and dopamine transporter activity at a moderate level, likely in the frontal cortex.[27] The unique properties of bupropion as an antidepressant may be related to its lack of serotonin activity. It is approved for smoking cessation and is used off-label to reduce craving for substances of abuse. Clinicians contend that the dopamine actions of this medication help to improve the loss of positive affect in MDD. Thus, it effectively increases joy, interest, pleasure, energy, enthusiasm, alertness, and self-confidence.[27] The norepinephrine and dopamine facilitation helps patients with attention-deficit/hyperactivity disorder as well.[19]

Several cases of psychosis and paranoia have been reported in patients taking bupropion, likely related to the dopamine effects of the drug.[37] Limited data suggest that this medication, like all antidepressants, may activate depressed patients with bipolar disorder, causing manic episodes. However, it is widely accepted that bupropion and the SSRI class may be less likely to activate mania compared with the TCA class of medications. Because it does not act on serotonin, this is one of the few antidepressants that does not cause sexual side effects or weight gain.[19,27] The medication is uniquely approved for the treatment of seasonal affective disorder.[2]

Benefits.Bupropion is indicated for the treatment of MDD, seasonal affective disorder, and nicotine dependence. It has very low sexual and weight gain side effect liability.

Drawbacks.There is limited serotonin activity with bupropion and less evidence for the treatment of anxiety. Bupropion lowers the seizure threshold in patients predisposed to these events (including patients with eating disorders and those with epilepsy).

Trazodone. Trazodone is a serotonin antagonist/reuptake inhibitor (SARI). It blocks serotonin 2A and 2C receptors and also acts as a mild serotonin reuptake inhibitor.[19,27] This medication typically is used at lower doses because of its properties as a strong antihistamine (H1) and alpha-1 adrenergic blocking medication. The blockade of these receptors causes significant sedation, which may help with insomnia, but may cause excessive somnolence and dizziness in the daytime. The blockade of serotonin also may explain trazodone’s properties as a hypnotic, providing more efficient sleep.[27] Although higher doses of this medication provide excellent benefit related to the synergistic effects of blocking serotonin 2A and 2C and by acting as a serotonin reuptake inhibitor, this medication is not typically given in full divided doses because of excessive side effects.[19,27] A new slow-release preparation has been approved to allow a better tolerated, full dose range.

Benefits.Trazodone is often called a sedating antidepressant. It helps insomnia, improves sleep efficiency, and has its action even at low doses. Sexual side effects and activating side effects are low.[19,27]

Drawbacks. Significant sedation may limit its use.

Mirtazapine. This medication is also considered to be sedating and is typically either avoided or sought because of its side effect profile. Side effects include sedation/hypnotic effects and appetite stimulation, but not sexual side effects. The lack of sexual side effects is again related to serotonin in that mirtazapine is not a serotonin reuptake inhibitor, but in this case acts as a serotonin 2A/2C receptor antagonist.[19,27] The blockade of these receptors may result in more dopamine and norepinephrine release in the prefrontal cortex. The histamine blockade (H1) results in sedation, anxiolytic/hypnotic effects, and weight gain.[19,27] Mirtazapine also acts as a 5HT3 receptor antagonist, resulting in reduction of gastrointestinal problems.[19,27] The primary mechanism of antidepressant action is through alpha 2/norepinephrine receptor antagonism. Through this antagonism, inhibition of norepinephrine is disinhibited through auto receptor blockade. This allows downstream effects on several pathways and may result in overall release of serotonin and norepinephrine. This effect can often be combined with an SNRI to obtain synergistic effects.[27]

Benefits.Mirtazapine has many unique mechanisms of actions that make it beneficial in particular populations. It lacks sexual side effects, reduces gastrointestinal upset, and is not activating. The sedating qualities of this medication are typically used to the medication’s and the patient’s benefit.

Drawbacks.Mirtazapine has significant weight gain/appetite stimulation effects, which could lead to metabolic disorders.

This review is both practical and factual. Clinicians ideally should be aware of regulatory approvals and appropriate use of them in certain patient populations. When used this way, clinicians may expect results comparable to those noted in the evidence base of regulatory trials. However, those who treat patients understand that not all are identical to those enrolled in research trials. What follows will provide some practical clinical approaches when responses do not meet expectations.

As noted, only one third of patients will fully remit on their first antidepressant trial.[38] These numbers hold true for patients who are fully treated with moderate to high dose SSRI for as long as 12 weeks. In clinical practice, patients may not even have such a rigorous dosing profile and failure rates are likely higher. What approaches should be taken when a patient is not responding to treatment?

Adherence and Dosing

First, ask and attempt to ensure adherence to the antidepressant treatment. This questioning should be nonjudgmental and empathic, as most patients will likely say they are compliant even when they are not. Oftentimes suggesting that most people tend to naturally miss a few doses and that you as the clinician are just checking up will diffuse the situation. As dosing becomes divided throughout the day and polypharmacy increases, compliance usually diminishes, making assessment for compliance and adherence to medical regimens even more important.

Tolerability

An important area to address to improve adherence to a regimen relates to side effects and antidepressant tolerability. Sometimes patients cease taking their antidepressant or fail to escalate the dose as advised when adverse effects are not well tolerated. Many mild side effects will dissipate over time and this should be discussed directly with the patient.[39] Patients should be instructed to inform prescribers of any moderate to severe side effects and the drug can then be safely stopped. Patients should also be told that there are many antidepressants, and these have different side effects.[2,39] For example, SSRI, SNRI, and NDRI may be activating, and thus cause insomnia or nervousness upon initiation of treatment. Patients may be switched to a less activating SARI or noradrenergic antagonist-selective serotonin antagonist mechanism-based product, as these tend to be less activating and more sedating.[2]

Some patients may experience drug-drug interactions depending upon their genetic make-up.[2] Switching away from hepatic inhibiting medications towards medications that are less likely to interact with other drugs may be warranted. Typical side effects of headaches, stomachaches, or even insomnia often can be treated very effectively with over the counter or prescription medications. Later onset side effects such as weight gain or sexual dysfunction may be more difficult to mitigate or treat. Open discussions with patients about these longer term risks are warranted because patients often have to stay on their antidepressants for a year or more to maintain remission and avoid a depressive relapse.[38] Because certain antidepressants may have a more, or less favorable weight or sexual side effect profile, they should be chosen based on a discussion about patient preference when possible.

Assuming adherence is adequate, the next step is to confirm that the antidepressant dose was at the moderate to high end of the approved range and has been taken for at least 4 to 6 weeks. If dosing is confirmed to be reasonable, consider a final maximization of dose or switch to a new antidepressant monotherapy.[39]

Switching Monotherapies

If it is necessary to consider switching monotherapies, no clear benefit has been attributed to any particular strategy.[38] Many experts agree, however, that a switch away from an SSRI is warranted if the fully dosed SSRI therapy has failed to improve the patient’s symptoms.[27,39] The theoretical implication is that the patient’s current depressive symptoms have been treated with aggressive serotonergic facilitation and that repeating this mechanism may not be fruitful. This suggests that, pharmacodynamically, the depression may not be entirely serotonin-based in regards to its etiology.[27,39] Given this, a cross titration on to an SNRI such as venlafaxine XR or duloxetine, a NDRI such as bupropion XL, a noradrenergic antagonist-selective serotonin antagonist such as mirtazapine, or a more aggressive serotonergic facilitating agent like a SARI such as trazodone ER or a serotonin partial agonist-reuptake inhibitor such as vilazodone theoretically may be warranted.[2]

One final concern regarding switching involves the use of generic vs brand-name drugs. The FDA ensures that the bioavailability between a brand name and its generic counterpart is approximately between 20% weaker and 20% stronger.[40,41] Most generics are highly comparable, but occasionally when a patient actually changes from one generic to another, the bioavailability could change from a 20% stronger to a 20% weaker generic drug and symptom relapse may occur. By contrast, going from a weaker to a stronger generic might actually improve depression outcomes but may also create new-onset side effects after months of stable treatment as the newer generic preparation is more potent, raising blood levels higher than previously. These types of events should be monitored and dosing adjusted as needed.

Finally, a generic drug may possess a different slow-release mechanism compared with the parent brand-name drug. Oftentimes the generic, despite being a slow-release drug itself may actually release active drug more quickly than the original brand’s slow-release technology. There may be no evidence of a clinical problem; however, some patients may develop side effects when taking the faster release preparation. In this case, the dose may need to be lowered while monitoring for relapse or a switch back to the brand-name slow-release product may be warranted.

In conclusion, this article seeks to identify treatments that match patients with MDD and their common comorbidities, as a first line approach to MDD management. Secondarily and more theoretically, patients’ MDD symptoms may be effectively treated if clinicians are aware of the neurotransmitters and receptors that each antidepressant modulates. Finally, patients may suffer issues with nonefficacy, noncompliance, and tolerability. Each patient is unique and these clinical situations may interfere with optimal depression outcomes. Each patient must be educated and given informed consent about the myriad effective antidepressant treatment options available.

Supported by an independent educational grant from Valeant Pharmaceuticals.

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Retrieved from: http://www.medscape.org/viewarticle/755180

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