Antidepressants, Part 1: 100 Years and Counting

Table 1. Treatment modalities for depression

Table 2. FDA-approved medications for the treatment of MDD

Table 3. Additional FDA-approved indications for at least one antidepressant

Table 4. Four steps of the STAR*D algorithm

Premiere Date: October 20, 2017
Expiration Date: April 20, 2019

This activity offers CE credits for:
1. Physicians (CME)
2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To understand the various classes of antidepressants and how they have evolved.

LEARNING OBJECTIVES

At the end of this CE activity, participants should be able to:

• Describe the origins of the early antidepressants and the discoveries that led to the first FDA-approved antidepressant

• Explain the monoamine hypothesis of depression

• Identify augmentation strategies for MDD and the first FDA-approved augmenting agent

TARGET AUDIENCE

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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John J. Miller, MD, reports that he is on the Speakers Bureau for Sunovion, Otsuka, and Allergan; and he is a Consultant for Sunovion and Otsuka.

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MDD has haunted human civilization throughout recorded history and has likely been a companion of humanity from our earliest evolutionary roots. Over the millennia, a major depressive episode has been explained by far-ranging and contradictory theories, including demonic possession, a conflict of our “soul” with our earthly body, childhood developmental dysfunction, hormonal imbalance, a symptom of a primary illness of the body, bad luck from our genetic lottery, a narcissistic injury to our ego structure, the outcome of a structural abnormality of our brain, or the result of ingestion of a substance of abuse or some other toxin -just to name a few. What is clear is that MDD is all too common; DSM-5 reports that it will affect approximately 7% of individuals in the US.

Depression: one of humanity’s greatest burdens

Despite its pervasive presence across cultures and time, depression continues to be under-recognized and undertreated. It remains one of the most common causes of disability worldwide and is a significant risk factor for suicide -which is currently the 10th most common cause of death in the US according to the CDC.

Treatments abound, and some individuals respond dramatically to a wide range of treatment options (Table 1). However, in the practice of medicine, especially in the subspecialty of psychiatry, complete remission of a depressive episode can be quite challenging to achieve. When we select an antidepressant to treat an episode of MDD, either as a primary modality or in addition to other complementary interventions, we have many medications to choose from; however, there is no clear first-line drug. Despite many antidepressants in our arsenal (Table 2), findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study suggest that only 49% of depressed patients have a 50% improvement in their depression with citalopram and only 37% achieve remission of symptoms.^1,2 Earlier case studies showed that roughly 30% of individuals achieve remission.³

Some critics have argued that antidepressants work no better than a placebo; however, the extensive evidence-based literature consistently demonstrates the efficacy of antidepressants. Although there is no “magic bullet,” mental health workers on an in-patient psychiatric unit will tell you that antidepressants are effective and, at times, lifesaving. There has also been criticism that antidepressants are overprescribed, citing the increase in prescriptions for antidepressants documented in large insurance company databases. These data are flawed, as the term “antidepressant” erroneously implies that these medications are only being used to treat depression.

Although rooted in the initial use of these drugs -to treat depression -there are many other indications, both FDA-approved and off-label, for which antidepressants are used as first- or second-line treatment (Table 3). A detailed review of the national patterns of antidepressant prescribing in the US reported that from 1996 to 2005, the rate of antidepressant use increased from 5.84% to 10.12%.⁴ The researchers concluded that part of this increase in antidepressant prescribing resulted from their use to treat anxiety disorders, bipolar disorder, and sleep-related disorders. In addition, they noted that during the study period several antidepressants were FDA-approved for anxiety disorders, and clinical guidelines were published that supported the use of some antidepressants for anxiety disorders as well as other conditions.

Considering our understanding of the neurobiology of depression and treatment options that existed a mere 100 years ago, and the knowledge and treatments that are currently available, psychiatry should be quite proud of the progress made. However, regarding the development of newer antidepressants, we have been immobilized in the comfortable and seductive monoamine hypothesis of depression. Fortunately, a new layer of the metaphorical onion has been peeled away, and the future holds promise of treatments with novel mechanisms of action. The treatment of depression should include all modalities available to us (Table 1).

Pre-FDA antidepressants: if it works, use it

It is hard for today’s prescribers to imagine a time when the FDA did not exist, and drugs were not systematically evaluated for safety and efficacy before they were allowed to be prescribed to patients. It was President Theodore Roosevelt who in 1906 signed the Food and Drug Act into law that evolved into the FDA. By 1930, a skeleton of our current FDA existed, and over the ensuing decades legislation to require that new drug applications provide evidence of efficacy and safety steadily broadened. This culminated in the passage in 1962 of the Kefauver-Harris Amendment to the Food, Drug, and Cosmetic Act, which is the foundation that the FDA is built on. This amendment was in response to the thalidomide crisis in Europe.

Before the first 2 FDA approvals of antidepressants in 1958 and 1959, many drugs and herbs were marketed for the treatment of depression. Frankincense and St. John’s wort have been used for hundreds of years to treat depression. Cocaine, an early ingredient in Coca-Cola, also has antidepressant properties. In 1904 cocaine was removed from the coca leaves used in the production of Coca-Cola, leaving caffeine from the kola nut as the remaining psychoactive ingredient. Benzedrine (amphetamine) was marketed for narcolepsy and depression starting in 1935. Opioids were also often a preferred drug to treat depression. In 1938 ECT was first used to treat severe depression, and it remains the gold standard with an approximate 74% response rate and 50% rate of remission.5 However, the time-intensive nature of ECT, its expense, and the continued stigmatization of ECT as a treatment continue to limit its use.

The monoamine hypothesis: a detective story involving tuberculosis and hypertension

Since it was first proposed in the 1950s, the monoamine hypothesis of depression has dominated medication development and the treatment of depression. As often is the case in medicine, serendipity provided the clues. Reserpine, which was extracted from Rauwolfia serpentina (Indian snakeroot) in 1952, was shown to be an effective antihypertensive medication; it also had been used for hundreds of years to treat “insanity” in India. As a direct result of reserpine’s ability to irreversibly inhibit the vesicular monoamine transporter in the intracellular environment, the free serotonin, norepinephrine, and dopamine present there are unable to be transported into the vesicles of the presynaptic nerve terminals. These monoamine neurotransmitters are easily degraded by the enzymes monoamine oxidase and catechol–O-methyltransferase in the cytoplasm. The resulting deficiency of synaptic norepinephrine lowers blood pressure but increases the likelihood of depression. The synaptic decrease of dopamine improves psychosis but causes pseudoparkinsonism.

In support of the reserpine evidence that monoamines contribute to depression, in 1952, iproniazid (isoniazid with a propyl group attached) was shown to irreversibly inhibit the cytoplasmic enzyme monoamine oxidase, with the resulting effect of increased neuronal levels of serotonin, norepinephrine, and dopamine. Although at that time both isoniazid and iproniazid were being used to treat tuberculosis, physicians observed that patients who received these drugs also demonstrated significant improvements in their mood, appetite, and sense of well-being. In 1952, Robitzek and Selikoff reported:

So accentuated has been the feeling of the sense of well-being, that disciplinary measures have been necessary; the feeling of well-being may be due to a “resurgent animal vigour.” Patients usually feel better before any objective measurements of improvement can be made.⁶

By 1957 Roland Kuhn had discovered that a drug derived from chlorpromazine, which itself was derived from an antihistamine, had significant antidepressant properties, especially in patients with psychomotor retardation. In collaboration with Geigy Pharmaceutical Company, he developed imipramine (originally known as G22355). Iproniazid was approved by the FDA in 1958, and imipramine was approved in 1959. These 2 drugs became the mechanistic foundation of all of our current antidepressant medications. In 1961, Julius Axelrod, who won a Nobel Prize in 1970, demonstrated that imipramine inhibited the reuptake of norepinephrine in cats. The iconic paper that summarized all of the evidence for monoamine and solidified the modulation of serotonin, norepinephrine, and dopamine in future drug development was published in 1965 by Joseph Schildkraut.⁷

Mechanism of action: stuck in the monoamine hypothesis paradigm

Despite an information explosion in our understanding of the human brain over the past 50 years, all current FDA-approved antidepressants continue to modulate some aspect of the serotonin, norepinephrine, or dopamine systems. Novel mechanisms of action have been pursued, but none successfully. Unlike in the treatment of psychotic disorders, where clozapine remains the gold standard of antipsychotic medication efficacy, no such gold standard exists for depression. Of the many choices we have, selecting the first-line antidepressant is largely a decision reached after weighing the risks and benefits of each drug with each patient’s presenting symptoms, functional impairment, lethality, past treatment history, preferences, comorbid psychiatric and medical conditions, motivation, and willingness to participate in other effective treatments such as cognitive behavioral or interpersonal psychotherapy (see Table 1).

Taking these patient-specific factors into consideration, a solid understanding of the wide-ranging pharmacokinetic and pharmacodynamic properties of each antidepressant can help inform antidepressant choice. There are basic mechanisms, pathways, and structures that are similar to each of the 3 monoamines targeted. As the MAOIs have shown, elevation of neuronal concentrations of serotonin, norepinephrine, and/or dopamine provides a robust antidepressant response.

Because of dietary restrictions and the associated serious medical complications of MAOIs, TCAs quickly became the antidepressants of choice following the FDA approval of imipramine. This was followed by the FDA approval of a large number of TCAs with variations in structure that provided a spectrum of differing binding affinities to the 5 TCA targets: the norepinephrine transport pump, the serotonin transport pump, the histamine-1 receptor, the cholinergic muscarinic receptor, and the alpha-1 adrenergic receptor.

Related to TCAs came the tetracyclic antidepressants, including amoxapine, maprotiline, and mirtazapine. Uniquely, mirtazapine lacks any clinically relevant monoamine reuptake inhibition; rather it is an antagonist at alpha-2 adrenergic, 5HT-2A, 5HT-2C, 5HT-3, and histamine receptors.

Although safer than MAOIs, TCAs still have a significant adverse-effect profile as well as lethality in overdose. The adverse effects of MAOIs and TCAs led to the development of novel molecules that target the same 3 monoamines. The structural modifications lessened the collateral receptor affinities that contribute to many of the burdensome and dangerous adverse effects.

Bupropion was the first and remains the only norepinephrine-dopamine reuptake inhibitor. In the US, fluoxetine was the first of many SSRIs that proved to be safe in overdose. Following the SSRIs, the SNRIs (venlafaxine, duloxetine, desvenlafaxine, and levomilnacipran) varied widely in their potencies to the serotonin and norepinephrine transport pumps.

Other novel antidepressants were developed that could target both the serotonin transport pump along with specific serotonin sub-receptors:

• Serotonin reuptake inhibition and 5HT-2A antagonism, as well as other receptors: trazodone, nefazodone

• SRI and 5HT-1A partial agonism: vilazodone

• SRI and 5HT-1A agonism; 5HT-1B partial agonism; and 5HT-1D, 5HT-3, and 5HT-7 antagonism: vortioxetine

Peer-reviewed analysis: no medication shows superiority

There is no lack of research attempting to differentiate the current armamentarium of antidepressants. Two studies provide credible conclusions about antidepressant efficacy, although both have significant limitations and biases.

The STAR*D study remains the largest prospective study in history to evaluate a series of 4 alternative treatment options in a cohort of 3671 patients with a unipolar major depressive episode, with the primary outcome of achieving remission. Patients could move along the algorithm through 4 steps, each of which had a defined menu of options including changing the monotherapy antidepressant, augmentation of the antidepressant, and changing to or adding cognitive therapy (Table 4).²

One of the most remarkable findings from the STAR*D study was that when a patient moved on to step 2 after failing to achieve remission or having poor tolerability with citalopram, he or she had an equal likelihood in step 2 to achieve remission with 3 different classes of antidepressants: bupropion SR, sertraline, or venlafaxine ER. This finding highlights the challenge of choosing which medication to change to after a patient does not respond to, or cannot tolerate, the first antidepressant. The mechanism of action did not have an impact on overall treatment response to a second antidepressant after failure to respond to the first. The likelihood of achieving symptom remission was almost the same at steps 1 and 2, but significantly lower at steps 3 and 4, despite what might have been more aggressive treatment. STAR*D has generated countless studies, many of which remain ongoing.

Cipriani and colleagues⁸ reviewed 117 randomized controlled trials (N = 25,928) from 1991 through 2007. They compared the effectiveness and tolerability of bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. Primary outcome was defined as the “proportion of patients who responded to or dropped out of the allocated treatment.” Escitalopram and sertraline had the overall best outcomes of efficacy and tolerability. Not surprisingly, many subsequent letters to the editor provided criticism and differing opinions in response to this study’s design and conclusions.

Augmentation: get by with a little help from a friend

When antidepressant monotherapy does not provide a satisfactory response to depressive symptoms, one strategy is to augment the antidepressant with another treatment modality. Options are numerous, and many are listed in Table 1. The first medication that was approved by the FDA as an augmentation agent for partial or nonresponse to antidepressant monotherapy was the atypical antipsychotic aripiprazole in 2007. Following this was the approval of quetiapine XR and an olanzapine-fluoxetine combination in 2009. In 2015, brexpiprazole was approved by the FDA as an adjunct to antidepressant monotherapy.

Although not FDA approved, many augmentation strategies and combination therapies (taking 2 antidepressants from different classes) have been used clinically for decades. These include augmentation with lithium, thyroid hormone, psychostimulants, and buspirone. In the 1980s, low doses of a TCA were slowly added to stable doses of an MAOI in patients who were partial responders, a practice that occasionally continues today. Other common antidepressant combinations include an SSRI/SNRI with bupropion, an SSRI/SNRI with a tricyclic antidepressant, and an SSRI/SNRI with nefazodone, trazodone, or mirtazapine. The clinician should be mindful of the pharmacokinetics and pharmacodynamics of the drugs, and choose combinations that have rational complementary mechanisms.

A recent review of augmenting antidepressants with nutraceuticals concluded that there is evidence of efficacy with S-adenosylmethionine (SAMe), L-methylfolate, omega-3 fatty acids, and vitamin D.9 SAMe and L-methylfolate are well established methyl-group donors in the metabolic synthesis of monoamines. The nutraceuticals do not require a prescription. St John’s wort (Hypericum perforatum) has been used for centuries to treat depression, and its mechanism of action appears to be that of a serotonin reuptake inhibitor.

Conclusion: from Coca-Cola to serotonin sub-receptor modulation

The past 100 years have been quite eventful in our understanding of depression and its treatment. However, much remains to be discovered, and it is time to move beyond the monoamine hypothesis of depression.

Part 1 of this article has provided a timeline of the progress made in the development of antidepressant medications since the early 1900s -and an overview of our current armamentarium of antidepressant medications and augmenting agents. Part 2 in the November issue will explore the pharmacokinetic and pharmacodynamic variables that differentiate antidepressants. In addition, the serotonin system is used as a model to explore medication targets to relieve depressive symptoms. Finally, an overview of antidepressants in the pipeline is provided.

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Disclosures:

Dr. Miller is Medical Director, Brain Health, Exeter, NH.

References:

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2. Nelson JC. The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry. 2006;163:1864-1866.

3. Valenstein M. Keeping our eyes on STAR*D. Am J Psychiatry. 2006;163:1484-1486.

4. Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009;66:848-856.

5. Gelenberg AJ. BTP’s 40th year. Bio Ther Psychiatry. 2016;39:48.

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7. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122:509-522.

8. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.

9. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry. 2016;173:575-587.

10. Lang UE, Beglinger C, Schweinfurth N, et al. Nutritional aspects of depression. Cell Physiol Biochem. 2015;37:1029-1043.

11. Bodnar LM, Wisner KL. Nutrition and depression: implications for improving mental health among childbearing-aged women. Biol Psychiatry. 2005;58:679-685.