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Antidepressants, Part 2: Kinetics, Dynamics, Mechanisms of Action, and the Future: Page 2 of 5

Antidepressants, Part 2: Kinetics, Dynamics, Mechanisms of Action, and the Future: Page 2 of 5

John J. Miller, MDJohn J. Miller, MD
Suggested variables included in an analysis before making a treatment decisionTable 1 – Suggested variables to be included in an analysis before mak...
Important pharmacokinetic properties to consider about any medicationsTable 2 – Important pharmacokinetic properties to consider about any m...
Important pharmacodynamic properties to consider about any medicationTable 3 – Important pharmacodynamicproperties to consider about any me...
The various elements of the serotonin systemTable 4 – The various elements of the serotonin system

In this 2-part series, the origins of antidepressants in the early 1900s and the discoveries that led to FDA approval of the first antidepressant in 1958 were reviewed in Part 1 (Psychiatric Times, October 2017). The development of the monoamine hypothesis of depression, our current FDA-approved armamentarium, and antidepressant augmentation strategies as well as the first FDA approval of an augmenting agent in 2007 were discussed.

Part 2 explores the significant pharmacokinetic and pharmacodynamic heterogeneity of current antidepressants and provides a review of the many potential drug targets that exist—with a focus on the serotonin system as we now understand it. Part 2 concludes with an overview of antidepressant drug development that is currently underway to hopefully provide novel agents.

Pharmacokinetics and pharmacodynamics: variety is the spice of life

No single antidepressant is considered superior. As such, choosing which antidepressant to prescribe to a patient is the result of a thoughtful analysis that includes many factors, both pharmacokinetic and pharmacodynamic. The analysis follows a careful history (Table 1). In addition, the patient’s understanding of depression as a psychiatric disorder that may improve with antidepressant treatment, his or her opinion about the use of antidepressant medication, ability to comply with a structured medication regimen, and competent understanding of the risk-to-benefit ratio of antidepressant treatment must be considered.

The criteria for a major depressive episode include both insomnia and hypersomnia, psychomotor retardation and agitation, decreased and increased appetite, and weight gain and loss. Hence, the specific symptoms of the patient’s depressive episode can inform which antidepressant choice may best improve these symptoms and which may worsen them. A comorbid psychiatric diagnosis can inform the choice of an antidepressant, which may help symptoms of both diagnoses. Family history can provide many clues about the likelihood of medication response, as shared genetic factors can contribute to the response to a particular antidepressant.

It is vital to obtain an accurate list of all current prescription medications, along with the reason it is being prescribed, its dose, and the duration of treatment. Factoring in the potential for drug-drug interactions on the basis of pharmacokinetics and pharmacodynamics can prevent significant adverse effects and possibly life-threatening outcomes.

Herbal supplements that patients often forget to list can have a major effect on a drug. One example is St John’s wort, which is a serotonin reuptake inhibitor and also a potent inducer of cytochrome P450 (CYP450) 3A4—the most common metabolic pathway of all prescription drugs. St John’s wort can dramatically lower the serum level of a medication that is metabolized by CYP450 3A4, which renders it less effective and possibly ineffective. Moreover, the use of an antidepressant that also has activity as a serotonin reuptake inhibitor can increase the risk of serotonin syndrome.

Many recreational drugs can contribute to antidepressant failure. Not uncommonly, use of the recreational drug may significantly contribute to the patient’s presenting symptoms. Alcohol use disorder can result in significant depression and anxiety. Excess caffeine intake can contribute to insomnia and psychomotor hyperactivity. Cigarette smoking (the smoke, not nicotine itself) results in significant induction of CYP450 1A2 levels, which will hypermetabolize any drug that utilizes this pathway. Methadone can cause depression and weight gain. Cocaine withdrawal can mimic a major depressive episode. These are just a few common examples.

If a patient has a history of nonadherence or poor adherence to treatment, consideration should be given to the use of a drug with a long half-life. Alternatively, recruiting a partner, friend, or family member to monitor medication adherence can have a huge impact on treatment effectiveness. Assessing the patient’s capacity to manage the medication regimen is also important. A person with psychomotor retardation, poor motivation, or cognitive impairment is less likely to successfully comply with treatment. Finally, a patient’s access to a particular treatment needs to be considered. Lack of health insurance, lack of medication coverage, rigid formularies, and geographical isolation can create barriers to access of medications. Tables 2 and 3 list pharmacokinetic and pharmacodynamic issues that need to be considered when choosing an antidepressant.

The more we learn, the less we know

In the early days of antidepressants, the 3 monoamines that helped transform our understanding of depression—serotonin, dopamine, and norepinephrine—created the hypothesis that changes in the brain levels of these neurotransmitters could treat depression. The importance of these 3 monoamines gained greater momentum in our understanding of mental illness as our medication armamentarium grew.

With the antipsychotic efficacy of chlorpromazine, it was discovered that too much dopamine in one part of the brain (mesolimbic tract) seemed to be related to psychosis and mania. Too much norepinephrine in another part of the brain ramped up anxiety and panic. Too little dopamine in the prefrontal cortex resulted in cognitive dysfunction and inattention. Decades of research in the basic science laboratories of universities around the world began to unravel the complexity of the monoamine story, which went far beyond a monoamine and its associated receptor communicating in a synapse of a neuron in the brain.


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