Antidepressant pharmacology columns published by Dr. Preskorn
Published in Journal of Psychiatric Practice
(formerly the Journal of Practical Psychiatry and Behavioral Health)

Understanding the basics of antidepressant pharmacology

The columns in this section discuss basic pharmacologic principles relevant to understanding the mechanistically defined classes of antidepressants. It reviews: (a) the history of antidepressant pharmacology from a developmental perspective eight classes, (b) the meaning of selectivity and specificity, (c) the extrapolation from in vitro binding affinity to different targets to clinical action, and (d) summarizes the clinical pharmacology of antidepressants as determined by formal clinical trials.

  • Jul. 2000 -- The Relative Adverse Effect Profile of Non SSRI Antidepressants: Relationship to In Vitro Pharmacology -- This article continues the discussion of the relationship between the in vitro binding affinity and the clinical pharmacology of the various classes of antidepressants. This article reviews the adverse effect profiles of non SSRI antidepressants: bupropion, imipramine, mirtazapine, nefazodone, and venlafaxine.

  • May. 2000 -- The Adverse Effect Profiles of the Selective Serotonin Reuptake Inhibitors: Relationship to In Vitro Pharmacology - This column reviews the relationship between the in vitro binding affinity and the clinical pharmacology of the various classes of antidepressants. In addition, the column will address how it relates to the adverse effect
    profiles of the five marketed selective serotonin reuptake inhibitors (SSRIs).

  • Mar. 2000 -- Imipramine, Mirtazapine and Nefazodone: Multiple Targets - General Bucky Turgeson in the Stanley Kubrick movie, Dr. Strangelove, was mighty proud of his aerial warriors and their B?52s. This series of planes, first rolled out in the 1950s, are still being used. The longevity and value of these planes are the result of their ability to deliver so many different types of payloads to their targets.

    For similar reasons, I suspect Bucky would have loved imipramine, mirtazapine, and nefazodone. These drugs are multiple action antidepressants that are capable of affecting multiple targets at the concentrations achieved over their clinically relevant dosing range. That fact distinguishes them from the norepinephrine selective reuptake inhibitors (NSRIs) (e.g., desipramine) and from the selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline). NSRIs and SSRIs have a binding affinity for the site believed to mediate their antidepressant efficacy that is at least an order of magnitude greater than their binding affinity for other neural mechanisms of action

    This column examines the differences between the in vitro pharmacology of the multiple mechanism of action antidepressants (e.g., imipramine, mirtazapine, nefazodone) and that of the single mechanism of action antidepressants (i.e., SSRIs and NSRIs) account for the differences in their clinical pharmacology.

  • Jan. 2000 -- Bupropion: What Mechanism of Action? - This column discusses how to assess the potential relevance of in vitro binding studies to the clinical use of a drug. The series has used the various classes of antidepressants as examples to illustrate basic pharmacologic principles. In the previous columns, I have focused on antidepressants that are serotonin uptake pump inhibitors (SRIs), the selective serotonin reuptake inhibitors (SSRIs), and venlafaxine. In this column, I will discuss bupropion, which has an in vitro and clinical pharmacology substantially different from that of a serotonin uptake pump inhibitor.

  • Nov. 1999 -- Two in One: The Venlafaxine Story - This column, examines the antidepressant medication, venlafaxine, to illustrate a drug with a binding affinity that sequentially affects two different neural sites of action over its clinically relevant dosing range. Specifically this column addresses the following questions:

    • Why does the adverse effect profile of venlafaxine qualitatively change as its dose is increased, in contrast to the adverse effect profile of an SSRI?

    • Why does venlafaxine have an ascending dose?antidepressant response curve in contrast to the flat dose response curve seen with SSRIs?

    • Why are higher concentrations of venlafaxine needed to achieve antidepressant efficacy in comparison to several of the SSRIs?.

  • Sep. 1999 -- De-Spinning In Vitro Data - "Spin" refers to framing events in a way that is favorable to the person doing the "spinning." It is a term that becomes commonplace during political campaigns. Candidates running for major office have one or more "spin doctors" who specialize in putting a "positive spin" on events affecting their candidate and a "negative spin" on events affecting their opponents. While generally not a lie, "spin" may nevertheless mislead the listener.

    So what does "spin" have to do with in vitro psychopharmacology?

    Companies naturally endeavor to portray their products in the most favorable light possible. Sometimes, they can do this using compelling, straightforward data. At other times, however, they have to rely on "spin." For that reason, clinicians need to be able to critically examine the basis for promotional claims. The goal of this column and the others in this series is to present a way of critically thinking about the potential relevance of in vitro data to actual clinical use of a drug.

  • Jul. 1999 -- Defining "Is" - The inspirations for this column often come from questions posed by colleagues around the country. One frequently asked question is whether differences in the in vitro potency of medications have any physiological/clinical implications.

    This column begins to look at the answers to questions such as::

        · What is the relationship between in vitro potency and in vivo effects?
        · What does "selectivity" mean?
        · How does "selectivity" relate to modern psychiatric drug development?
        · What are the implications of such development for our understanding
           of psychiatric illnesses and their treatment?

    This column is based in part on material contained in two of my recent books and briefly reviews in vitro binding affinity and the concept of pharmacological selectivity.

  • Mar. 1999 -- Finding the Signal through the Noise: The Use of Surrogate Markers -- Surrogate markers have been used successfully in clinical trials in a number of therapeutic areas such as lipid reduction with statin drugs. This article discusses how surrogate markers might be used in psychiatric clinical trials to enhance the power and efficacy of studies by increasing the signal:noise ratio. The goals are to:

    • Better define the optimal dose (i.e., concentration) of psychiatric medications, and
    • Elucidate clinically important biological variance in the site of action of a drug.

  • Mar. 1998 -- Marooned: Only one choice - This column presents a way of conceptualizing and
    organizing available antidepressants into eight classes based on their mechanisms of action and
    illustrates how this classificatory system can help the prescriber:

    Anticipate what effects these medications will produce in a patient when
    used alone or in combination with other medications.

    Rationally move from one class of antidepressant to another in the event
    that the first one selected either did not produce an adequate response or
    aused treatment-limiting adverse effects.


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