Chapter 1
Introduction to Psychopharmacology
Principles of Psychopharmacology
Pharmacology
Psychiatry, perhaps uniquely in health care, operates from an established multidisciplinary
approach. The opportunity, as well as the responsibility, exists for all clinicians to be involved in
medication decisions as appropriate to their discipline. As treatment approaches in mental
health continue to evolve, it is likely that current practices will expand and demand participation
from knowledgeable therapists. From a practical standpoint, possessing fundamental
knowledge is critical in the rapidly changing field of psychopharmacology, along with the
attendant challenge of understanding emerging treatments, new applications of existing
medications, and multiple drug regimens. Additionally, medical co-morbidity in psychiatric
patients (coexisting medical illness and psychiatric disorder) mandates at least a familiarity with
psychotropics’ potential actions and interactions with various non-psychotropic therapeutic
agents. In your practice as a psychotherapist, it is not essential to become an expert in the area
of physiology, pharmacology, or biochemistry. However, it is important to become generally
familiar with a few preliminary concepts. Pharmacodynamics and pharmacokinetics of
psychotropic agents. Principles of pharmacodynamics
Pharmacodynamics is the study of how drugs interact with biological systems to produce their
effects. It encompasses the biochemical and physiological effects of drugs on the body and the
mechanisms underlying these effects. Understanding pharmacodynamics is crucial for
predicting and interpreting the actions of drugs, optimizing therapeutic outcomes, and
minimizing adverse effects.
1. Receptor Theory: Drugs act like keys that fit into specific locks (receptors) in our body. When
they fit, they can cause different effects, like turning a light on or off. The cornerstone of
pharmacodynamics, this theory proposes that drugs exert their effects by binding to specific
receptors on target cells. This binding initiates a series of biochemical events that ultimately
lead to the observed pharmacological response.
2. Drug-Receptor Interactions: Some drugs turn things on (agonists), some turn things off
(antagonists), and some can change how things work (allosteric modulators), just like keys can
open, close, or change locks. Drugs interact with receptors through various mechanisms,
including agonism, antagonism, and allosteric modulation. Agonists activate receptors,
antagonists block receptor activation, and allosteric modulators influence receptor activity
indirectly by binding to sites other than the agonist-binding site.
3. Dose-Response Relationship: The more keys you have (the higher the dose of a drug), the
stronger the effect. It's like turning up the volume on your phone—the louder it gets, the more
you hear. The relationship between the dose of a drug and its pharmacological effect is central
to pharmacodynamics. Dose-response curves depict the magnitude and intensity of the drug's
effect as a function of its concentration or dose.
4. Efficacy and Potency: Some drugs are really effective and can produce big effects (efficacy),
while others need only a tiny bit to work (potency), just like some people need a lot of coffee to
wake up, while others just need a sip. Efficacy refers to the maximum pharmacological effect a
drug can produce, irrespective of dose, while potency refers to the concentration or dose of a
drug required to produce a specific effect. Drugs with high efficacy produce maximal effects,
whereas potency reflects the drug's ability to produce effects at low concentrations.
5. Therapeutic Index: This is like a safety measure. We want the right amount of drug to work
(effective dose), but not too much that it becomes dangerous (toxic dose). The therapeutic
index (TI) quantifies the margin of safety of a drug by comparing its effective dose (ED50) with
its toxic dose (TD50). A high therapeutic index indicates a wide margin of safety, whereas a low
therapeutic index suggests a narrow margin and greater risk of toxicity.
6. Drug Selectivity: Some drugs are very picky and only work on certain things in our body,
while others can affect lots of different things, like a superhero with laser vision. Selective drugs
exert their effects predominantly on specific receptors or tissues, minimizing off-target effects
and enhancing therapeutic specificity. Non-selective drugs interact with multiple receptors or
tissues, potentially leading to broader effects and increased risk of adverse reactions.
7. Desensitization and Tolerance: Sometimes our body gets used to drugs, so we need more to
get the same effect. It's like needing more and more sugar to make your tea taste sweet.
Prolonged exposure to certain drugs can lead to desensitization, whereby the responsiveness of
receptors decreases over time. Tolerance occurs when repeated drug administration results in
diminished pharmacological effects, necessitating higher doses to achieve the same response.
8. Drug-Drug Interactions: When drugs hang out together, they can sometimes change each
other's effects, like friends influencing each other. They can work together (synergistic) or cancel
each other out (antagonistic). Drugs can interact with each other through various mechanisms,
altering their pharmacokinetics or pharmacodynamics. Synergistic interactions enhance the
effects of both drugs, whereas antagonistic interactions diminish or negate the effects of one or
both drugs. Principles of pharmacokinetics
The broad definition of a drug as “any substance that brings about a change in biologic function
through its chemical actions” is helpful in understanding the relationship between the body and
administered medications. This is a fluid and interactive process, composed of two elements:
pharmacodynamics and pharmacokinetics.
Pharmacodynamics can be viewed as the drug’s effect on the body. Conversely,
pharmacokinetics can be considered the body’s effect on the drug. There are four basic
pharmacokinetic factors: absorption, distribution, biotransformation, and excretion. Every drug
will exhibit a unique kinetic profile composed of these factors.
a. Absorption Most drugs are initially, and predominantly, absorbed in the stomach or small
intestine. The degree of absorption in the digestive tract can be affected by patient- dependent
factors, such as whether the medication is taken with or without food. Further, as a drug
proceeds to its ultimate destination, it may have numerous barriers to cross, depending on the
absorption characteristics of the drug itself. For instance, in the central nervous system (CNS),
the blood-brain barrier allows passage of only certain molecules into the brain. Penetration of
medication into the CNS is restricted by a host of factors that protect the CNS from exposure to
toxins, although this barrier is not absolute or impenetrable.
b. Distribution Once a drug has been absorbed and reaches the bloodstream, it is then
distributed to various organs or sites of action throughout the body. Certain medications have
characteristic distribution patterns, which are extremely important in understanding response
to treatment. A critical example in psychiatry is the extensive depositing of tricyclic
antidepressants and antipsychotic medications in fat and muscle cells. In effect, these areas act
as reservoirs or holding tanks. In some instances, concentrations of a drug in reservoir areas will
exceed levels in the bloodstream. This explains why serum levels of antidepressants are not
absolutely indicative of total body concentration.
Case Study
Mark T. is a 32-year-old overweight man who has been prescribed the tricyclic antidepressant
nortriptyline. He was started on a small dose, which was gradually increased to 250 mg daily,
and he has been taking this dose for the past three months. While he noticed little change at
first, over the last two months he has reported clear improvement in his mood and has not
experienced any major side effects.
His physician has been monitoring his blood levels, and all results remain within the therapeutic
range. Recently, Mark learned that a friend of his is also taking nortriptyline but at a much lower
dose (125 mg daily) and is doing well. This made Mark feel that his own dose might be too high.
Without telling his physician, he reduced his dose by half for the past two weeks.
In a follow-up discussion, he was advised that:
His current 250 mg dose is still within the accepted standard range.
Blood-level monitoring shows the dose is safe and effective for him.
Lowering his medication on his own increases the risk of relapse.
It was also explained that tricyclic antidepressants are often stored in fat tissue, which can
influence the required dose for each individual. Mark was encouraged to discuss any concerns
directly with his doctor instead of adjusting the dose himself.
c. Biotransformation The body’s reaction to drugs as foreign substances results in several
processes of elimination, one being metabolism (biotransformation) and the other excretion.
Metabolism occurs primarily in the liver, via specific action of enzymes that change the original
chemical into compounds that are more easily excreted by the kidneys. Biotransformation is a
complex process. Understanding metabolic activity is crucial in medication management,
especially when medication treatment is not working adequately. When medications are
chemically altered by the process of biotransformation, the results are the production of
numerous chemical by-products, called metabolites. Some metabolites are useful and desirable,
in that they produce desired effects; for instance, the reduction of psychiatric symptoms.
Unfortunately, some metabolites affect various bodily tissues and result in undesirable side
effects. In addition, since most medications undergo significant metabolism, the risks of drug
toxicity (poisoning due to excessively high levels of a drug) must be considered whenever
metabolism is impaired. Antidepressants, antipsychotics, and anticonvulsants are all extensively
metabolized by liver enzymes. Thus, impaired liver functioning can result in abnormal
metabolism of these medications. Conversely, increased activity of liver enzymes can cause
excessive metabolism, resulting in a decreased drug level and an inadequate response to
treatment.
Case Study: David R. is a 50-year-old man whom you have seen intermittently in therapy over
the past few years. He has a long history of persistent depressive symptoms, consistent with
dysthymia, and he currently meets the criteria for major depressive disorder. In the past, both
you and his primary care physician recommended antidepressant treatment, but David
preferred to avoid “chemicals.” He has instead relied on daily walking, meditation, and support
from family to help manage his mood.
Recently, David has reported worsening insomnia, daytime fatigue, and difficulty concentrating.
His doctor also suggested that some of these issues may be linked to midlife hormonal changes
and stress, which can affect mood and sleep. Because of the increased severity of his symptoms,
David finally agreed to try antidepressant medication.
First trial: His doctor prescribed paroxetine (Paxil), 20 mg daily (starting at 10 mg). Within two
weeks, David developed intense drowsiness, dry mouth, and constipation, and discontinued the
drug.
Second trial: He was then switched to venlafaxine (Effexor) at a very low starting dose, but after
several weeks he experienced dizziness, blurred vision, and excessive sweating, and again
stopped the medication.
Third trial: Despite his frustration, David agreed to try one more option. He was started on
sertraline (Zoloft), 75 mg daily, which he has now taken for two weeks without significant side
effects. He is encouraged and feels more hopeful about continuing treatment.
Because of the side-effect pattern, you discuss the case with his physician, who suspects that
David may be a slow metabolizer for the CYP2D6 enzyme system. This could explain his
intolerance to paroxetine and venlafaxine, both of which are primarily metabolized through
CYP2D6. In contrast, his better tolerability of sertraline, which is mainly metabolized by CYP2C9
and CYP3A enzymes, supports this explanation.
Excretion
Excretion is the process by which drugs are eliminated from the body. Excretion occurs
primarily via the kidneys, although other routes include the gastrointestinal tract; the
respiratory system; and sweat, saliva, and breast milk. Adequate excretion is dependent on
effective kidney function. Disease- or drug-induced damage to the kidneys can lead to kidney
failure, resulting in a toxic accumulation of medications in the bloodstream. An important
characteristic of medications is the half-life (t½), which is defined as the amount of time
required for the serum concentration to be reduced by 50 percent. Half-life is used to determine
dosage amounts and intervals for most medications. Half-life measurements are used to
estimate the time required for a drug to reach what is called steady state. Steady state occurs
when concentrations of a medication in the bloodstream have reached a plateau so that the
amount administered is equal to the amount being eliminated. It is generally accepted that for
most drugs, steady state is attained after four half-lives; for example, if the half-life is twenty-
four hours, then steady state is usually reached in four days. It is important to remember that
reaching steady state does not always correspond to a drug’s onset of desired action. With
antidepressants, for instance, steady state will be reached long before a therapeutic effect is
noted.
Case Study
Emily S. is a twenty-six-year-old graduate student in psychology, whom you have been seeing for
the past four months at the university counseling center. She initially presented with major
depressive disorder, though she has never expressed suicidal thoughts. Emily shows personality
features of perfectionism and underlying dependency traits.
Two weeks ago, she began treatment with sertraline (Zoloft), 50 mg daily in the morning. Her
agreement to try medication came only after extensive conversations with you and the
prescribing psychiatrist, covering expected dosage range, time to onset, and possible side
effects.
In today’s session, Emily appears frustrated and insists that the medication “isn’t working.” She
challenges you with a list of questions she prepared after reading extensively on medical blogs
and forums. Based on her interpretation of what she read, she argues that the drug should
already be fully effective, and she doubts whether antidepressants work at all. She even
suggests that she might stop both therapy and medication, suspecting that treatment is “just a
psychological trick.”
Recognizing that this reaction is consistent with Emily’s personality style, you remain calm and
supportive. You acknowledge her desire to fully understand the medication and validate her
frustration with the waiting process. You gently remind her that the average onset of
antidepressant benefit is three to four weeks, and that improvement is not solely determined
by blood levels. You also point out the positive sign that she has tolerated sertraline without
significant side effects. Finally, you provide her with reliable, patient-friendly educational
resources and encourage her to continue treatment while monitoring her progress.
When medications are chemically reorganized into various metabolites, these resulting
compounds produce a variety of effects—some desirable, some undesirable. All medications,
including psychotropics, typically have five primary effects:
a. Pharmacological Effect: the desired therapeutic effect, such as antipsychotics reducing
hallucinations.
b. Side Effect: typically considered to be undesirable effects, such as constipation, dry mouth,
blurry vision, and so on. Occasionally, side effects can be used to benefit the patient; for
example, using a medication’s sedating side effect to help an anxious patient fall asleep at night.
Side effects, although generally undesirable, are by definition fairly common and predictable
and may be somewhat preventable. Side effects are generally considered extensions of the
pharmacological properties of a drug and account for 70 to 80 percent of adverse drug events.
c. Idiosyncratic Effects: extremely rare, adverse effects that is difficult to predict. They are often
specific to an individual or to certain groups of patients who share common genetic or biologic
features.
d. Allergic Reactions: some individuals have an immune response to medications, generally a
skin rash or hypersensitivity. The body may respond to the medication as if it were a foreign
substance or organism, and produce allergic symptoms. A severe type of allergic reaction, called
anaphylaxis, can include difficulty breathing, fever, and irregular heartbeat. Anaphylactic
reactions are potentially fatal, as is, for example, an allergy to penicillin.
e. Discontinuance Syndrome: response to stopping or interrupting medication treatment.
Examples are narcotic withdrawal or “cholinergic rebound” when tricyclic antidepressants or
antipsychotics are abruptly stopped.
Drug Interactions: Basic pharmacologic principles apply as much to drug interactions as to drug
actions. Each kinetic property i.e., absorption, distribution, metabolism (biotransformation), and
excretion—is potentially affected by the presence of co-administered medications. Drug
interactions involving metabolism are of particular clinical significance. Drug interactions follow
a variable time-course pattern, from immediate to delayed. Consequently, it is important to
remember that several weeks may elapse before the effects of an interactive combination are
evident. And the co-morbidity of medical and psychiatric disorders requires at least some
degree of multiple drug prescribing. For example, many patients suffering from serious physical
disorders as well as depression will require medication treatment for both conditions. Examples
include diabetes mellitus, cancer, and cardiovascular disease. Familiarity with drug interactions
can be an important addition to diagnostic skills. This interaction occurs when two drugs rely on
the same enzyme system for metabolism. In this “competition,” one drug usually wins over the
other and is preferentially and completely metabolized. Conversely, metabolism of the other
drug is inhibited, leading to an increased serum level. This increase can at times produce greater
effectiveness than anticipated from a given dose, or it can produce serious adverse effects, such
as toxicity.
Case Study: Meli is a 68-year-old woman who is receiving treatment for her first episode of
major depressive disorder. Her husband passed away suddenly about a year ago, and she has
struggled to “adjust” to living alone. She reports poor appetite, disturbed sleep, frequent
tearfulness, and loss of interest in daily activities.
She began treatment with fluoxetine 10 mg daily one week ago, with plans to increase the dose
to 20 mg daily tomorrow. This is her first psychiatric treatment. Meli also has a history of
hypertension, well managed for years with atenolol (a beta-blocker).
During a therapy session this week, she appeared tired and complained of shortness of breath
and dizziness. At home that morning, her blood pressure reading was 95/58 mmHg. She asked
whether her new antidepressant could be causing these problems. You advised her to see her
physician immediately and arranged an appointment for the same day.
Later, her doctor informed you that Meli’s blood pressure and heart rate were dangerously low,
likely due to a drug interaction between fluoxetine and atenolol, which increased the effect of
the latter. The physician switched her antidepressant to citalopram (Celexa), which she tolerated
without difficulty.
This case illustrates how psychiatric patients particularly older adults are often at risk of
complications from multiple medications.
People with clinical syndromes that include associated physical symptoms, such as anxiety
disorders and depression, are often initially treated by a nonpsychiatric prescriber. The
medications prescribed can include gastrointestinal agents, anti-hypertensives, and sedative-
hypnotics. Subsequent referral to a psychiatrist may result in the addition of a psychotropic
medication. Thus, the psychotherapist may ultimately inherit this patient with the attendant
possibilities of drug interactions. The presentation of this material does not suggest that
psychotherapists are responsible for identifying and monitoring drug interactions. That is a job
best left to physicians and pharmacists. However, in certain cases the effects of interactive drugs
will be evident in therapy. For example, when a previously good medication response has
declined, or when the intensity of side effects is inconsistent with dosage, ruling out drug
interactions is helpful. Also, psychotherapists often have more complete information about a
client’s treatment than do individual physicians, each of whom may be independently
prescribing potentially interactive medications. In these situations, it is the psychotherapist who
often sounds the initial warning.