Psychiatry

III: General Principles

of Psychopharmacology
Rowalt Alibudbud, MD, DSBPP
School of Medicine
Emilio Aguinaldo College
Psychopharmacology
• Psychopharmacologic advances continue dramatically to expand the
parameters of psychiatric treatments.
• Greater understanding of how the brain functions has led to more
effective, less toxic, better-tolerated, and more specifically targeted
therapeutic agents.
• Newer drugs may lead ultimately to side effects that are not recognized
initially.
• Keeping up with the latest research findings is increasingly important as
these findings proliferate.
• A thorough understanding of the management of medication-induced side
effects is necessary.
 Drug Selection
• Psychotropics are similar in overall effectiveness for their indicated disorder
• Differ considerably in their pharmacology and in their efficacy and adverse
effects on individual patients.
• The ability of a drug to prove effective is only partially predictable and is
dependent on poorly understood patient variables
• No drug is universally effective, and no evidence indicates the unambiguous
superiority of any single agent as a treatment for any major psychiatric
disorders.
• The only exception, clozapine, is a treatment for cases of treatment-
refractory schizophrenia.
Pharmacodynamics
Receptors
• Drug actions are mediated through the effects of drug ligand
molecules on drug receptors in the body.
• Most receptors are large regulatory molecules that influence
important:
• Biochemical processes (eg, enzymes involved in glucose
metabolism) or
• Physiologic processes (eg, ion channel receptors, neurotransmitter
reuptake transporters, and ion transporters).
Receptors
• Agonist - drug-receptor binding results in activation of the receptor
• Antagonist – if inhibition results
• Reverse Agonist – if opposite effect results
• Dose-response curves – Quantitation of the effects of drug-receptor
binding as a function of dose
Therapeutic Index
• Ratio of the dose that produces toxicity to the dose
that produces a clinically desired or effective response
in a population of individuals
• Doses that produce the therapeutic effect and the
toxic effect in fifty percent of the population are
employed (ED50 and TD50 )
Mode of Action
• The mechanisms through which most psychotropic drugs produce
their therapeutic effects remain poorly understood.
• Standard explanations focus on ways that drugs alter synaptic
concentrations of dopamine, serotonin, norepinephrine, histamine,
gamma-aminobutyric acid (GABA), or acetylcholine.
Side effects
• Side effects are an unavoidable risk of medication treatment.
• Side effect considerations include the probability of its occurrence, its
impact on a patient's quality of life, its time course, and its cause.
• No side effect, no matter how common, occurs in every patient.
• Side effects can result from the same pharmacological action that is
responsible for a drug's therapeutic activity or from an unrelated
property.
Side Effects
• Somnolence • Sweating
• Gastrointestinal Disturbance • Cardiovascular disturbance such
• Movement disorders as increased QTc interval
• Sexual dysfunction • Rash
• Weight gain/loss • Idiosyncratic reactions such as
sleepwalking, binge-eating and
• Glucose changes aggressive outbursts
• Hyponatremia
• Cognitive impairment
Overdose
• Almost all of the newer agents, however, have a wide margin of safety
when taken in overdose.
• By contrast, older agents such as TCAs could be fatal.
• In cases in which suicide is a major concern, an attempt should be
made to verify that the medication is not being hoarded:
• Random pill counts
• asking a family member to dispense daily doses may be helpful
• Large quantities of medications with a low therapeutic index should be
prescribed judiciously.
Pharmacokinetics
Absorption
• Bioavailability - amount absorbed into the systemic circulation divided
by the amount of drug administered
• Determinants:
• Route
• Blood flow (IM and SQ)
• Permeability
Common
Routes
Common
Routes
Distribution of the Drug
•Determinants:
• Blood flow
• Organ size
• Solubility
• Binding of the drug
• Capillary permeability
Metabolism
• The action of many drugs (eg, sympathomimetics,
phenothiazines) is terminated before they are excreted
because they are metabolized to biologically inactive
derivatives.
• In contrast, prodrugs (eg, levodopa, minoxidil) are inactive as
administered and must be metabolized in the body to
become active.
• Many drugs are active as administered and have active
metabolites as well (eg, morphine, some benzodiazepines).
• Some drugs (eg, lithium, many others) are not modified by
the body; they continue to act until they are excreted.
Elimination
• Removal of a drug from the body occurs via a number of
routes, the most important being through the kidney into
the urine.
• Other routes include the bile, intestine, lung, or milk in
nursing mothers.
Patient related factors
• Response to medication and sensitivity to side effects are influenced
by factors related to the patient:
• Diagnosis
• Past treatment response
• Response in family members
• Concurrent psychiatric or medical disorders
Dosing
• Clinically effective dose for treatment depends on the characteristics
of the drug and patient factors, such as:
• inherited sensitivity
• Ability to metabolize a drug
• Concurrent medical disorders
• Use of concurrent medications
• History of exposure to previous medications
• Drug potency
Duration of treatment
• Factors that affect the duration of treatment:
1. nature of the disorder
2. the duration of symptoms
3. the family history
4. the extent to which the patient tolerates and benefits from the medication
• Treatment is usually divided into 3 phases:
1. the initial therapeutic trial
2. the continuation phase
3. the maintenance phase
Frequency of Follow-up
• Determined by clinical judgment.
• In severely ill patients, this might mean several times a week.
• Patients on maintenance therapy, even when stable, need
monitoring, but no consensus exists on the frequency of follow-up
therapy.
• Three months is a reasonable interval between visits, but 6 months
may be adequate after long-standing treatment.
Laboratory testing
• Laboratory testing and therapeutic blood monitoring should be based
on clinical circumstances and the drugs being used.
• For most commonly used psychotropic drugs, routine testing is not
required.
• No currently available laboratory test can confirm the diagnosis of a
mental disorder.
• Pretreatment tests are routine as part of a workup to establish
baseline values and to rule out underlying medical problems
Laboratory testing
• Common Laboratory testing requested:
• CBC
• Electrolytes
• Renal function tests
• Hepatic function tests
• Lipid profile
• Blood glucose
• Cranial imaging
• EEG
• ECG
Treatment outcome
• The goal of psychotropic treatment is to eliminate all manifestations
of disorder
• Enable the patient to regain the ability to function as well and to
enjoy life as fully as before he or she became ill.
• This degree of improvement to below the syndromal threshold is
defined as remission.
Treatment Failure
• Was the original diagnosis correct?
• Are the observed symptoms related to the original disorder, or are
they actually adverse effects of the drug treatment?
• Was the drug administered at an appropriate dosage for a sufficient
length of time?
• Did a pharmacokinetic or pharmacodynamic interaction with another
drug that the patient was taking reduce the efficacy of the newly
prescribed drug?
• Did the patient take the drug as directed?
Monotherapy vs Polypharmacy
• Use of multiple agents should be avoided if possible in the treatment
of psychiatric disorders. (APA guidelines)
• Although monotherapy represents the ideal, polypharmacy, the
simultaneous use of psychotropic medications, has been
commonplace
Combined psychotherapy and
pharmacotherapy
• Studies have demonstrated that the results of combined therapy are
superior to those of either type of therapy alone.
• When pharmacotherapy and psychotherapy are used together, the
approach should be coordinated, integrated, and synergistic.
Special populations
• Children – low volume of distribution, high metabolism
• Elderly – more sensitive to side effect, lower drug metabolism and
excretion
• Pregnant women – WOF for teratogenic drugs
• Nursing women – WOF for drugs that cross that are secreted in breast
milk
• Medically ill – WOF drugs that may complicate medical illness
• Substance abuse – WOF drug interactions
Psychiatry III: Pharmacologic
interventions for Psychotic
Disorders
Rowalt Alibudbud, MD, DSBPP
School of Medicine
Emilio Aguinaldo College
Introduction
• Chlorpromazine (Thorazine) in 1952 may be the most important
single contribution to the treatment of a psychiatric illness.
• Chlorpromazine was shown to be effective at reducing hallucinations
and delusions, as well as excitement.
• It was also noted that it caused side effects that appeared similar to
Parkinsonism.
• Antipsychotics diminish psychotic symptom expression and reduce
relapse rates.
• Approximately 70 percent of patients treated with any antipsychotic
achieve remission.
Introduction
• The drugs used to treat schizophrenia have a wide variety of
pharmacological properties, but all share the capacity to antagonize
postsynaptic dopamine receptors in the brain.
• Antipsychotics can be categorized into two main groups:
• First-generation antipsychotics or dopamine receptor antagonists
• Second-generation antipsychotics or serotonin dopamine antagonists (SDAs).
• Clozapine (Clozaril), the first effective antipsychotic with negligible
extrapyramidal side effects, was discovered in 1958
• In 1976, it was noted that clozapine was associated with a substantial
risk of agranulocytosis.
Phases of treatment
• Acute phase
• Stabilization phase
• Maintenance phase
Acute Phase
• GOAL: alleviate the most severe psychotic symptoms.
• Acute psychotic symptoms require immediate attention.
• Lasts from 4 to 8 weeks.
• Patients with akathisia can appear agitated when they experience a
subjective feeling of motor restlessness.
• If patients are receiving an agent associated with extrapyramidal side
effects, usually a first-generation antipsychotic, a trial with an
anticholinergic anti-Parkinson medication, benzodiazepine, or
propranolol (Inderal) may be helpful in making the discrimination.
Acute Phase
• Options: Antipsychotics and benzodiazepines
• With highly agitated patients, intramuscular administration produces
a more rapid effect.
• An advantage of an antipsychotic is that a single intramuscular
injection of haloperidol (Haldol), fluphenazine (Prolixin, Permitil),
olanzapine (Zyprexa), or ziprasidone (Geodon) will often result in
calming without an excess of sedation.
• WOF: sedation, postural hypotension, and extrapyramidal side effects
Acute Phase
• Benzodiazepines are also effective for agitation during acute
psychosis.
• Lorazepam (Ativan) has the advantage of reliable absorption when it
is administered either orally or intramuscularly.
• Benzodiazepines may also reduce the amount of antipsychotic that is
needed to control psychotic patients.
• Some studies suggest that a longer time between the first onset of
psychosis and the initiation of treatment is related to a worse
outcome.
Stabilization and Maintenance Phases
• In the stable or maintenance phase, the illness is in remission.
• GOALS: prevent psychotic relapse and to assist patients in improving their
level of functioning.
• Stable patients who are maintained on an antipsychotic have a much lower
relapse rate than patients who have their medications discontinued.
• 16 to 23 percent of patients receiving treatment will experience a relapse within a
year
• 53 to 72 percent will relapse without medications.
• The duration of maintenance treatment after the first episode suggest that
1 or 2 years might not be adequate.
• Multiepisode patients receive maintenance treatment for at least 5 years,
and many experts recommend pharmacotherapy on an indefinite basis.
Pharmacotherapy Concerns
• Non compliance
• Poor responders
• Side effects
• Extrapyramidal symptoms
• Tardive dyskinesia
• Others
• Health monitoring while on Antipsychotics
Non Compliance
• Noncompliance with long-term antipsychotic treatment is very high.
(40 to 50 percent of patients become noncompliant within 1 or 2
years)
• Compliance increases when long-acting medication is used. Examples:
haloperidol, fluphenazine, aripiprazole, paliperidone, risperidone,
fluphenthixol
• Advantages of Long Acting Antipsychotics:
• Clinicians know immediately when noncompliance occurs and have some
time to initiate appropriate interventions before the medication effect
dissipates
• Less day-to-day variability in blood levels, making it easier to establish a
minimum effective dose
• Patients prefer it to having to remember dosage schedules of daily oral
preparations
Poor responders
• Before considering a patient a poor responder to a particular drug, it
is important to assure that they received an adequate trial of the
medication.
• 4 - to 6-week trial on an adequate dose of an antipsychotic represents
a reasonable trial for most patients.
• Patients who demonstrate mild improvement may continue to
improve at a steady rate for 3 to 6 months.
• Helpful to confirm that the patient is receiving an adequate amount
of the drug by monitoring the plasma concentration.
Poor responders
• If proven to be a poor responder:
• Shift to another antipsychotic class (from 1st gen to 2nd gen)
• Use adjunct
• Clozapine (after 2 failed drug trials of different class)
Extra pyramidal side effects
• Tremors, Rigidity, Akinesia/Akathisia, Postural Instability
• Treatment options:
• Anticholinergic anti-parkinsonian drugs
• Propranolol (akathisia)
Tardive dyskinesia
• About 20 to 30 percent of patients on long-term treatment with a
conventional DRA will exhibit symptoms of tardive dyskinesia.
• Three to five percent of young patients receiving a DRA develop
tardive dyskinesia each year.
• The risk in elderly patients is much higher.
Tardive dyskinesia
• Recommendations:
1. Using the lowest effective dose of antipsychotic
2. Prescribing cautiously with children, elderly patients, and patients with
mood disorders
3. Examining patients on a regular basis for evidence of tardive dyskinesia
4. Considering alternatives to the antipsychotic being used and considering
dosage reduction when tardive dyskinesia is diagnosed
5. Considering a number of options if the tardive dyskinesia worsens, including
discontinuing the antipsychotic or switching to a different drug
• Clozapine has been shown to be effective in reducing severe tardive
dyskinesia or tardive dystonia.
Other Side Effects
• Sedation and postural hypotension can be important side effects for
patients who are being treated with low-potency DRAs, such as
perphenazine. (initial doses)
• Most patients develop tolerance to sedation and postural hypotension,
sedation may continue to be a problem.
• All DRAs, as well as SDAs, elevate prolactin levels, which can result in
galactorrhea and irregular menses.
• Long-term elevations in prolactin and the resultant suppression in
gonadotropin-releasing hormone can cause suppression in gonadal
hormones. (leads to abnormal libido and sexual functioning; and
osteoporosis)
Health Monitoring
• Because of the effects of the SDAs on insulin and metabolism,
psychiatrists should monitor a number of health indicators, including:
• BMI
• Fasting blood glucose
• Lipid profiles
• Patients should be weighed and their BMI calculated for every visit for
6 months after a medication chane.
The risk of clozapine
• Seizure risk reaches nearly 5 percent at doses of more than 600 mg.
• Patients who develop seizures with clozapine can usually be managed by
reducing the dose and adding an anticonvulsant, usually valproate
(Depakene).
• Myocarditis has been reported to occur in approximately 5 patients
per 100,000 patient-years.
• Other side effects with clozapine include hypersalivation, sedation,
tachycardia, weight gain, diabetes, fever, and postural hypotension.
Psychiatry III: Pharmacologic
interventions for Depressive
Disorders
Rowalt Alibudbud, MD, DSBPP
School of Medicine
Emilio Aguinaldo College
Introduction
• GOALS:
1. The patient's safety must be guaranteed
2. Complete diagnostic evaluation
3. Address not only the immediate symptoms but also the patient's
prospective well-being should be initiated.
4. Address the number and severity of stressors in patients' lives.
• Because the prognosis for each episode is good, optimism is always
warranted
• Mood disorders are chronic, however, and the psychiatrist must
educate the patient and the family about future treatment strategies.
Introduction
• The use of specific pharmacotherapy approximately doubles the
chances that a depressed patient will recover in 1 month.
• All currently available antidepressants may take up to 3 to 4 weeks to
exert significant therapeutic effects, although they may begin to show
their effects earlier.
• Choice of antidepressants is determined by:
1. Side effect profile least objectionable to a given patient's physical status
2. Temperament
3. Lifestyle
4. Previous response
Principles
• Dosage of an antidepressant should be raised to the maximum
recommended level and maintained at that level for at least 4 or 5
weeks before a drug trial is considered unsuccessful.
• When a patient does not begin to respond to appropriate dosages of
a drug after 2 or 3 weeks, clinicians may decide to obtain a plasma
concentration of the drug.
• Result may indicate either noncompliance or particularly unusual
pharmacokinetic disposition of the drug.
Duration
• Antidepressant treatment should be maintained for at least 6 months
or the length of a previous episode, whichever is greater.
• Prophylactic treatment with antidepressants is effective in reducing
the number and severity of recurrences.
• Episodes that have involved significant suicidal ideation or
impairment of psychosocial functioning may indicate that clinicians
should consider prophylactic treatment.
• When antidepressant treatment is stopped, the drug dose should be
tapered gradually over 1 to 2 weeks, depending on the half-life of the
particular compound.
Prophylaxis
• Prevention of new mood episodes is the aim of the maintenance
phase of treatment.
• Only those patients with recurrent or chronic depressions are
candidates for maintenance treatment.
Medication selection
• The available antidepressants do not differ in overall efficacy, speed of response,
or long-term effectiveness.
• They differ in their pharmacology, drug-drug interactions, short- and long-term
side effects, likelihood of discontinuation symptoms, and ease of dose
adjustment.
• Selection of the initial treatment depends on:
• Chronicity of the condition
• Course of illness
• Family history of illness and treatment response
• Symptom severity
• Concurrent general medical or other psychiatric conditions
• Prior treatment responses to other acute phase treatments
• Potential drug-drug interactions
• Patient preference
Treatment of Depressive Subtypes
• Major depressive disorder with atypical features (sometimes called
hysteriod dysphoria) – MAOIs or SSRIs or Bupropion
• Melancholic depressions – SNRI
• Seasonal winter depression – light therapy
• Major depressive episodes with psychotic features – combination of
an antidepressant and an atypical antipsychotic.
• Several studies have also shown that ECT is more effective than
pharmacotherapy.
Comorbid Disorders
• The non-mood disorder dictates the choice of treatment in comorbid
states.
• Concurrent substance abuse raises the possibility of a substance-
induced mood disorder, which must be evaluated by history or by
requiring abstinence for several weeks.
• The successful treatment of OCD associated with depressive
symptoms usually results in remission of the depression.
• When panic disorder occurs with major depression, medications with
demonstrated efficacy in both conditions are preferred
• Presence of a major depressive episode is associated with increased
morbidity or mortality of many general medical conditions
Therapeutic use of side effects
• Using Sedating antidepressants for more anxious, depressed patients
or Using Activating agents for more psychomotor-retarded patients is
not generally helpful.
• These drugs often continue their side effects in the longer run, which
can lead to patients prematurely discontinuing medication
• Use adjunctive medications combined with antidepressants to
provide more immediate symptom relief. .
Treatment failures
• Patients may not respond to a medication, because:
• they cannot tolerate the side effects
• An idiosyncratic adverse event may occur
• Clinical response is not adequate
• Wrong diagnosis has been made
• Acute phase medication trials should last 4 to 6 weeks to determine if
meaningful symptom reduction is attained.
• Approximately one half of patients require a second medication
treatment trial because the initial treatment is poorly tolerated or
ineffective.
Second line agents
• The choice between switching depends on:
1. Patient's prior treatment history
2. Degree of benefit achieved with the initial treatment
3. Patient preference
• As a rule, switching rather than augmenting is preferred after an initial
medication failure.
• Augmentation strategies are helpful with patients who have gained some
benefit from the initial treatment but who have not achieved remission
• Augmentation strategies:
1. Lithium (Eskalith)
2. Thyroid hormone
3. Bupropion (Wellbutrin)
Combined treatment
• Medication and formal psychotherapy are often combined in practice.
• Combination of pharmacotherapy and psychotherapy for chronically
depressed outpatients have shown a higher response and higher
remission rates for the combination than for either treatment used
alone.
 Psychiatry III: Pharmacologic
interventions for Bipolar-related
Disorders
Rowalt Alibudbud, MD, DSBPP
School of Medicine
Emilio Aguinaldo College
Introduction
• The pharmacological treatment of bipolar disorders is divided into:
1. Acute (mania or depression) phase
2. Maintenance phase
• Mood stabilizers are associated with unique side effect sand safety
profiles
• No one drug is predictably effective for all patients.
Acute mania
• The treatment of acute mania, or hypomania, usually is the easiest
phases of bipolar disorders to treat
• Patients with severe mania are best treated in the hospital where
aggressive dosing is possible and an adequate response can be
achieved within days or weeks.
• Adherence to treatment, however, is often a problem
• Patients with mania frequently lack insight, and refuse to take
medication.
Lithium
• Prototypical mood stabilizer
• Onset of antimanic action with lithium can be slow
• Usually supplemented in the early phases of treatment by atypical
antipsychotics, mood-stabilizing anticonvulsants, or high-potency
benzodiazepines.
• Therapeutic lithium levels are between 0.6 and 1.2 mEq/L
• Limitations:
• Unpredictable efficacy
• Problematic side effects
• Need for frequent laboratory tests
Valproate
• Surpassed lithium in use for acute mania
• Only indicated for acute mania although most experts agree it also
has prophylactic effects
• Typical dose are 750 to 2,500 mg per day
• Therapeutic blood levels between 50 and 120 µg/mL
• Rapid oral loading with 15 to 20 mg/kg of divalproex sodium from day
1 of treatment has been well tolerated and associated with a rapid
onset of response.
• Laboratory tests are required during valproate treatment
Carbamazepine and oxcarbazepine
• First-line treatment for acute mania
• Typical doses to treat acute mania range between 600 and 1,800 mg
• Therapeutic blood level is between 4 and 12 µg/mL.
• The keto congener of carbamazepine, oxcarbazepine, may possess
similar antimanic properties.
• Higher doses than those of carbamazepine are required, because 1,500 mg of
oxcarbazepine approximates 1,000 mg of carbamazepine.
Benzodiazepines
• The high-potency benzodiazepine is used in acute mania include
(clonazepam and lorazepam)
• Effective and widely used for adjunctive treatment of acute manic
agitation, insomnia, aggression, and dysphoria, and panic
• Safety and the benign side effect profile of these agents render them
ideal adjuncts to lithium, carbamazepine, or valproate.
Antipsychotics
• All of the atypical antipsychotics olanzapine, risperidone, quetiapine,
ziprasidone, and aripiprazole have demonstrated antimanic efficacy
and are FDA approved for this indication.
• ADVANTAGES: lesser liability for excitatory postsynaptic potential and
tardive dyskinesia; many do not increase prolactin.
• LIMITATIONS: insulin resistance, diabetes, hyperlipidemia,
hypercholesteremia, and cardiovascular impairment
Bipolar Depression
• Antidepressants - propensity to induce cycling, mania, or hypomania.
But, it is enhanced by a mood stabilizer in the first-line treatment for
a first or isolated episode of bipolar depression.
• Combination of olanzapine and fluoxetine (Symbyax) – effective in
treating acute bipolar depression without inducing a switch to mania
or hypomania.
• Lamotrigine, Quetiapine or low dose ziprasidone – are also effective
• Electroconvulsive therapy – for patients with intense suicidal
tendency
Other agents
• When standard treatments fail, other types of compounds may prove
effective. Such as:
• Calcium channel antagonist verapamil (Calan, Isoptin)
• Gabapentin, topiramate, zonisamide, levetiracetam, and tiagabine
Maintenance phase
• GOAL: sustained euthymia
• Preventing recurrences of mood episodes is the greatest challenge
facing the clinician.
• Sedation, cognitive impairment, tremor, weight gain, and rash are
some side effects that lead to treatment discontinuation.
• Lithium, carbamazepine, and valproic acid, alone or in combination,
are the most widely used agents in the long-term treatment
• Lamotrigine has prophylactic antidepressant and, potentially, mood-
stabilizing properties.
Maintenance phase
• Thyroid supplementation is frequently necessary during long-term
treatment.
• Many patients treated with lithium develop hypothyroidism
• Many patients with bipolar disorder have idiopathic thyroid dysfunction.
• T3 (25 to 50 µg per day), because of its short half-life, is often recommended
for acute augmentation strategies
• T4 is frequently used for long-term maintenance. In some centers,
hypermetabolic doses of thyroid hormone are used.