Handbook of psychiatric drug
therapy
-Labbate, Lippincot, Williams & Wilkins- ISBN 978-07-8177-486-4 –
1. Psychiatric drug Therapy
Psychotherapies: cognitive behavioral therapies or other symptom focused therapy. It has been
shown to be affective in clinical trials. The benefits of medication and psychotherapy are additive and
occasionally synergistic.
Psychotherapy makes mania worse when acute symptoms abate.
Downsides clinical trails
- No comorbidity
- Small studies
- Taking no other medications
Before initiating medications
1) The diagnosis is clear or a clear set of diagnostic hypotheses should be established, and a systematic
approach to clarifying the diagnosis should be outlined.
2) Before prescribing psychotropic medications, it is important to be aware of medical problems or drug
interactions that could (a) be responsible for the patient's psychiatric symptoms, (b) increase the
toxicity of prescribed drugs), or (c) decrease the effectiveness of the planned therapy
3) Be aware of the possibility of alcohol or drug abuse, which might confound treatment. Unless
symptoms are so severe as to demand immediate intervention, it is recommended that patients
first be detoxified from alcohol or drugs.
4) Before prescribing a psychiatric medication, it is imperative to identify target symptoms that can be
followed during the course of therapy to monitor the success of treatment. It is also important to
monitor changes in the patient's quality of life. The use of identified target symptoms and quality-
of-life assessment is especially important when the medication is being given as an empirical
trial in a patient whose diagnosis is unclear.
5) If medication was previously effective and well tolerated, it’s a reasonable judgement to use that
medication again even if newer drugs are available.
6) If there is significant doubt about diagnosis or therapy, consolation should be sought.
Administration of medication
1) Administer a full trial with adequate doses and duration of treatment. Not doing this is the main
reason for failure. If the target symptoms do not improve, there will be no need to use it again.
2) Be aware of side effects, and warn patients in advance if appropriate.
Recall that the side effects of some psychotropic agents may mimic symptoms of the disorder being treated
3) Keep regimens as simple as possible both to improve adherence and to avoid additive toxicity.
4) Engage patients in a dialog about the time course of expected improvement. Take concerns about
side effects seriously.
5) Patients who are psychotic, demented, or retarded need careful supervision.
6) Readjust the dosage of medication to determine the lowest effective dose for the particular stage of
the patient’s illness.
7) In elderly patients, it is prudent to initiate treatment with lower doses of medication. Dosage changes
should be less frequent in elderly patients because the time required for drugs to achieve steady-
state levels is often prolonged.
,8) Follow-up care includes evaluating efficacy of treatment; monitoring and managing side effects,
treatment-relevant intercurrent life events, and comorbid medical and psychiatric conditions;
obtaining and evaluating appropriate laboratory data; and, when necessary, planning changes in
the treatment regimen.
Discontinuation of medications
All too often ineffective medications are continued indefinitely
When discontinuing psychotropic medications, it is best to taper dosages slowly, which can
help prevent rebound or withdrawal symptoms. It is important to distinguish among
temporary symptom rebound; recurrence of the disorder, in which original symptoms return
long-term; and withdrawal. In general, conditions that have been chronic before
treatment, recurrent, or have emerged late in life are more likely to require long-term
maintenance treatment.
Other issues in psychopharmacology
It’s important to document the observations and side effects. It is also important for the
record to indicate that the patient understands the reason for treatment, its risks and
benefits, alternative treatments, and the risks of no treatment. If a patient isn’t competent to
make decisions the clinician should obtain permission to include family or a formal legal
mechanism.
Many of the drugs discussed in this book have not yet been approved. However, a physician is
free to choose any approved drug for non-approved indications (Off-label use).
The cost of therapeutic drugs is an important issue in treatment selection when drugs are
equally safe and effective.
2. Drugs for the treatment of psychotic disorders
Schizophrenia
Comorbid disorders: anxiety disorders, depression, untreated medical conditions (neglect) &
substance abuse -> complicate treatment & medication doesn’t treat the full syndrome
Other psychotic disorders:
- Schizophreniform disorder
- Schizoaffective disorder
- Delusional disorder (without hallucinations or language impairment)
,General comments about antipsychotics
The antipsychotic drugs are the cornerstone of treatment of schizophrenia. Chlorpromazine provided
a model for the development of a wide variety of chemically distinct compounds effective for the
psychoses, but all of these first-generation compounds had a liability for causing extrapyramidal
symptoms (EPS) by virtue of their major shared property, potent antagonism of the D2 dopamine
receptor. Newer second-generation/ atypical drugs have a reduced liability for EPS. The EPS burden
also led to use of the term neuroleptic for these older drugs because these drugs could produce
neurologic disorders that looked similar to Parkinson's disease or dystonia. In addition, long-term use
of these drugs, as is typically required in schizophrenia, posed a high risk of a permanent movement
disorder, tardive dyskinesia (TD). this change began with the reintroduction of clozapine, an older
drug with very low risk for EPS liability and the greatest efficacy in schizophrenia. Clozapine had not
been marketed because it carried approximately a 1% risk of potentially lethal agranulocytosis.
Studies that demonstrated the drug's not only very low EPS liability but also greater efficacy for
treating schizophrenia than any other antipsychotic drug led to its reintroduction. Because of the risk
of agranulocytosis, however, cumbersome and expensive weekly monitoring of white blood cell
(WBC) counts became part of any clozapine regimen. However, the benefits of clozapine have been
demonstrated to outweigh its risks for many individuals with schizophrenia who respond poorly to
other treatments. Although it is still unclear what gives clozapine its enhanced efficacy (it has
relatively low affinity for D2 receptors compared with the other older drugs, exhibits potent
antagonism of serotonin 5-HT2A receptors.
Pharmacology
The distinction between potency and efficacy is helpful to an understanding of the pharmacology of
antipsychotic drugs. Efficacy refers to the therapeutic benefits that can be achieved by a drug,
whereas potency describes the amount of the drug needed to achieve the therapeutic effect. All of
the first-generation antipsychotic drugs are equivalent in efficacy, meaning that at an optimal dosage
each of the older drugs has been found to be equally efficacious in treating psychotic disorders. A
useful generalization about the older antipsychotic drugs is that those with low potency (which
means that they must be given in higher doses) tend to be more sedating, tend to be more
anticholinergic, and tend to cause more postural hypotension than the high-potency drugs. The high-
potency drugs tend to cause more EPS. Clozapine is the only drug that has convincingly shown
greater efficacy than the older drugs. Antipsychotics are also highly lipophilic; thus, they readily cross
the blood-brain barrier and attain high concentrations in the brain. Indeed, concentrations in the
brain appear to be greater than those in blood. Traditional antipsychotic drugs are available for both
oral and parenteral use, whereas second-generation drugs until recently have only been available for
oral use. Many antipsychotic drugs are metabolized in the liver to demethylated and hydroxylated
forms. These are more water soluble than the parent compounds and thus more readily excreted by
the kidneys. The hydroxylated metabolites often are further metabolized by conjugation with
glucuronic acid. Long-acting preparations of haloperidol and fluphenazine are available in which the
active drug is esterified to a lipid side chain. These drugs have a way longer halftime that can go up to
days or even a week. Higher concentrations are associated with more toxicity and
electroencephalographic changes. Some antipsychotic drugs have so many active metabolites (e.g.,
thioridazine) that measurement to assess dose-response relationships is impractical.
Mechanism of action
The first generation of medication works more on the D2 receptor while second generation
medication seems to act more on the 5-HT2A receptor or other 5-HT receptors. This complex picture
of binding properties makes it difficult to pinpoint the mechanism of action. The EPS symptoms seem
to be related to the D2 receptor in the striatum and not the 5-HT receptor. The full therapeutic effects
of antipsychotic drugs take weeks to accrue (similar to the antidepressants) and are far slower than
the time required to block central nervous system (CNS) receptors or, in most cases, to achieve
steady-state plasma levels of the drug. Such observations suggest that the therapeutic response to
, antipsychotic drugs is a secondary or adaptive response to receptor blockade. The therapeutically
relevant delayed-onset neurobiological effects of antipsychotic drugs remain unknown but are
believed to reflect drug-activated changes in gene expression, protein synthesis, and subsequent
synaptic reorganization. However, there is clearly an early response to antipsychotics as well, and
acutely ill patient can show benefit after a few doses. Among the second-generation drugs, clozapine
and olanzapine also have substantial anticholinergic potency. As a result, these drugs can produce
side effects such as dry mouth and constipation. Postural hypotension is produced by antagonism of
α1-adrenergic receptors. Antipsychotic drugs with substantial affinity for this receptor include many
first-generation compounds, especially chlorpromazine and thioridazine. Sedation appears to result
from antagonism of several neurotransmitter receptors, including α1-adrenergic, muscarinic, and
histamine H1 receptors. The mechanism of weight gain is unknown and may be multifactorial.
Blockade of histamine H1 receptors and increases in plasma leptin or insulin levels are currently being
investigated as possible mechanisms. New-onset diabetes or worsening of existing diabetes may
occur with clozapine or olanzapine and sometimes with other antipsychotic drugs. In addition, many
antipsychotic drugs block certain calcium channels on neurons, cardiac muscle, and smooth muscle.
Long-term treatment of schizophrenia
The relapse is much less likely to occur if the patient is on drugs. There is no evidence of extra benefit
at very high doses of antipsychotic drugs, although side effects are clearly worsened. Currently, for
patients who have failed to respond to adequate doses of several antipsychotic drugs, including
atypical drugs, a trial of clozapine is indicated.
Therapeutic use
Because antipsychotic drugs can produce striking changes in the thinking, language, and behavior
(including motor behavior) of the patients who receive them, a thorough examination of physical and
mental status should be performed before initiating therapy. The latency of response of psychotic
symptoms such as delusions, hallucinations, and bizarre behavior is usually several days, with
nonspecific sedation occurring more rapidly. The full benefit in antipsychotic-responsive disorders
usually takes at least 2 to 6 weeks. Unfortunately, physicians are often impatient in treating psychoses
given the level of patient and family distress and the pressure of disruptive behavior on the inpatient
unit. Thus, premature dosage increases occur. Before switching, the clinician should be certain that
the patient is taking the drug. The switch should generally be made slowly, tapering the previous drug
while titrating the first. Some patients may have a relapse if the change happens too abruptly.
However, most switches can be accomplished in about 1 month to avoid the phenomenon of “stalled
taper.” In the treatment of any psychotic disorder, certain paradigmatic situations arise, each
requiring a distinct approach to the use of antipsychotic drugs. These include (a) acute psychoses in
which the symptoms may constitute a medical emergency, (b) long-term treatment aimed at
minimizing residual symptoms or prophylaxis of recurrent psychosis, and (c) use of antipsychotics on
an asneeded basis. When a patient with known or suspected schizophrenia develops an exacerbation
of psychotic symptoms, it is important to consider all possible causes. These include worsening
course of illness (despite medication), noncompliance with medication, a superimposed medical
disorder, a superimposed mood disorder, drug abuse, psychosocial crises, or toxic effects of the
antipsychotic drugs (especially akathisia or neuroleptic-induced catatonia). Sometimes medication
has to be used first to calm a patient down before examination can be done.
To make a diagnosis the following must be considered:
1) Clinical presentation
2) Medical history, incl. any prescription of other drug use
3) Physical examination and any relevant laboratory tests
4) Psychiatric history
5) Mental status examination
6) Baseline of premorbid functioning
