Psychopharmacology

Until the late 1940s, patients with serious psychiatric illnesses had few treatment options. They might have received insulin shock therapy, electroconvulsive therapy (without anesthesia), or barbiturate or narcotic sedation. They almost certainly were confined for the tenure of their illness to a secure institution where they may have been kept in physical restraints.
In the 1950s, the treatment of psychiatric patients changed dramatically. With the discovery of medications to treat specific symptoms of psychiatric illness, the most florid and debilitating symptoms of psychotic and mood disorders could now be controlled. For this reason, as well as for economic and humanitarian concerns, attitudes toward the treatment of the mentally ill also changed at that time. The focus of therapeutic intervention shifted from long-term institutionalization to outpatient treatment and support in the form of day-care programs and partial-care centers.
The mechanisms by which biological therapies such as psychopharmacologic agents and electroconvulsive therapy (ECT) work is not completely clear. Studies suggest that these treatments work primarily by regulating abnormal concentrations of synaptic neurotransmitters that are believed to play a role in the production of psychiatric symptoms .

TABLE : Putative Mode of Action of Psychopharmacologic Agents on Psychiatric Symptoms

MAJOR TARGET SYMPTOM
CATEGORY OF AGENT
MAJOR PUTATIVE MODES OF ACTION

Psychosis

Antipsychotics
Block postsynaptic dopamine-2 (D2) and serotonin 2A (5-HT2A) receptors inhibiting the hyperactivity of dopamine and serotonin

Depression

Antidepressants
Downregulate postsynaptic β-noradrenergic and serotonin receptors over a 3-6 week period by increasing synaptic norepinephrine and serotonin concentrations via inhibition of reuptake mechanisms or blockade of monoamine oxidase activity

Mania

Lithium
Modifies second messenger signal transduction, stabilizes neuronal membranes, augments the function of serotonin, and corrects desynchronization in circadian rhythms


Anxiety
Benzodiazepines
Activate binding sites on the GABAA receptor, causing an influx of chloride leading to hyperpolarization of the neuronal membrane and decreased neuronal firing

Antipsychotic Agents

Antipsychotic agents (formerly called neuroleptics or major tranquilizers) are used to treat psychotic symptoms associated with schizophrenia and other psychiatric and physical disorders. They can also relieve symptoms such as anxiety and agitation resulting from medical and psychiatric conditions. long-acting injectable depot forms, such as haloperidol decanoate or fluphenazine decanoate, administered intramuscularly every 2 to 4 weeks, can be used to treat noncompliant patients.. Drug interactions can occur between antipsychotics and commonly used medications such as antihypertensives, anticholinergics, antidepressants, centralnervous system depressants, antacids, nicotine, epinephrine, propranolol, and warfarin. Antipsychotic agents are classified as traditional or atypical depending on their neurological action and side effect profiles.
Traditional antipsychotics
Hyperactivity of dopamine in the mesolimbic tract is associated with production of positive psychotic symptoms . Traditional antipsychotic agents act primarily by blocking central dopamine-2 (D2) receptors on postsynaptic neurons, an action that is believed to inhibit the activity of dopamine along this tract. Thus, although negative symptoms of schizophrenia, such as withdrawal, may improve with continued treatment, traditional antipsychotic agents are most effective against positive symptoms such as hallucinations and delusions .

Traditional Antipsychotic Agents

AGENT
ORAL DOSE (MG/DAY)
CLINICAL USES IN ADDITION TO PSYCHOTIC DISORDERS

Traditional Low-Potency Agents

Chlorpromazine (Thorazine)
100-800
Nausea and vomiting
Hiccups


Thioridazine (Mellaril)
200-600
Depression with intense anxiety or agitation

Traditional High-Potency Agents

Haloperidol (Haldol)
2-20
Psychosis secondary to organic syndromes, Tourette's disorder, and Huntington's disease
Available in long-acting decanoate form

Fluphenazine (Prolixin)

2-15
Available in long-acting decanoate form

Trifluoperazine (Stelazine)

4-20
Nonpsychotic anxiety (may be used for up to 12 weeks)

Perphenazine (Trilafon)

8-64
Nausea and vomiting


Pimozide (Orap)
1-10
Tourette's disorder
Body dysmorphic disorder
Adjuvant to SSRIs in obsessive compulsive disorder

Adverse effects

SYSTEM
ADVERSE EFFECTS

Circulatory

Orthostatic (postural) hypotension (most common with chlorpromazine)
Electrocardiogram abnormalities (prolongation of QT and PR intervals)
Thioridazine is most cardiotoxic in overdose

Endocrine

Increase in prolactin level results in gynecomastia (breast enlargement), galactorrhea, erectile dysfunction, amenorrhea, and decreased libido

Hematologic

Leukopenia; agranulocytosis (decreased number of certain white blood cells, particularly polymorphonuclear leukocytes)
Usually occur in the first 3 months of treatment


Hepatic
Jaundice; elevated liver enzyme levels
Usually occur in the first month of treatment
More common with chlorpromazine

Dermatologic

Skin eruptions, photosensitivity, and blue-gray skin discoloration
More common with chlorpromazine

Ophthalmologic

Irreversible retinal pigmentation with thioridazine
Deposits in lens and cornea with chlorpromazine

Anticholinergic

Peripheral effects: dry mouth, constipation, urinary retention, and blurred vision
Central effects: agitation and disorientation

Antihistaminergic

Weight gain and sedation
Chlorpromazine is most sedating


Neurological Adverse Effects of Antipsychotic Agents (More Common With Traditional, High-Potency Agents)

EFFECT

ADVERSE DESCRIPTION
OCCURRENCE
TREATMENT (IN ORDER OF HIGH TO LOW UTILITY)

Pseudo parkinsonism

Muscle rigidity
Slowed movement (bradykinesia)
Shuffling gait
Resting tremor
Mask-like facial expression
Cogwheel rigidity
Drooling
Develops within a few weeks of treatment
More common in women over age 40 years
Anticholinergic agent [e.g., benztropine (Cogentin)]
Propranolol Amantadine (Symmetrel)
Benzodiazepine
Reduce dose of medication


Akathisia
Subjective feeling of motor restlessness
Inability to remain still
Pacing
Rocking
Develops within 1€“6 weeks of treatment
Antihistaminergic agent (e.g., diphenhydramine [Benadryl])
Propranolol
Benzodiazepine
Anticholinergic agent
Reduce dose of medication

Acute dystonia

Prolonged muscular spasms of the neck (torticollis), eyelids (blepharospasm), pharynx (glossopharyngeal dystonia), eyes (oculogyric crisis), jaw, tongue or whole body (opisthotonus)
Develops within a few hours of treatment
More common in men under age 40 years
Benzodiazepine dystonia administered intramuscularly
Anticholinergic or antihistamine

Neuroleptic malignant syndrome

High fever (hyperpyrexia)
Sweating (diaphoresis)
Increased pulse and blood pressure
Dystonia
Apathy
Decreased gesturing (akinesia)
Agitation
Develops early in treatment
More common in men
Lasts up to 2 weeks
Mortality rate about 20%
Stop agent
Provide medical support
Dantrolene (Dantrium)
Bromocriptine (Parlodel)


Tardive dyskinesia (TD)
Abnormal writhing movements of the tongue, face, and body
Develops after at least 6 months of treatment
More common in women
Substitute low-potency or atypical antipsychotic agent
Tetrabenzene (a central amine depleting agent which is not yet approved for TD)

Atypical antipsychotics

Atypical antipsychotic agents include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify) . In contrast to traditional agents, a major mechanism of action of atypical agents appears to be on serotonergic systems, particularly as antagonists of serotonin type 2A (5-HT2A) receptors. They also act on dopaminergic and noradrenergic systems .
Like traditional agents, atypical antipsychotics are effective against the positive symptoms of schizophrenia. However, they may be more effective than traditional agents against the negative, chronic, and refractory symptoms of this disorder . Improvement in both positive and negative symptoms results from the ability of these agents to not only block dopaminergic activity in the mesolimbic tract like traditional agents, but to increase dopaminergic activity in the mesocortical tract .
Compared with traditional agents, atypical agents are less likely to cause extrapyramidal symptoms , tardive dyskinesia, and neuroleptic malignant syndrome. Atypical agents can also decrease the risk of relapse in clinically stable patients with schizophrenia or schizoaffective disorder . Because of these advantages, atypical agents such as risperidone and olanzapine are being used more frequently as first-line agents in treating psychotic symptoms.
Disadvantages of atypical agents (clozapine in particular) include increased likelihood of hematologic problems such as agranulocytosis. This disorder, characterized by white blood count under 2,000 or granulocyte count less than 1,000, can lead to life-threatening infections that typically present with pharyngitis and high fever. To identify the disorder early, patients who take clozapine must be monitored with weekly blood tests for the first 6 months of treatment, and every other week after that. Atypical agents also increase the risk of seizures, anticholinergic effects and pancreatitis. Weight gain is also problematic,clozapine and olanzapine cause the most weight gain, and ziprasidone causes the least. The tendency to cause weight gain may be linked to the propensity of some atypical agents to induce or exacerbate type 2 diabetes.
Antidepressant Agents
At the beginning of the 21st century, more than 7 million Americans were taking antidepressant agents, making this group the second largest selling class (with cardiovascular agents first) of prescription drug in the United States. The antidepressants include heterocyclic antidepressants (HCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), and atypical agents. All antidepressants are believed to increase the availability of neurotransmitters in the synapse via inhibition of reuptake mechanisms (HCAs, SSRIs, SSNRIs) or blockade of MAO (MAOIs), which ultimately leads to down-regulation of post-synaptic receptors and improvement in mood. Besides treating depression, antidepressants have other clinical uses in medicine and psychiatry
All antidepressants take approximately 3 to 6 weeks to work and all have about equal efficacy in relieving depression. In part because they do not elevate mood in nondepressed people, antidepressants have no abuse potential. However, these agents can be dangerous in overdose (particularly HCAs and MAOIs) and can precipitate manic episodes (particularly tricyclic HCAs) in potentially bipolar patients. Although HCAs were once the mainstay of treatment for depression, SSRIs such as fluoxetine (Prozac), SSNRIs such as venlafaxine (Effexor), and atypical agents such as bupropion (Wellbutrin) are now used as first-line agents because of their more positive side-effect profiles
Antidepressants that target other neurotransmitter systems (e.g., agents that block substance P, which is believed to be involved in physical and emotional pain) are in development

Antidepressant Agents

AGENT (CURRENT OR FORMER BRAND NAME)
ORAL DOSE (MG/DAY)
EFFECTS
CLINICAL USES IN ADDITION TO DEPRESSION


HETEROCYCLIC AGENTS (HCAS)

Desipramine (Norpramin, Pertofrane)

75-300
20 tricyclic
Least sedating
Least anticholinergic
Most potent norepinephrine reuptake inhibitor
Stimulates appetite
Depression in the elderly
Eating disorders

Nortriptyline (Aventyl, Pamelor)

50-150
20 tricyclic
Unlikely to cause orthostatic hypotension
Depression in the elderly
Depression in patients with cardiac disease
Pruritus (itching)

Amitriptyline (Elavil)

75-300
30 tricyclic
Most sedating and anticholinergic of HCAs
Depression with insomnia
Chronic pain
Migraine prophylaxis
Enuresis


Clomipramine (Anafranil)
100-250
30 tricyclic
Most serotonin-specific of the HCAs
OCD
Panic disorder

Doxepin (Adapin, Sinequan)

150-300
30 tricyclic
Sedating
Antihistaminergic
Anticholinergic
GAD
Peptic ulcer disease
Pruritus

Imipramine (Tofranil)

150-300
30 tricyclic
Likely to cause orthostatic hypotension
Panic disorder with agoraphobia
Enuresis
Eating disorders


Maprotiline (Ludiomil)
150-225
Tetracyclic
Low cardiotoxicity
May cause seizures
Anxiety with depressive features

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)

Citalopram (Celexa)
20-60
May be more dangerous in overdose than other SSRIs (cardiac conduction problems)
Low cytochrome P450 effects
OCD (all SSRIs)
Premenstrual dysphoric disorder (fluoxetine [Sarafem], sertraline)
Premature ejaculation (fluoxetine)
Hypochondriasis (fluoxetine)
Social phobia (paroxetine)
Chronic pain (paroxetine)
PTSD (sertraline)
Panic disorder (all SSRIs except citalopram)
Paraphilias (all SSRIs Prozac except citalopram)
Depression in children (fluoxetine, sertraline)


Escitalopram (Lexapro)
10-20
Isomer of citalopram
Most serotonin-specific of the SSRIs
Low cytochrome P450 effects
Fewer side effects than citalopram

Fluoxetine (Prozac, Sarafem, Weekly)

20-80 (Prozac)20-60 (Sarafem)90 (Prozac Weekly)
Initial agitation and insomnia
Sexual dysfunction

Paroxetine (Paxil, Paxil CR [long-acting form])

20-60
Most sedating SSRI
Potent serotonin reuptake inhibition
Most anticholinergic SSRI
Shorter half-life than other SSRIs (must be tapered off more slowly)
Sexual dysfunction

Sertraline (Zoloft)

50-200
Most likely of the SSRIs to cause gastrointestinal disturbances (e.g., diarrhea)
Sexual dysfunction


Fluvoxamine (Luvox)
100-300
Currently indicated only for OCD

OTHER ANTIDEPRESSANTS

Amoxapine (Asendin)
200-400
Antidopaminergic effects such as
Parkinsonian symptoms, galactorrhea, and sexual dysfunction
Most dangerous in overdose
Depression with psychotic features

Bupropion (Wellbutrin, Wellbutrin SR [sustained-release form], Wellbutrin XL [extended-release form], Zyban)
200-450 (Wellbutrin)200-400 (Wellbutrin SR)150-300 (Wellbutrin XL and Zyban)
Norepinephrine and dopamine reuptake inhibition
No effect on serotonin
Insomnia
Seizures
Sweating
Decreased appetite
Fewer adverse sexual effects
Refractory depression (inadequate clinical response to other agents)
Smoking cessation (Zyban)
Seasonal affective disorder
Adult ADHD
SSRI-induced sexual dysfunction


Mirtazapine (Remeron)
15-45
Stimulates release of serotonin and norepinephrine
Targets specific serotonin receptors
Fewer adverse sexual effects
More sedation
May increase appetite
Refractory depression
Insomnia

Nefazodone (Serzone)

300-600
Related to trazodone but with less sedation and priapism (persistent erection)
Dizziness
Fewer sexual side effects
Refractory depression
Depression with anxiety
Insomnia
SSRI-induced sexual dysfunction

Trazodone (Desyrel)

200-600
Sedation
Rarely, causes priapism
Hypotension
Insomnia


ADHD, attention deficit/ hyperactivity disorder; GAD, generalized anxiety disorder; OCD, obsessive-compulsive disorder; PTSD, post-traumatic stress disorder.

Mood-Stabilizing Agents

Mood stabilizers are used to prevent both the manic and depressive phases of bipolar disorder. They include lithium carbonate or citrate and anticonvulsant agents, such as carbamazepine and valproic acid. The atypical antipsychotic olanzapine is also used as a mood stabilizer.
Lithium is used to treat bipolar disorder and to increase the effectiveness of antidepressant agents in depressive illness. It is also used to help control aggressive behavior.
.
TABLE Mood Stabilizers

AGENT (BRAND NAME)

ORAL DOSE (MG/DAY)
ADVERSE EFFECTS
Clinical Uses in Addition to Mood Stabilization

Lithium (Eskalith)

900-1800 (titrated to a blood level of 0.8-1.2 mEq/L)
First trimester congenital abnormalities (especially of the cardiovascular system, e.g., Ebstein's anomaly of the tricuspid valve)
Renal dysfunction
Cardiac conduction problems
Hypothyroidism
Tremor
Gastric distress
Mild cognitive impairment
Prophylaxis for both manic and depressive episodes
Control of aggressive behavior
Enhancement of the activity of tricyclic antidepressants (at blood levels of 0.6-0.8 mEq/L)
Premenstrual dysphoric disorder
Borderline personality disorder
Bulimia nervosa
Cluster headaches


Carbamazepine (Tegretol)
400-1000 (titrated to blood level of 4-12 µg/mL)
Aplastic anemia
Agranulocytosis
Sedation
Dizziness
Ataxia
Anticonvulsant
Trigeminal neuralgia
Mixed episode and rapid cycling bipolar disorder
Impulse control disorders
Alcohol and benzodiazepine withdrawal

Oxcarbamazepine (Trileptal)

300-1200 (titrated to blood level of 4-12 µg/mL)
No blood dyscrasias
No autoinduction
Dizziness
Ataxia
Visual disturbances
Anticonvulsant
Trigeminal neuralgia
Mixed episode and rapid cycling bipolar disorder


Valproic acid (Depakene, Depakote [more slowly absorbed])
500-1500 (titrated to blood level of 50-100 µg/mL)
Gastrointestinal symptoms
Liver problems
Congenital neural tube defects
Weight gain
Alopecia
Anticonvulsant
Migraine headache
Bipolar symptoms resulting from cognitive disorders
Mixed episode and rapid cycling bipolar disorder
Impulse control disorders
Alcohol and benzodiazepine withdrawal

Olanzapine (Zyprexa)

10-20
Sedation
Weight gain
Diabetes
Bipolar disorder with psychotic features
Adjunct to SSRIs for obsessive-compulsive disorder
Refractory depression


SSRIs, selective serotonin reuptake inhibitors.

Antianxiety Agents

The antianxiety agents are also known as anxiolytics or minor tranquilizers. They include benzodiazepines, buspirone, and carbamates(eg.meprobamate). Some of these agents also have antiseizure and muscle-relaxant activity. The more sedating agents, hypnotics, are used particularly to treat insomnia

Antianxiety Agents (in Order of Duration of Action by Category)

AGENT (CURRENT OR FORMER BRAND NAME)
ORAL DOSE (MG/DAY)
ONSET OF ACTION
DURATION OF ACTION
CLINICAL USES IN ADDITION TO ANXIETY

BENZODIAZEPINES

Chlorazepate (Tranxene)
15-60
Short
Short
Adjunctive use in the management of partial seizures


Oxazepam (Serax)
30-120
Intermediate
Short
Alcohol withdrawal

Triazolam (Halcion)

0.125-0.25
Intermediate
Short
Insomnia

Alprazolam (Xanax)

0.5-6
Short
Short
Depression (adjunct to antidepressants)
Panic disorder
Social phobia
High abuse potential


Lorazepam (Ativan)
2-6
Intermediate
Intermediate
Psychotic agitation
Acute seizure control
Alcohol withdrawal

Temazepam (Restoril)

15-30
Intermediate
Intermediate
Insomnia

Chlordiazepoxide (Librium)

15-100
Short
Long
Alcohol withdrawal

Clonazepam (Klonopin)

0.5-4
Short
Long
Seizures
Mania
Social phobia
Panic disorder
Obsessive-compulsive disorder


Diazepam (Valium)
2-60
Short
Long
Muscle relaxation
Analgesia
Seizures of alcohol withdrawal

Flurazepam (Dalmane)

15-30
Short
Long
Insomnia

NONBENZODIAZEPINES

Zolpidem (Ambien)
5-10
Short
Short
Indicated only for insomnia


Zaleplon (Sonata)
10-20
Short
Short
Indicated only for insomnia

Buspirone (BuSpar)

15-60
Very long
Very long
Anxiety in the elderly
Generalized anxiety disorder
Adjunct to antidepressants for major depressive disorder and OCD
No abuse potential, sedation or withdrawal symptoms

Buspirone (BuSpar), an azaspirodecanedione, is a serotonin 5-HT1A receptor agonist that also is active at 5-HT2 and D2 receptors. Buspirone is not related to the benzodiazepines and, in contrast to them, is not associated with sedation, dependence, abuse, or withdrawal problems.
Acetylcholinesterase inhibitors (AChIs) block the enzyme that breaks down acetylcholine . This improvement in cholinergic transmission decelerates the progression of memory loss and may even result in transient improvement in memory and other cognitive function in about 25% of patients with Alzheimer's disease. The first AChI, tacrine (Cognex), caused gastrointestinal disturbances and had significant hepatic toxicity, which limited its usefulness for many patients. The newer agents donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl) cause fewer adverse side effects than tacrine.
Antihypertensive agents, including the B-blockers) such as propranolol (Inderal) and alpha 2-adrenergic receptor antagonists such as clonidine (Catapres) decrease the autonomic hyperarousal associated with some psychiatric conditions. These agents are particularly useful for treating symptoms associated with anxiety disorders and withdrawal from opiates and sedatives.They also used for treatment of ADHD and tic disorders.
electroconvulsive therapy
The primary indication for ECT is depression in major depressive or bipolar disorder. Although it is most commonly used to treat patients who are refractory to or intolerant of antidepressants, ECT may also be indicated for depressive symptoms from any cause, particularly when rapid symptom resolution is imperative because of suicide risk . Thus, ECT is a first-line treatment for suicidal, malnourished, catatonic, or psychotic agitated patients. In fact, ECT is more effective for psychotic depression than antidepressants or antipsychotics administered alone or combined.
In some patients (e.g., the elderly and pregnant women), ECT may be safer than long-term use of antidepressant agents. ECT is also useful for patients with mania, mixed manic-depressive states, schizophrenia with prominent affective symptoms, or schizoaffective disorder.
Administration
In ECT, a generalized seizure lasting 25 to 60 seconds is induced by passing an electric current through the brain. Prior to the procedure, an intravenous line is established and the patient is premedicated with a drug such as atropine to prevent bradyarrhythmias and to dry secretions. Next, the patient is given a short-acting general anesthetic such as methohexital (Brevital) and a muscle relaxant such as succinylcholine (Anectine) to prevent injury during the seizure. A bite block protects the teeth and tongue during the seizure. Because succinylcholine also paralyzes breathing muscles, 100% oxygen is administered until spontaneous respiration resumes.
Electroconvulsive therapy can be administered in at least three ways: bitemporal ECT (one electrode placed on each temple), right unilateral ECT (two electrodes placed on the nondominant hemisphere), and bifrontal ECT (one electrode placed above the end of each eyebrow).The usual ECT course is 6-8 sessions