Psychopharmacology and Other Biological Therapies



Psychopharmacology and Other Biological Therapies





I. Introduction

Since the last edition, many psychotropic medications have received approval by the U.S. Food and Drug Administration (FDA) to treat a range of psychiatric disorders. The use of terminology that classified these medicines belonging to a certain class of drugs like antipsychotic and mood stabilizers is becoming obsolete. All second-generation drugs have received approval to be used as monotherapy or adjunctive therapy in the treatment of bipolar disorder while some have also been approved for major depression, and their wider application in generalized anxiety disorder (GAD) is on the horizon. This is a fundamental shift in psychiatric thinking and conceptualization, and hence, it is preferable to think of drugs in terms of their pharmacological actions rather than their therapeutic indications, which often change and overlap. This wider application is, however, mostly restricted to serotonin–dopamine antagonists (SDAs), and hence in this chapter, the drugs are grouped in an outline format according to their primary therapeutic indications: anxiolytics and hypnotics, antipsychotics, antidepressants, antimanics and mood stabilizers, stimulants, cholinesterase inhibitors (cognitive enhancers), and other drugs.


II. Basic Principles of Psychopharmacology


A. Pharmacological actions.

Pharmacological actions are divided into two categories: pharmacokinetic and pharmacodynamic. In simple terms, pharmacokinetics describes what the body does to the drug and pharmacodynamics describes what the drug does to the body. Pharmacokinetic data trace the absorption, distribution, metabolism, and excretion of a drug in the body. Pharmacodynamic data measure the effects of a drug on cells in the brain and other tissues of the body.



  • 1. Pharmacokinetics



    • Absorption. Orally administered drugs dissolve in the fluid of the gastrointestinal (GI) tract and then reach the brain through the bloodstream. Some drugs are available in depot preparations, which are injected intramuscularly (IM) once every 1 to 4 weeks. Intravenous (IV) administration is the quickest route for achieving therapeutic blood concentrations, but it also carries the highest risk for sudden and life-threatening adverse effects. Few drugs, however, are given in IV form.


    • Distribution and bioavailability. Drugs that circulate bound to plasma proteins are protein-bound, and those that circulate unbound are said to be free. Only the free fraction can pass through the blood–brain barrier. The distribution of a drug to the brain is promoted
      by high rates of cerebral blood flow, lipid solubility, and receptor affinity.

      Bioavailability refers to the fraction of administered drug that can eventually be recovered from the bloodstream.








      Table 30-1 Representative Psychotropic Drug Substrates of Human Cytochromes P450, Along with Representative Inhibitors




































































































      CYP 3A CYP 2D6 CYP 2C19
      Substrates Substrates Substrates
         Triazolam (Halcion)    Desipramine (Norpramin)    Diazepama
         Alprazolam (Xanax)    Nortriptyline (Aventyl)    Amitriptylinea
         Midazolam (Versed)    Paroxetine (Paxil)    Citaloprama
         Quetiapine (Seroquel)    Venlafaxine (Effexor) Inhibitors
         Nefazodone (Serzone)    Tramadol (Ultram)    Fluvoxamine
         Buspirone (BuSpar)    Fluoxetinea (Prozac)    Omeprazole (Prilosec)
         Trazodone (Desyrel)    Citaloprama  
         Zolpidema (Ambien) Inhibitors  
         Amitriptylinea (Endep)    Quinidine (Cardioquin)  
         Imipraminea (Tofranil)    Fluoxetine  
         Haloperidola (Haldol)    Paroxetine  
         Citaloprama (Celexa)    Bupropion (Wellbutrin)  
         Clozapinea (Clozaril)    Terbinafine (Lamisil)  
         Diazepama (Valium)    Diphenhydramine (Benadryl)  
      Inhibitors    
         Ritonavir (Norvir)    
         Ketoconazole (Nizoral)    
         Itraconazole (Sporanox)    
         Nefazodone    
         Fluvoxamine (Luvox)    
         Erythromycin (E-Mycin)    
         Clarithromycin (Biaxin)    
      aIndicates partial substrate.


    • Metabolism and excretion. The four metabolic routes—oxidation, reduction, hydrolysis, and conjugation—usually produce metabolites that are readily excreted. Metabolism usually yields inactive metabolites that are more polar and, therefore, more readily excreted. However, metabolism also transforms many inactive prodrugs into therapeutically active metabolites. The liver is the principal site of metabolism (Table 30-1), and bile, feces, and urine are the major routes of excretion. Psychotherapeutic drugs are also excreted in body fluids, such as sweat and saliva.



Clinical Hint

Drugs are excreted in breast milk, an important fact to be considered for mothers who want to nurse their children.

The half-life of a drug is the amount of time it takes for its plasma concentration to be reduced by half during metabolism and excretion. A greater number of daily doses are required for drugs with shorter half-lives than for drugs with longer half-lives. Drug interactions or
disease states that inhibit the metabolism of psychoactive drugs can produce toxicity.



  • d. Cytochrome P450 enzymes. Most psychotherapeutic drugs are oxidized by the hepatic cytochrome P450 (CYP) enzyme system, which is so named because it absorbs light strongly at a wavelength of 450 nm.

    The CYP enzymes are responsible for the inactivation of most psychotherapeutic drugs (see Table 30-1). Expression of the CYP genes may be induced by alcohol, by certain drugs (barbiturates, anticonvulsants), or by smoking. For example, an inducer of CYP 3A4, such as cimetidine, may increase the metabolism and decrease the plasma concentrations of a substrate of 3A4, such as alprazolam (Xanax). Administration of a CYP 2D6 inhibitor, such as fluoxetine (Prozac), may inhibit the metabolism and thus raise the plasma concentrations of CYP 2D6 substrates, including amitriptyline (Elavil).



  • 2. Pharmacodynamics. The major pharmacodynamic considerations include the molecular site of action, dose–response curve, therapeutic index, and development of tolerance, dependence, and withdrawal symptoms.



    • Molecular site of action. The molecular site of action is determined in laboratory assays and may or may not correctly identify the drug–receptor interactions responsible for a drug’s clinical effects, which are identified empirically in clinical trials.


    • Dose–response curve. The dose–response curve plots the effects of a drug against its plasma concentration. Potency refers to the ratio of drug dosage to clinical effect. For example, risperidone (Risperdal) is more potent than olanzapine (Zyprexa) because about 4 mg of risperidone is required to achieve the comparable therapeutic effect of 20 mg of olanzapine. However, because both are capable of eliciting a similar beneficial response at their respective optimal dosages, the clinical efficacies of risperidone and olanzapine are equivalent.


    • Therapeutic index. The therapeutic index is the ratio of a drug’s toxic dosage to its maximally effective dosage.



Clinical Hint

Lithium has a low therapeutic index, so close monitoring of plasma concentrations is required to avoid toxicity.



  • D. Tolerance, dependence, and withdrawal symptoms. When a person becomes less responsive to a particular drug with time, tolerance to the effects of the drug has developed. The development of tolerance can be associated with the appearance of physical dependence, which is the need to continue taking a drug to prevent the appearance of withdrawal symptoms.



III. Clinical Guidelines

Optimizing the results of psychotropic drug therapy involves consideration of the six Ds: diagnosis, drug selection, dosage, duration, discontinuation, and dialogue.


A. The six Ds



  • Diagnosis. A careful diagnostic investigation should identify specific target symptoms with which the drug response can be objectively assessed.


  • Drug selection. Factors that determine drug selection include diagnosis, past personal and family history of response to a particular agent, and the overall medical status of the patient. Certain drugs will be excluded because concurrent drug treatment of medical and other psychiatric disorders creates a risk for drug–drug interactions. Other drugs will be excluded because they have unfavorable adverse effect profiles. A choice of the ideal drug should emerge based on the clinician’s experience and preferences.

    The Drug Enforcement Administration (DEA) has classified drugs according to their potential for abuse (Table 30-2), and clinicians are advised to use caution when prescribing controlled substances.


  • Dosage. The two most common causes of failure of psychotropic drug treatment are inadequate dosing and an incomplete therapeutic trial of a drug.


  • Duration. For antipsychotic, antidepressant, and mood-stabilizing drugs, a therapeutic trial should continue for 4 to 6 weeks. In the treatment of these conditions, drug efficacy tends to improve with time, whereas drug discontinuation is frequently associated with relapses. In contrast, for most anxiolytic and stimulant drugs, the maximum therapeutic benefit is usually evident within an hour of administration.


  • Discontinuation. Many psychotropic agents are associated with a discontinuation syndrome when they are stopped. Drugs with a short half-life are most prone to causing these withdrawal symptoms, especially if they are stopped abruptly after extended use. Thus, it is important to discontinue all drugs as slowly as possible, if clinical circumstances permit.


  • Dialogue. Informing patients about likely side effects at the outset of treatment, as well as the reasons they are taking a specific drug, serves to improve treatment compliance. Clinicians should distinguish between probable or expected adverse effects and rare or unexpected adverse effects.


B. Special considerations



  • Children. Begin with a small dosage and increase until clinical effects are observed. Do not hesitate to use adult dosages in children if the dosage is effective and no adverse effects develop. Some children need higher doses because their livers metabolize drugs more quickly than adults. Special caution should be used when prescribing selective
    serotonin reuptake inhibitors (SSRIs) in children because of the risk of suicidality, which is discussed in the following text.








    Table 30-2 Characteristics of Drugs at Each Drug Enforcement Agency Level




























    DEA Control Level (Schedule) Characteristics of Drug at Each Control Level Examples of Drugs at Each Control Level
    I High abuse potential
    No accepted use in medical treatment in the United States at the present time and, therefore, not for prescription use
    Can be used for research    		 Lysergic acid diethylamide (LSD), heroin, marijuana, peyote, 3, 4-methylenedioxymethamphetamine (MDMA), methcathinone, gamma hydroxybutyrate (GHB), phencyclidine (PCP), mescaline, psilocybin, nicocodeine, nicomorphine
    II High abuse potential
    Severe physical dependence liability
    Severe psychological dependence liability
    No refills; no telephone prescriptions    		 Amphetamine, opium, morphine, codeine, hydromorphone, phenmetrazine, amobarbital, secobarbital, pentobarbital, methylphenidate, ketamine
    III Abuse potential less than levels I and II
    Moderate or low physical dependence liability
    High psychological liability
    Prescriptions must be rewritten after 6 months or five refills    		 Glutethimide, methyprylon, nalorphine, sulfonmethane, benzphetamine, phendimetrazine, chlorphentermine; compounds containing codeine, morphine, opium, hydrocodone, dihydrocodeine, naltrexone, diethylpropion, dronabinol
    IV Low abuse potential
    Limited physical dependence liability
    Limited psychological dependence
    Prescriptions must be rewritten after 6 months or five refills    		 Phenobarbital, benzodiazepines,a chloral hydrate, ethchlorvynol, ethinamate, meprobamate, paraldehyde, phentermine
    V Lowest abuse potential of all controlled substances Narcotic preparations containing limited amounts of nonnarcotic active medicinal ingredients
    a In New York State, benzodiazepines are treated as schedule II substances, which require a triplicate prescription for a maximum of 1 month’s supply.


  • The elderly. Begin treating elderly patients with a small dosage, usually approximately one-half the usual dosage. The dosage should be increased in small amounts, until either a clinical benefit is achieved or unacceptable adverse effects appear.


  • Pregnant and nursing women. Clinicians are best advised to avoid administering any drug to a woman who is pregnant (particularly during the first trimester) or nursing a child. This rule, however, occasionally needs to be broken when the mother’s psychiatric disorder is severe. It has been suggested that withdrawing a drug during pregnancy could cause a discontinuation syndrome in both mother and fetus. Most psychotropic drugs have not been linked to an increased rate of specific birth defects.


  • Medically ill persons. Medically ill persons should be treated conservatively, which means beginning with a small dosage, increasing it slowly,
    and watching for both clinical and adverse effects. If applicable, plasma drug concentrations are helpful during the treatment of these persons.


IV. Anxiolytics and Hypnotics


A. Treatment recommendations



  • Treatment of acute anxiety. Acute anxiety responds best to either oral or parenteral administration of benzodiazepines. In the presence of mania or psychosis, a benzodiazepine in combination with antipsychotics is appropriate.


  • Treatment of chronic anxiety



    • Antidepressants. SSRIs and venlafaxine (Effexor) are antidepressants that are used for the control of chronic anxiety disorders, including obsessive–compulsive disorder (OCD). All antidepressants may increase anxiety when they are started.


    • Benzodiazepines. Benzodiazepines may be used on a long-term basis for the treatment of generalized anxiety symptoms and panic disorder, but are generally used on a short-term basis.



Clinical Hint

Careful monitoring of benzodiazepine use should be done with long-term use. If the patient starts to increase the dose, tolerance and dependence should be considered.



  • c. Buspirone (BuSpar). Buspirone is approved by the FDA for the treatment of anxiety disorders, specifically GAD.


  • d. Mirtazapine (Remeron). Mirtazapine is effective for the treatment of anxiety symptoms, but its utility is limited by its marked sedative qualities and the tendency for increased appetite and weight gain.


  • e. Other treatments. Monoamine oxidase inhibitors (MAOIs) and tricyclic and tetracyclic drugs are effective in treating anxiety, but are not used as first-line agents because of side effects and safety concerns.



  • 3. Treatment of insomnia



    • Nonbenzodiazepines. The nonbenzodiazepine agents zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata) have a rapid onset of action, specifically target insomnia, lack muscle relaxant and anticonvulsant properties, are completely metabolized within 4 or 5 hours, and rarely cause withdrawal symptoms or rebound insomnia. The usual bedtime dose of each is 10 mg. Zolpidem is said to be effective for 5 hours and zaleplon for 4 hours. The usual dose for eszopiclone is 2 mg, which can be increased to 3 mg. Adverse events may include dizziness, nausea, and somnolence.


    • Benzodiazepines. Benzodiazepines shorten sleep latency and increase sleep continuity, so they are useful for the treatment of insomnia. The five benzodiazepines used primarily as hypnotics are
      flurazepam (Dalmane), temazepam (Restoril), quazepam (Doral), estazolam (ProSom), and triazolam (Halcion).

      Benzodiazepines also curtail sleep stages III and IV (deep or slow-wave sleep) and are useful for sleepwalking and night terrors, which occur in those stages of sleep. Benzodiazepines suppress disorders related to rapid eye movement (REM) sleep, most notably violent behavior during REM sleep (REM behavior disorder).


    • Trazodone (Desyrel). Low-dose trazodone, 25 to 100 mg at bedtime, is widely used to treat insomnia. It has a favorable effect on sleep architecture.


    • Quetiapine (Seroquel). This SDA is often used as an off-label medicine in a dosage of 25 to 100 mg for insomnia but may cause daytime somnolence and sedation.


    • Ramelteon (Rozerem). Ramelteon is an orally active hypnotic, and is indicated for the treatment of insomnia characterized by difficulty with sleep onset. It is a melatonin receptor agonist, with high binding affinity at the melatonin MT1 and MT2 receptors, and mimics and enhances the action of endogenous melatonin, which has been associated with maintenance of circadian sleep rhythm. The usual starting and maintenance dose is 8 mg, but some patients may need up to 16 mg.

      It is available in an 8-mg strength tablet, and the usual dose is 8 mg taken within 30 minutes of going to bed.


B. Benzodiazepine agonists and antagonists.

The benzodiazepines available for clinical use in the United States are listed in Table 30-3. They are widely prescribed, with at least 10% of the population using one of these drugs each year. They are safe, effective, and well tolerated in both short- and long-term use. The pharmacological effects of the benzodiazepines are listed in Table 30-4.



  • 1. Indications. Benzodiazepines are often used to augment the effects of antidepressant drugs during the first month of use, before the antidepressant drug has begun to exert its anxiolytic effects; they are then tapered once the antidepressant becomes effective.


  • 2. Choice of drug. The most important differences among the benzodiazepines relate to potency and elimination half-life.



    • Potency. High-potency benzodiazepines, such as alprazolam (Xanax), alprazolam XR, and clonazepam (Klonopin), are effective in suppressing panic attacks. In general, at doses needed to control panic attacks, low-potency benzodiazepines such as diazepam may produce unwanted sedation.


    • Duration of action. Diazepam (Valium) and triazolam (Halcion) are readily absorbed and have a rapid onset; chlordiazepoxide (Librium) and oxazepam (Serax) work more slowly.

      Compounds with a long half-life tend to accumulate with repeated dosing so that the risk for excessive daytime sedation, difficulties with concentration and memory, and falls is increased. Rates

      of hip fractures resulting from falls are higher in elderly persons taking long-acting drugs than in those taking more rapidly eliminated compounds. Benzodiazepines with short half-lives also have the advantage of causing less impairment with regular use. However, they appear to produce a more severe withdrawal syndrome. Drugs affecting the rate of elimination of benzodiazepines are listed in Table 30-5.








Table 30-3 Half-Lives, Doses, and Preparations of Benzodiazepine Receptor Agonists and Antagonists





















































































































































Drug Dose Equivalents Half-Life (hr) Rate of Absorption Usual Adult Dosage Dose Preparations
Agonists          
   Clonazepam 0.5 Long (metabolite, >20) Rapid 1–6 mg b.i.d. 0.5-, 1.0-, and 2.0-mg tablets
   Diazepam 5 Long (>20) (nordiazepam—long, >20) Rapid 4–40 mg b.i.d. to q.i.d. 2-, 5-, and 10-mg tablets (slow-release 15-mg capsules)
   Alprazolam 0.25 Intermediate (6–20) Medium 0.5–10 mg b.i.d. to q.i.d. 0.25-, 0.5-, 1.0-, and 2.0-mg tablets
   Lorazepam 1 Intermediate (6–20) Medium 1–6 mg t.i.d. 0.5-, 1.0-, and 2.0-mg tablets, 2 mg/mL, 4 mg/mL parenteral
   Oxazepam 15 Intermediate (6–20) Slow 30–120 mg t.i.d. or q.i.d. 10-, 15-, and 30-mg capsules (15-mg)
   Temazepam 5 Intermediate (6–20) Medium 7.5–30 mg hs 7.5-, 15-, and 30-mg capsules
   Chlordiazepoxide 10 Intermediate (6–20) (desmethylchlordiazepoxide—intermediate, 6–20) (demoxapam—long, >20) (nordiazepam—long, >20) Medium 10–150 mg t.i.d. or q.i.d. 5-, 10-, and 25-mg tablets and capsules
   Flurazepam 5 Short (<6) (N-hydroxyethylflurazepam—short, <6) (N-desalkylflurazepam—long, >20) Rapid 15–30 mg hs 15- and 30-mg capsules
   Triazolam 0.1–0.03 Short (<6) Rapid 0.125 mg or 0.250 mg hs 0.125- or 0.250-mg tablets
   Clorazepate 7.5 Short (<6) (nordiazepam—long, >20) Rapid 15–60 mg b.i.d. or q.i.d. 3.75-, 7.5-, and 15-mg tablets (slowrelease 11.25- and 22.5-mg tablets)
   Halazepam 20 Short (<6) (nordiazepam—long, >20) Medium 60–160 mg t.i.d. or q.i.d. 20- and 40-mg tablets
   Prazepam 10 Short (<6) (nordiazepam—long, >20) Slow 30 mg (20–60 mg) q.i.d. or t.i.d. 5-, 10-, or 20-mg capsules
   Estazolam 0.33 Intermediate (6–20) (4-hydroxyestazolam— intermediate, 6–20) Rapid 1.0 or 2.0 hs 1- and 2-mg tablets
   Quazepam 5 Long (>20) (2-axoquazepam-N-desalkylflurazepam—long, >20) Rapid 7.5 or 15 mg hs 7.5- and 15-mg tablets
   Midazolam 1.25–1.3 Short (<6) Rapid 5–50 mg parenteral 5 mg/mL parenteral, 1-, 2-, 5-, and 10-mL, vials
   Zolpidem 2.5 Short (<6) Rapid 5 mg or 10 mg hs 5- and 10-mg tablets
   Zaleplon 2 Short (1) Rapid 10 mg hs 5- and 10-mg capsules
Antagonist          
   Flumazenil 0.06 Short (<6) Rapid 0.2–0.5 mg/min injection over 3–10 min (total, 1–5 mg) 0.1 mg/mL (5 mL, and 10-mL vials)








Table 30-4 Pharmacological Effects of Benzodiazepines















































Effects Clinical Application/Consequences
Therapeutic effects  
   Sedative Insomnia, conscious sedation, alcohol withdrawal
   Anxiolytic Panic attacks, generalized anxiety
   Anticonvulsant Seizures
   Muscle relaxant Muscle tension, muscle spasm
   Amnestic Adjunct to chemotherapy or anesthesia
   Antistress Mild hypertension, irritable bowel syndrome, angina
Adverse effects  
   Sedative Daytime sleepiness, impaired concentration
   Amnestic Mild forgetfulness, anterograde memory impairment
   Psychomotor Accidents, falls
   Behavioral Depression, agitation
   Decreased CO2 response Worsening of sleep apnea and other obstructive pulmonary disorders
   Withdrawal syndrome Dependence—anxiety, insomnia, excess sensitivity to light, excess sensitivity to sound, tachycardia, mild systolic hypertension, tremor, headache, sweating, abdominal distress, craving, seizures








Table 30-5 Drugs Affecting the Rate of Elimination of Oxidized Benzodiazepines



































Increase Elimination Half-Life Decrease Elimination Half-Life
Cimetidine Chronic ethyl alcohol use
Propranolol Rifampin
Oral contraceptives (estrogens)  
Chloramphenicol  
Propoxyphene  
Isoniazid  
Disulfiram  
Allopurinol  
Tricyclic antidepressants  
Acute ethyl alcohol use  



  • c. Dependence and withdrawal symptoms. A major concern with long-term benzodiazepine use is the development of dependence, particularly with high-potency agents. Not only can discontinuation of benzodiazepines result in symptom recurrence and rebound, but it can also precipitate withdrawal symptoms. Several factors contribute to the development of benzodiazepine withdrawal symptoms (Table 30-6). Drug type and duration of use are the most significant
    factors, but other considerations such as personality makeup are also important.








    Table 30-6 Key Factors in the Development of Benzodiazepine Withdrawal Symptoms























    Factor Explanation
    Drug type High-potency, short half-life compounds (e.g., alprazolam, triazolam, lorazepam)
    Duration of use Risk increases with time
    Dose level Higher doses increase risk
    Rate of discontinuation Abrupt withdrawal instead of taper increases risk for severe symptoms, including seizures
    Diagnosis Panic disorder patients more prone to withdrawal symptoms
    Personality Patients with passive-dependent, histrionic, somatizing, or asthenic traits more likely to experience withdrawal



Clinical Hint

Withdrawal symptoms can mimic signs and symptoms of the underlying disorder. Do not unnecessarily continue the drug when this occurs.



  • 3. Benzodiazepine antagonist. Flumazenil (Romazicon) is a benzodiazepine antagonist used to reverse the effects of benzodiazepine receptor agonists in overdose and in clinical situations such as sedation or anesthesia. It has also been used to reverse benzodiazepine effects immediately before the administration of electroconvulsive therapy (ECT). Adverse effects include nausea, vomiting, and agitation. Flumazenil can precipitate seizures, particularly in persons who have seizure disorders, who are dependent on benzodiazepines, or who have taken large overdoses. The usual regimen is to give 0.2 mg intravenously over 30 seconds. If consciousness is not regained, an additional 0.3 mg can be given intravenously over 30 seconds. Most persons respond to a total of 1 to 3 mg. Doses larger than 3 mg are unlikely to add benefit.


V. Antipsychotic Drugs

These are classified into first-generation (conventional) antipsychotics or second-generation antipsychotics (SDAs, novel or atypical). Historically, conventional antipsychotics were efficacious for treating the positive symptoms of schizophrenia with worsening of negative, cognitive, and mood symptoms. Atypical antipsychotics have been suggested to show improvement in (1) positive symptoms such as hallucinations, delusions, disordered thoughts, and agitation, and (2) negative symptoms such as withdrawal, flat affect, anhedonia, poverty of speech, catatonia, and cognitive impairment. There has been controversy regarding the benefits of atypical antipsychotics compared to conventional antipsychotics. NIMH funded research studies like the CATIE Trial
has brought attention to the long-term metabolic complications of atypical antipsychotics and showing no significant advantages over conventional antipsychotics. Overall, atypical antipsychotic agents represent a major advance in the pharmacological treatment for schizophrenia. The clinicians are advised to determine the best course of treatment based on each individual patient, taking into account risk benefit analysis in the long-term.


A. Second-generation antipsychotic drugs (SDAs, atypical antipsychotic drugs).

The second-generation antipsychotic drugs include risperidone (Risperdal, Risperidal Consta [long acting]), olanzapine, quetiapine (Seroquel), quetiapine XR (Seroquel XR), ziprasidone (Geodon), aripiprazole (Abilify), paliperidone (Invega), asenapine (Saphris), iloperadone (Fanapt) and clozapine (Clozaril). These drugs improve three classes of disability typical of schizophrenia: (1) positive symptoms (hallucinations, delusions, disordered thoughts, agitation), (2) negative symptoms (withdrawal, flat affect, anhedonia, catatonia), and (3) cognitive impairment (perceptual distortions, memory deficits, inattentiveness). Second-generation drugs have largely replaced the typical antipsychotics (dopamine receptor antagonists) because they are associated with a lower risk of extrapyramidal symptoms and eliminate the need for anticholinergic drugs. Second-generation drugs are also effective for the treatment of bipolar disorder and mood disorders with psychotic or manic features. A few are also approved for the treatment of major depressive disorder (MDD) and will also have an indication in GAD. All of these drugs except clozapine are FDA approved for the treatment of bipolar I mania. Olanzapine is approved for bipolar I maintenance therapy. Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies are not clear as to what extent these mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Asenapine is not approved for the treatment of patients with dementia-related psychosis.



  • Pharmacological actions



    • Risperidone. About 80% of risperidone is absorbed from the GI tract, and the combined half-life of risperidone averages 20 hours so that it is effective in once-daily dosing. Risperidal Consta is given once every two weeks because of its long half life.


    • Olanzapine. Approximately 85% of olanzapine is absorbed from the GI tract, and its half-life averages 30 hours. Therefore, it is also effective in once-daily dosing.


    • Quetiapine. Quetiapine is rapidly absorbed from the GI tract. Its half-life is about 6 hours, so dosing two or three times per day is necessary. Quetiapine XR has a comparable bioavailability to equivalent dose of quetiapine administered two to three times daily. Quetiapine XR is given once daily preferably in the evening.



    • Ziprasidone. Ziprasidone is well absorbed. Its half-life is 5 to 10 hours, so twice-daily dosing is optimal.


    • Clozapine. Clozapine is absorbed from the GI tract. Its half-life is 10 to 16 hours, and it is taken twice daily.


    • Aripiprazole. Aripiprazole is well absorbed from the GI tract. It has a long half-life of about 75 hours and can be given as a single daily dose.


    • Paliperidone. Paliperidone has a peak plasma concentration of approximately 24 hours after dosing. It is available only in extended release tablets, usually prescribed at 3 mg once daily.


    • Asenapine. Asenapine is well absorbed sublingually with a half life of 24 hours. It is prescribed at a daily dose of 5 mg sublingually twice a day. Steady state is reached in three days.


    • Iloperidone. Well absorbed. Ninety-six percent bioavailability. Peak plasma level in 2 to 4 hours. Starting dose 1 mg b.i.d. Target dose is 12 to 24 mg given as 6 to 12 mg b.i.d.


  • Therapeutic indications. Second-generation drugs are effective for initial and maintenance treatment of psychosis in schizophrenia and schizoaffective disorders in both adults and adolescents. They are also effective in the acute treatment of manic or mixed episodes in bipolar disorder and for psychoses of all types—secondary to head trauma, dementia, and drug-induced psychosis. Aripiprazole (Abilify) is the first medication approved by the FDA for add-on treatment to antidepressants for adults with MDD. Other SDAs are in the process of receiving this indication and extending it to GAD as well. Second-generation drugs are effective in acutely ill and treatment-refractory persons and prevent relapses. By comparison to persons treated with dopamine receptor antagonists, persons treated with second-generation drugs require less frequent hospitalization, fewer emergency room visits, less phone contact with mental health professionals, and less treatment in day programs.

    The parenteral form of olanzapine is indicated for the treatment of acute agitation associated with schizophrenia and bipolar disorder, while ziprasidone is indicated for the treatment of agitation related to schizophrenia. Aripiprazole (Abilify) injection is indicated for the acute treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed in adults. Quetiapine (Seroquel, Seroquel XR) is indicated in the treatment of bipolar depression.



Clinical Hint

Because clozapine can cause severe agranulocytosis, it should be used only in refractory cases of schizophrenia. Clozapine provides a therapeutic niche for patients with severe tardive dyskinesias, unmanageable extrapyramidal symptoms, refractory bipolar disorder, and psychosis secondary to antiparkinsonian drugs.




  • 3. Clinical guidelines. Dosing for the second-generation drugs vary considerably. Table 30-7 summarizes the usual dosing recommendations for these agents.



    • Risperidone. Risperidone is available in 0.25-, 0.5-, 1-, 2-, 3-, and 4-mg tablets, in M-tab form (rapidly dissolving), and as an oral solution with a concentration of 1 mg/mL. The initial dosage is usually 1 to 2 mg/day, taken at night. It can then be raised gradually (by 1 mg every 2 or 3 days) to 4 to 6 mg at night. Dosages higher than 6 mg/day are associated with increased adverse effects. Dosages below 6 mg/day have generally not been associated with extrapyramidal symptoms, but dystonic and dyskinetic reactions have been seen at dosages of 4 to 16 mg/day.

      Risperidal Consta is available in dosages of 25-, 37.5- or 50-mg risperidone provided as a dose-pack and a prefilled syringe. The recommended dosage is 25 mg IM every two weeks which can be titrated upward to 50 mg if needed. Fluoxetine and paroxetine double the plasma concentration of risperidone.


    • Olanzapine. Olanzapine is available in 2.5-, 5-, 7.5-, 10-, 15- and 20-mg oral and Zydis form (orally disintegrating) tablets. The initial dosage is usually 10 to 15 mg once daily. A starting dosage of 5 mg/day is recommended for elderly and medically ill persons and for persons with hepatic impairment or hypotension. The dosage can be raised to 20 mg/day after 5 to 7 days. Dosages in clinical use range from 5 to 20 mg/day, but benefit in both schizophrenia and bipolar mania is noted in most people at dosages of 10 to 15 mg/day. The IM formulation for the treatment of agitation associated with schizophrenia and bipolar disorder is 10 mg. Coadministration with benzodiazepines is not approved. The higher dosages are occasionally associated with increased extrapyramidal and other adverse effects. Assessment of transaminases in patients with significant hepatic disease should be done periodically.


    • Quetiapine. Quetiapine is available in 25-, 100-, 200-, and 300-mg tablets. The dosage should begin at 25 mg twice daily and can be raised by 25 to 50 mg per dose every 2 to 3 days up to a target dosage of 400 to 500 mg/day, divided into two daily doses. Studies have shown efficacy in the range of 300 to 800 mg/day, with most people receiving maximum benefit at 300 to 500 mg/day. Quetiapine XR is given once daily preferably in the evening without food or a light meal to prevent increase in Cmax. The usual starting dosage is 300 mg and may be increased to 400 to 800 mg.


    • Ziprasidone. Ziprasidone is available in 20-, 40-, 60-, and 80-mg capsules. Dosing should be initiated at 40 mg/day, divided into two daily doses. Studies have shown efficacy in the range of 40 to 200 mg, divided into two daily doses; taken with meals, the absorption is increased up to twofold.









      Table 30-7 Comparison of Usual Dosinga for the Currently Available Second-Generation Antipsychotics in Schizophrenia














































































      Antipsychotic Typical Starting Dosage Maintenance Therapy Dose Range Titration Maximum Recommended Dosage
      Clozapine (tablets) 12.5 mg once or twice a day 150–300 mg/day in divided doses, or 200 mg as a single dose in the evening The dosage should be increased to 25–50 mg on the second day. Further increases may be made in daily increments of 25–50 mg to a target dose of 300–450 mg per day. Subsequent dosage increases should be made no more than once or twice weekly in increments of no more than 100 mg. 900 mg/day
      Risperidone (tablets and oral solution) 1 mg once a day 2–6 mg once a day Increase to 2 mg once a day on the second day and 4 mg once a day on the third day. In some patients, a slower titration may be appropriate. When dosage adjustments are necessary, further dosage increments of 1–2 mg/day at intervals of not less than 1 week are recommended. 16 mg/day
      Risperidone IM long acting 25–50 mg every 2 weeks Start with oral risperidone for 3 weeks Starting dose: 25 mg every 2 weeks 50 mg for 2 weeks
      Olanzapine (tablets and orally disintegrating tablets) 5–10 mg/day 10–20 mg/day Dosage increments of 5 mg once a day are recommended when required, at intervals of not less than 1 week. 20 mg/day
      Quetiapine (tablets) 25 mg twice a day Lowest dose needed to maintain remission Increase in increments of 25–50 mg two or three times a day on the second and third day, as tolerated, to a target dosage of 500 mg daily by the fourth day (given in two or three doses/day). Further dosage adjustments, if required, should be of 25–50 mg twice a day and occur at intervals of not fewer than 2 days. 800 mg/day
      Ziprasidone (capsules) 20 mg twice a day with food 20–80 mg b.i.d. Dosage adjustments based on individual clinical status may be made at intervals of not fewer than 2 days. 80 mg b.i.d.
      Ziprasidone (intramuscular) For acute agitation: 10–20 mg, as required, up to a maximum of 40 mg/day. Not applicable For acute agitation: Dosages of 10 mg may be administered every 2 hr, and dosages of 20 mg may be administered every 4 hr up to a maximum of 40 mg/day. For acute agitation: 40 mg/day, for not more than 3 consecutive days
      Aripiprazole (tablets) 10–15 mg once a day 10–30 mg/day Dosage increases should not be made before 2 weeks. 30 mg/day
      Paliperidone (extendedrelease tablets) 3–9 mg once a day 3–6 mg/day Plasma concentration rises to a peak approximately 24 hr after dosing. 12 mg/day
      Asenapine 5 mg sublingual twice a day 5 10 mg sublingual twice a day For bipolar I manic patients: dosage is started at 10 mg and decreased eventually to 5 mg twice a day. 10 mg twice a day sublingual
      Iloperidone 1 mg b.i.d. 12 24 mg in divided doses Acute schizophenia. 24 mg in divided doses
      Note: Information taken from U.S. Prescribing Information for individual agents.
      aDosage adjustments may be required in special populations.



    • Clozapine. Clozapine is available in 25- and 100-mg tablets. The initial dosage is usually 25 mg one or two times daily, although a conservative initial dosage is 12.5 mg twice daily. The dosage can then be raised gradually (by 25 mg every 2 or 3 days) to 300 mg/day, usually divided into two daily doses, with the higher dose in the evening. Dosages of up to 900 mg/day can be used, although most patients respond in the 600 mg/day range.


    • Aripiprazole. Aripiprazole is available in 2-, 5-, 10-, 15-, 20-, and 30-mg tablets. The recommended starting and target dose is 10 to 15 mg/day given once a day. Dosages higher than 10 to 15 mg/day have not shown increased efficacy in clinical trials. The recommended starting dose for aripiprazole as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The efficacy of aripiprazole as an adjunctive therapy for MDD was established within a dose range of 2 to 15 mg/day. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week. The most commonly reported dose-related adverse effect is somnolence.


    • Paliperidone. Paliperidone is available in 3-, 6-, and 9-mg extended-release tablets. The usual dose is 3 to 6 mg/day. The maximum recommended dose is 12 mg/day.


    • Asenapine. Asenapine is available in 5- and 10-mg sublingual tablets. The recommended starting dose is 5 mg twice daily except for mania when 10 mg twice daily should be used and then reduced to 5 mg after the patient is stabilized. Do not use in demented patients because of increased mortality.


    • Iloperidone. Available in 1-, 2-, 4-, 6-, 8-, 10-, 12-, and 24-mg non-scored tablets. Usual dose is 12 to 24 mg per day.


  • 4. Pretreatment evaluation. Before the initiation of treatment, an informed consent procedure should be documented. The patient’s history should include information about blood disorders, epilepsy, cardiovascular disease, hepatic and renal diseases, and drug abuse. The presence of a hepatic or renal disease necessitates the use of low starting dosages. The physical examination should include supine and standing blood pressure measurements to screen for orthostatic hypotension. The laboratory examination should include an electrocardiogram (ECG); several complete blood cell counts including white blood cell counts, which can then be averaged; and tests of hepatic and renal function.

    As second-generation drugs and SDAs have become the first-line treatment for various disorders, new controversies have arisen regarding their role in causing metabolic abnormalities (hyperglycemia, insulin resistance, and dyslipidemias). At this time, the American Psychiatric Association (APA) and American Diabetic Association (ADA) have developed a consensus guideline to help physicians monitor their
    patients. Olanzapine and clozapine have been the agents most often reported to be associated with treatment-emergent diabetes mellitus, a fact that may be linked to their propensity to cause marked weight gain.

    The prevalence of diabetes in patients with schizophrenia and bipolar disorder is thought to be two to four times that of the general population. This is further complicated by the fact that obesity is on the rise and schizophrenics have an elevated risk of premature death from numerous medical problems. Obesity poses a serious health risk, contributing to such disorders as hypertension, dyslipidemia, cardiovascular disease, non–insulin-dependent diabetes, gallbladder disease, respiratory problems, gout, and osteoarthritis. Metabolic syndrome (disturbed glucose and insulin metabolism, obesity, dyslipidemia, and hypertension) is also more prevalent in patients with schizophrenia and numerous studies have suggested causal linkage to the use of antipsychotics, particularly the second generations. There are differences among the antipsychotics in regards to the risk for weight gain and diabetes, but the FDA has recommended the following guidelines for all second-generation antipsychotics.



    • Baseline monitoring



      • Personal and family history of obesity, diabetes, dyslipidemia, hypertension, and cardiovascular disease.


      • Weight and height (so that body mass index [BMI] can be calculated).


      • Waist circumference (at the level of the umbilicus).


      • Blood pressure.


      • Fasting plasma glucose.


      • Fasting lipid profile.

      Patients with pre-existing diabetes should have regular monitoring including HgA1C and, in some cases, insulin levels. The oral glucose tolerance test (OGTT) is not recommended for routine clinical use, but it may be required in the evaluation of patients with impaired fasting glucose or when diabetes is suspected despite normal fasting plasma glucose.

      It is recommended that clinicians screen, evaluate, and monitor patients for metabolic changes irrespective of the antipsychotic class, as these patients have an increased risk of metabolic syndrome and diabetes.


  • 5. Monitoring during treatment. All patients on second-generation drugs should be routinely monitored for side effects. Although these drugs are presumed to have a lowered risk of tardive dyskinesia, some risk remains, so patients should be assessed for any movement abnormalities. According to FDA recommendations, all patients should have their blood glucose levels monitored, especially early in treatment or if weight gain occurs.


    Clozapine requires special monitoring. During treatment with clozapine, weekly white blood cell counts are indicated for the first 6 months to monitor for the development of agranulocytosis; they should be obtained every 2 weeks thereafter. Although monitoring is expensive, early detection of agranulocytosis can prevent a fatal outcome. Probably more important than screening blood cell counts is educating persons to seek immediate medical evaluation if fever or any signs of infection develop. If the white cell count is less than 2,000/mm3 or the granulocyte count is less than 1,000/mm3, clozapine should be discontinued, a hematological consultation should be obtained, and a bone marrow biopsy should be considered. Persons with agranulocytosis should not be re-exposed to the drug. Clinicians can monitor the white blood cell count through any laboratory. Proof of monitoring must be presented to the pharmacist to obtain the medication. See Table 30-8 for guidelines of clinical management of clozapine-associated hematological abnormalities.



    • Maintenance monitoring for SDAs. Patients maintained on SDAs for prolonged periods should be monitored periodically as illustrated in Table 30-9.


  • 6. Switching from and to another antipsychotic drug. The transition from a dopamine receptor antagonist to an SDA can be accomplished easily but should be done slowly. It is wise to overlap administration of the new drug with the old drug, lowering the dose of the former while raising the dose of the latter.

    Because the SDAs such as risperidone, quetiapine, asenapine, and ziprasidone lack anticholinergic effects, the abrupt transition from a dopamine receptor antagonist to one of these agents may cause cholinergic rebound, which consists of excessive salivation, nausea, vomiting, and diarrhea. The risk for cholinergic rebound can be mitigated by initially augmenting the SDA with an anticholinergic drug, which is then tapered slowly.

    With depot formulations of a dopamine receptor antagonist, the first dose of the SDA is given on the day the next injection is due. At present, the only SDA available in long-acting formulation is risperidone.


  • 7. Adverse effects



    • All second-generation drugs



      • Neuroleptic malignant syndrome. The development of neuroleptic malignant syndrome is considerably rarer with second-generation drugs than with dopamine receptor antagonists. This syndrome consists of muscular rigidity, fever, dystonia, akinesia, mutism, oscillation between obtundation and agitation, diaphoresis, dysphagia, tremor, incontinence, labile blood pressure, leukocytosis, and elevated creatine phosphokinase. Clozapine, especially if combined with lithium, and risperidone have been associated with neuroleptic malignant syndrome.









        Table 30-8 Clinical Management of Reduced White Blood Cell (WBC) Count, Leukopenia, and Agranulocytosis















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        Jun 8, 2016 | Posted by in PSYCHIATRY | Comments Off on Psychopharmacology and Other Biological Therapies

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        Problem Phase WBC Findings Clinical Findings Treatment Plan
        Reduced WBC WBC count reveals a significant drop (even if WBC count is still in normal range). “Significant Drop” = 1) drop of over 3,000 cells from prior test, or 2) three or more consecutive drops in WBC counts No symptoms of infection

        1. Monitor patient closely
        2. Institute twice-weekly complete blood cell (CBC) tests with differentials, if deemed appropriate by attending physician
        3. Clozaril therapy may continue
        Mild leukopenia WBC = 3,000–3,500