1. Pharmacology of Psychotherapeutic Drugs
By : Dr Seddigh
HUMS
Good day to all of you, and thank you for inviting me to talk with you about psychotropic medications. There is no way to justice to the topic of psychopharmacology in one hour, but I hope to give you a sense of perspective about the brain, neurobiology and some useful tips about the psychoactive medications that you will encounter in Notice that I just gave you my first of many qualified statements, this material is only good in Psychopharmacology is changing literally by the hour, and every manufacturer is trying to create a new molecule that will do whatever, faster and with fewer side effects.

2. Psychiatric Diagnoses

3. Diagnoses of Concern Mood Disorders Substance abuse related
Somatoform Disorders
Anxiety Disorders
Psychotic Disorders
Personality Disorders
Impulse Control Disorders
Factitious Disorders (Munchausen’s)
Malingering

4. Critical Situations Suicide risk v. accidental overdose
Potential for violence toward others
Multi-substance abuse
Undiagnosed depression
Opioids and benzodiazepines
Poor impulse control

5. What is Multi-Axial Diagnosis?
Axis I: Clinical Disorders & other conditions that may be focus of attention
Axis II: Personality Disorders, Mental Retardation
Axis III: General Medical Conditions
Axis IV: Psychosocial and Environmental Problems
Axis V: Global Assessment of Functioning
Am Psychiatric Association, Quick Reference to the Diagnostic Criteria from DSM-IV-TR. Washington, DC: APA Press.

6. Mood Disorders Major Depressive Disorder Dysthymic Disorder
Depressive Disorder (NOS)
Bipolar

7. Psychotic Disorders

8. Psychotic Disorders Schizophrenia Schizophreniform
Schizoaffective Disorder
Delusional Disorder
Brief Psychotic Disorder

9. Pharmacology Basics

10. Classes of Psychiatric Drugs
Nonbenzodiazepine anxiolytics
Antipsychotics
“Atypical” antipsychotics
Lithium
Antiepileptic drugs
Stimulants
Anti-EPS agents
Tricyclics & Tetracyclics
Selective Serotonin Reuptake Inhibitors
Monoamine Oxidase Inhibitors
“Atypical” antidepressants
Benzodiazepines
When we talk about psychotropic medications we are really discussing a broad spectrum of agents producing many different effects. It is not possible to lump all of these agents into a single group, and we must look at each subgroup separately.

11. Cyclic Antidepresants
Imipramine (Tofranil)
Desipramine (Norpramin)
Amitriptyline (Elavil)
Nortriptyline (Pamelor)
Clomipramine (Anafranil)
Trimipramine (Surmontil)
Doxepin (Sinequan)
Protriptyline (Vivactil)
Amoxapine (Asendin)
Maprotiline (Ludiomil)
The tri- and tetracyclics have been the mainstay of treatment for depression since 1960 through the late 1980’s. They still provide the surest antidepressant response for moderately to severe nondelusional depressed patients, especially those with a primary depression of the endogenous or melancholic type.
The original tertiary amine tricyclics all included in their biochemical spectrum of effects at least a moderate degree of serotonin reuptake inhibition at therapeutic doses. It was the recognition of this fact that led to the development of the selective serotonin reuptake inhibitors (SSRI’s). There are 9 tricyclic agents and 1 tetracyclic agent.
The classic TCA’s are imipramine, amitriptyline and their close structural analogues. They block the reuptake of the neurotransmitters 5-HT and NE into their respective nerve terminals, which formed the basis of the monoamine hypothesis of depression.
They are well absorbed orally; have a half-life of 24 hours, allowing once a day dosing, and are excreted about 5% unchanged, with the majority of the dose undergoing liv er metabolism.

12. Cyclic Antidepressant Indications
Generalized Anxiety Disorder
Obsessive-Compulsive Disorder
Panic Disorder with Agoraphobia
Anorexia Nervosa &Bulimia
Cataplexy & narcolepsy
Depression
Childhood enuresis
Migraine & pain
Urticaria & itching
Their major indications are Major Depression, Melancholia, Atypical depression, OCD, Enuresis, Itch, Panic, Peptic Ulcer and Pain.
Side effects include cardiovascular changes, anticholinergic effects, sedation and wt. gain.
TCA’s do interact with MAOI’s, catecholamines NE & Epinephrine, phenothiazines, barbiturates, cimetidine, clonidine, haloperidol, methylphenidate, phenytoin, and warfarin.

13. Cyclic Adverse Effects
Weight gain
Inducing mania
Anticholinergic
dry mouth, constipation, blurred vision, urinary retention
Sedation
Autonomic
orthostatic hypotension, profuse sweating, palpitations, hypertension
Cardiac
tachycardia, flattened T waves, prolonged QT intervals, depressed ST segments
Neurological
delirium, psychomotor stimulation, myoclonic twitches, tremors, paresthesias, peroneal palsies, ataxia

14. Selective Serotonin Reuptake Inhibitors
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
The SSRI’s were discovered in 1962, but not really utilized as medications until There are now 4 agents on the market, with others in development. All inhibit 5-HT uptake but manifest diverse structural and activity relationships.
Side effects include agitation, anxiety, sleep disturbance, tremor, sexual dysfunction, and headache.
Interactions may occur with alcohol, anticholinergic and antihistaminic compounds. Alterations in the cyctochrome P450 enzyme systems may change the metabolism of other medications.
Overdose is generally benign, and rarely, if ever fatal.

15. SSRI Indications Depression & suicidality
Obsessive-Compulsive Disorder
Panic Disorder
Eating Disorders
Alcoholism
Obesity
SSRI’s are indicated for depression, OCD, Panic disorder, Schizophrenia, eating disorders (bulimia), alcoholism, obesity, sleep, suicidality, and a variety of other problems.

16. Features of Serotonin Syndrome
Diarrhea
Diaphoresis
Tremor
Ataxia
Myoclonus
Hyperactive reflexes
Disorientation
Rigidity
Uncontrollable shivering
Hyperthermia
Delirium
Coma
Status epilepticus
Cardiovascular collapse
Death

17. MAO Inhibitors

18. MAOI Indications Obsessive-compulsive Narcolepsy Headache
Atypical depression
Major depression
Dysthymia
Melancholia
Panic disorder
Bulimia
Atypical facial pain
Parkinson’s Disease
Obsessive-compulsive
Narcolepsy
Headache
Chronic pain disorder
Generalized anxiety
MAOI’s have been used to treat many conditions, especially those which are relatively refractory to more conventional agents.

19. MAO Inhibitor Drugs MAO A MAO B Nonselective inhibitors
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Avoid tyramine-containing foods
MAO B
Selective inhibitor
Selegiline [deprenyl] (Eldepryl)
Avoid tyramine and SSRIs
Lose selectivity at high doses

20. MAO Inhibitor drug interactions
Antidepressants
SSRIs
Tricyclic antidepressants
Sympathomimetics
Ephedrine
Some opioids
Meperidine
Pentazocine
Dextromethorphan

21. MAOI Dietary Interactions
Contain Tyramine
Cheese
Overripe aged fruit
Fava beans
Sausage, salami
Sherry, liquors
Sauerkraut
MSG (glutamate)
Pickled fish
Brewer’s yeast
Beef & chicken liver
Fermented products
Red wine
Caffeinated beverages
Chocolate
Some of the most difficult problems associated with MAOI’s include the need for the patient to adhere to a strict diet avoiding many foods. The importance of the diet often limits the ability to use MAOI’s with certain patients.

22. Medications to Avoid with MAOIs
Antiasthmatics
Antihypertives (methyldopa, guanethidine)
Buspirone
Levodopa
Opioids
Cold, allergy or sinus medications with dextromethorphan or sympathomimetics
SSRIs, clomipramine, venlafaxine, sibutramine
Sympathomimetics
L-Tryptophan

23. Medications to Use Carefully with MAOIs
Anticholinergics
Antihistamines
Disulfiram
Bromocriptine
Hydralazine
Sedative-hypnotics
Terpin hydrate with codeine
Tricyclics & tetracyclics

24. Atypical Antidepressants

25. Atypical Antidepressants
Buproprion (Wellbutrin, Zyban)
Duloxetine (Cymbalta)
Mirtazapine (Remeron)
Nefazodone (Serzone)
Trazodone (Desyrel)
Venlafaxine (Effexor)
Trying to find alternatives to TCA’s has led to the discovery of atypical antidepressants. Side effects profiles have made these agents particularly useful for patients not able to tolerate TCA’s; and all are less toxic than TCA’s, especially in over doses.
Amoxapine has the unusual characteristic of being metabolized into an antipsychotic agent, theoretically making it an attractive medication for psychotically depressed patients.
Buproprion is more stimulating than most antidepressants, allowing it to be useful for retarder depressions, and to be least likely to cause interference in sexual functioning. mIt’s main drawback has been a three fold increase in seizure potential over the other antidepressants, requiring a careful assessment for it’s use.
Venlafaxine is a unique agent, and is effective for depression, but has a number of dose related side effects often limiting it’s utility at higher doses.
Nefazodone, a cleaned up version of trazodone, has few adverse side effects, and may be found over time to be useful for a variety of problems.

26. Atypical Antidepressant Indications
Depression
Generalized Anxiety Disorder
Obsessive-Compulsive Disorder
Smoking Cessation
Panic Disorder
Agoraphobia
Chronic pain

27. Atypical Antidepressant Adverse Effects and Problems
Buproprion: headache, insomnia, upper respiratory complaints, nausea, restlessness, agitation & irritability
Duloxetine: nausea, dry mouth, fatigue, dizziness, constipation, somnolence & sweating
Mirtazapine: somnolence, dizziness, increased appetite, increased cholesterol and triglycerides, orthostatic hypotension
Nefazodone: postural hypotension, activation of mania, liver dysfunction
Trazodone: sedation, orthostatic hypotension, dizziness, headache, nausea, priapism
Venlafaxine: nausea, somnolence, dry mouth, hypertension, dizziness, nervousness, constipation, etc.

28. Benzodiazepines

29. Benzodiazepines Triazolam (Halcion) Alprazolam (Xanax)
Lorazepam (Ativan)
Oxazepam (Serax)
Temazepam (Restoril)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Diazepam (Valium)
Clorazepate (Tranxene)
Halazepam (Paxipam)
Prazepam (Centrax)
Flurazepam (Dalmane)
Estzolam (ProSom)
Midazolam (Versed)
BZD’s were the salvation from barbiturates.
They exert their effects through the GABA pathways, and generally inhibit the nervous system.
They are well tolerated orally, with minimal side effects, and rarely, if ever, cause death in over doses.

30. Benzodiazepine Indications
Nocturnal myoclonus
Tic douloureux
Tetanus
Cerebral malaria
Chloroquine toxicity
Maternal eclampsia
Sedative-hypnotics
Muscle relaxants
Anticonvulsants
Alcohol withdrawal
Anxiety disorders
Agitation control
BZD’s have been widely prescribed for three decades for a variety of conditions.

31. Nonbenzodiazepine Anxiolytics
Meprobamate (Miltown)
Buspirone (Buspar)
Gepirone (Ariza)
Ipsapirone
Tandospirone
Because of concerns about habituation and dependence, non-BZD agents have been created.
Buspirone, exerts it’s effects through the blocking of the serotonin pathways, and also has some DA system effects.
Buspirone has been used as an adjunct in depression, alcoholism treatment, and anxiety states.

32. Antipsychotics

33. Antipsychotics
Phenothiazines: Chlorpromazine (Thorazine), Fluphenazine (Prolixin), Mesoridazine (Serentil), Trifluoperazine (Stelazine), Perphenazine (Trilafon), Thioridazine (Mellaril)
Butyrophenones: Haloperidol (Haldol)
Thioxanthenes: Thiothixene (Navane)
Dihydroindolones: Molindone (Moban, Lidone)
Dibenzoxazepines: Loxapine (Loxitane)
Diphenylbutylpiperidines: Pimozide (Orap)
Antipsychotics are used to treat nearly all forms of psychosis. These medications have become standard treatments in psychiatry, yet they are not effective for all patients, and do unfortunately produce undesirable toxic side effects.
The traditional antipsychotic agents have been classified into groups based upon their structural characteristics. They all produce behavioral, motor, endocrine effects.
They show high affinity for D2 receptors, giving rise to the “dopamine hypothesis of schizophrenia.” Interestingly, the fact that traditional antipsychotic medications relieve the schizophrenic psychosis by decreasing dopaminergic activity does not mean that schizophrenia is caused by increased dopamine activity. Recent research suggests that antipsychotic medications blocking D2 receptors may be an oversimplification.

34. Antipsychotic Mechanisms
D2 receptor antagonists
5HT2 receptor antagonists
Older agents generally have higher 5HT/DA binding ratios
The atypical antipsychotics have less potential for extrapyramidal side effects (EPS)

35. Antipsychotic Indications
Acute Schizophrenia
Chronic Schizophrenia
Schizoaffective Disorders
Depression with Psychotic Features
Agitation
Mania
Chorea
Antipsychotic medications have been used for a variety of psychiatric and medical conditions.
Unfortunately, they do cause Tardive dyskinesia, acute extrapyramidal side effects, neuroleptic malignant syndrome, cardiac, endocrine, and other side effects.

36. Antipsychotic Adverse Effects
Cardiac toxicity & sudden death
Orthostatic hypotension
Hematological toxicity
Increased secretion of prolactin
Sexual dysfunctions
Weight gain
Jaundice
Dermatitis and photosensitivity
Sadock BJ & Sadock VA, Kaplan & Sadock’s Synopsis of Psychiatry 9th Ed. Philadelphia, PA: Lippincott Williams & Wilkins.
Neuroleptic-induced Parkinsonism
Neuroleptic-induced Acute Dystonia
Neuroleptic-induced Tardive Dyskinesia
Neuroleptic Malignant Syndrome
Lowered seizure threshold
Sedation
Anticholinergic effects

37. Atypical Antipsychotics

38. Atypical Antipsychotics
Aripiprazole (Abilify)
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Quentiapine (Seroquel)
Risperidone (Risperdal)
Ziprazadone (Geodon)

39. Advantages of Atypical Antipsychotic Agents
These are serotonin-dopamine antagonists (except aripiprazole which is partial agonist for D2 receptors, but behaves as functional antagonist in hyper DA states & agonist in hypo DA states)
Lower risk for Extrapyramidal Side Effects (EPS) than DA antagonists
Effective for positive & negative symptoms
Effective for treatment of mood disorders with psychotic or manic features & for behavioral disturbances with dementia

40. Toxicities of Atypical Antipsychotic Agents
Aripiprazole: Too new to be fully known (mild nausea & vomiting, wt. loss, lowered prolactin levels, low levels of EPS)
Clozapine: sedation, dizziness, syncope, tachycardia, hypotension, ECG changes, leukopenia (aplastic anemia), wt. gain
Olanzapine: Somnolence, dry mouth, dizziness, constipation, dsypepsia, increased appetite & wt. gain, tremor
Quetiapine: somnolence, postural hypotension, dizziness, modest wt. gain
Risperidone: dose-dependent EPS, wt. gain, anxiety, nausea, erectile and orgasmic dysfunction
Ziprasidone: somnolence, headache, dizziness, nausea, QT prolongation (fatal in pts with Hx of cardiac arrhythmia)
Many cause abnormalities with glucose & lipid metabolism leading to DM & hyperlipidemias

41. Risk Factors Leading to Acute Dystonic Reactions
Male gender
Younger age
Previous dystonic reaction
Using higher doses of medication
Giving higher potency antipsychotics
Intramuscular route of administration
Possible risks for the development of dystonic reactions have included these factors.

42. Drugs to Treat Extrapyramidal Side Effects
Benztropine (Cogentin)
Trihexyphenidyl (Artane)
Procyclidine (Kemadrin)
Diphenhydramine (Benadryl)
Biperiden (Akineton)
Amantadine (Symmetrel)
To control the acute EPS problems, a number of agents have been utilized. Most of these are anticholinergic agents which in effect cause a double lesion in the nervous system to bring the neurotransmitters back into balance.
Amantadine is able to cause the release of DA, and other catecholamines from the nervous system.

43. Strategies for Extrapyramidal Side Effects (EPS)
Reduce antipsychotic medication dose
Substitute lower-potency antipsychotic
Add an anticholinergic agent, titrate up
Add amantadine to anticholinergic agent
Add a benzodiazepine or beta-blocker
Stop antipsychotic medication
Substitute an atypical agent
The treatment of EPS currently involves these strategies.

44. Antimania Medications
Lithium
Benzodiazepines
Anticonvulsants
Carbamazepine (Tegretol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Valproate (Depakote); valproic acid (Depakene)
Calcium Channel Antagonists
Amlodipine
Isradipine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Verapamil
Atypical antipsychotic agents
Lithium has become the mainstay of therapy for mania over the past two decades. Besides replacing sodium inside of the cells, lithium also leads to an accumulation of serotonin in the CNS.
Anticonvulsants have also been shown to be effective, and valproate now has a primary FDA indication for the treatment of bipolar disorder.
BZD’s are anticonvulsants and have been useful in the acute stabilization of bipolars, but tend to be discouraged for the long term management of mania.
Calcium channel blockers are being investigated for possible antimanic therapy. They may be safer than lithium or anticonvulsants during pregnancy, and do not require blood level monitoring.

45. Anticonvulsant Issues
Carbamazepine: blood dyscrasias, hepatitis, exfoliative dermatitis, GI upset, acute confusional state, decreased cardiac conduction, SIADH, birth defects
Gabapentin: somnolence, dizziness, ataxia, fatigue, nystagmus
Lamotrigine: decreased valproic acid level, increased carbamazepine epoxide metabolite, life-threatening skin rashes
Topiramate: increased phenytoin and valproic acid levels, psychomotor slowing, speech & language problems, dizziness, ataxia, fatigue, poor concentration, wt. loss, tremor
Valproate: GI distress, sedation, tremor, wt. gain, hair loss, elevated transaminases, fatal hepatotoxicity, platelet dysfunction
Sadock BJ & Sadock VA, Kaplan & Sadock’s Synopsis of Psychiatry 9th Ed. Philadelphia, PA: Lippincott Williams & Wilkins.

46. Responsiveness to Lithium
Unfavorable
Borderline features
Neuroticism
Rapid cycling
Mixed manic/depressive Sx
Substance abuse
Psychosis
Depression followed by mania
Sadock BJ & Sadock VA, Kaplan & Sadock’s Synopsis of Psychiatry 9th Ed. Philadelphia, PA: Lippincott Williams & Wilkins.
Favorable
Prior long-term response to Lithium
Classic euphoric or pure mania
Family history of bipolar disorder
Secondary mania
Family history of response to lithium
Obsessional features
Mania followed by depression

47. Recognizing Lithium Toxicity
GI (mild)
Vomiting
Abdominal pain
Dryness of mouth
Neurological (mild)
Ataxia
Dizziness
Slurred speech
Nystagmus
Lethargy or excitement
Muscle weakness
GI (moderate-severe)
Anorexia
Neurological (mod-sev)
Muscle fasciculations
Clonic limb movements
Hyperactive DTRs
Choreoathetoid movement
Convulsions
Delirium
Stupor
Coma
Death

48. Stimulants

49. Stimulants Cocaine Amphetamines Methylphenidate (Concerta, Ritalin)
Amphetamine (Adderall)
Dextroamphetamine (Dexedrine)
Methamphetamine (Desoxyn)
Methylphenidate (Concerta, Ritalin)
Modafinil (Provigil)
Pemolin (Cylert)
They are indicated for the treatment of ADHD. Cocaine is not used any longer in psychiatry, only amphetamines, methylphenidate and pemolin are utilized.
Stimulants release and prevent the reuptake of catecholamines, giving an adrenaline like effect.

50. Stimulant Indications
Narcolepsy
Attention Deficit Hyperactivity Disorder
Enhanced alertness and combat readiness (military only)
Unofficial uses:
Reversing opioid induced sedation
Refractory depression
Chronic pain
Stroke
There are few approved uses for stimulants, but some have been used for “off label” indications.

51. Psychopharmacological Treatment of Agitation
Anticonvulsants
Antipsychotics
Benzodiazepines
Beta-blockers
Buspirone
Lithium
Serotoninergic antidepressants
In trying to reduce agitation and aggression, a number of medications have been used.

52. Impediments to Adherence to Recommended Treatment
Excessively complex regimens
Early onset & persistence of side effects
Slow onset of beneficial effects
Low apparent relapse risk experienced if treatment is interrupted
Psychosis, confusion, dementia, low intelligence, impaired hearing or vision
Lack of information & need for education
Involvement of multiple clinicians

53. Conclusions
Medications play a vital role in the management of mental illness.
There is still a role for therapy, and working with families.
There is much to still learn about drug therapy for mental illness.
Keep studying and asking questions.

54. References
Sadock BJ & Sadock VA. Kaplan & Sadock’s Synopsis of Psychiatry 9th Ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2003
Am Psychiatric Association Quick Reference to the Diagnostic Criteria from DSM-IV-TR. Washington, DC: APA Press. 2000
Drugs for Pain. Hanley & Belfus, Philadelphia. Misc. chapters