1. Chapter 25 Drugs and Treatment of Psychiatric Disorders

2. Classification of Psychosis
Positive: hallucinations, delusions,
Schizophrenia disturbance in thought
Negative: loss of affect,
social withdrawal
Mania
Affective disorder Depression
Bipolar disorder
(manic-depressive disorder)
Neurosis or anxiety-associated disorders

3. Classification of Psychotropic agents
Antipsychotics or neuroleptic drugs
chlorpromazine (氯丙嗪）
Antimanics or mood-stabilizing drugs
lithium carbonate（碳酸锂）
Antidepressants or mood-elevating agents
imipramine (丙咪嗪）
Antianxiety-sedative agents
diazepam, nitrazepam, clonazepam

4. Hypothesis related to psychosis
Dopamine hypothesis
Functional overactivity of dopamine in the limbic system or cerebral cortex in schizophrenia or mania
Tryptophan hypothesis
Monoamine theory
> Functional excess of amine neurotransmitters for mania
> Functional deficit of amine transmitters for depression

6. Dopamine Hypothesis

10. The Distribution of DA Receptors
DA Pathway
Type of Receptors D1 D2 D3 D4 D5
Nigrostriatal Pathway
Mesolimbic Pathway
Mesocortical Pathway
Tuberoinfundibular Pathway ＋
* D3 is a autorecepor

12. Antipsychotic Drugs Phenothiazines: Chlorpromazine (氯丙嗪)
Perphenazine (奋乃静)
Fluphenazine (氟奋乃静)
Trifluoperazine (三氟拉嗪)
Butyrophenones: Haloperidol (氟哌啶醇)
Thioxanthenes: Chlorprothixene (氯普噻吨）
Others: Clozapine （氯氮平）

13. PHENOTHIAZINES

14. Chlorpromazine（Wintermine)
Mechanism of Action
Mechanism of antipsychosis: blockade of the postsynaptic dopamin (D2)–like receptors in the mesolimbic and mesocortical areas in the brain, and inactivating dopaminergic neurotransmission.
Mechanism of adverse effects: blockade of the postsynaptic dopamine D2-like receptors in the tuberoinfundibular and nigrostriatal areas.

16. PHARMACOLOGIC EFFECTS
Central nervous system
Antipsychotic Effect
MECHANISM: blockade of the postsynaptic D2–like receptors
in the mesolimbic and mesocortical pathways.
Antiemetic Effect
> Low doses: blocking D2-like receptors in the Chemoreceptor Trigger Zone (CTZ) of medulla
> High doses: directly inhibition of the vomiting centre
> No effect on vomiting caused by vestibular stimulation.
> Inhibit the Hiccough Centre near the CTZ.

18. PHARMACOLOGIC EFFECTS
Effect on Body-Temperature Regulation
Inhibit the regulation center of body temperature in hypothalamia
and make the body-temperature regulation malfunction.
Characteristics:
Cause body temperature shift towards the ambient temperature.
Lower the body temperature both in febrile and normal states.
Induce hypothermia by lowering the ambient temperature.
Effects on Autonomic Nervous System
blockade of a-adrenergic, histamine (H1-) and M-cholinergic receptors

20. PHARMACOKINETICS Absorption and Distribution > absorbed irregularly
> binding to many tissues results in a large Vd (> 7 L/kg)
> highly lipid-soluble and protein-bound (92-99%)
> longer clinical duration of action
Metabolism and Excretion
> being metabolized in liver
> There are many drug metabolites.
> excreted in urine
Individual difference

21. THERAPEUTIC USES Treatment of schizophrenia Antiemetic effects
Effective in eliminating the positive symptoms (delusions, hallucinations and thought disorders) , especially for acute cases.
Less effective on negative symptoms (withdrawal, blunted emotions）
Antiemetic effects
Treatment of emesis caused by some drugs, but no effect on emesis caused by vestibular stimulation.
Hibernation therapy
Intractable hiccough（呃逆）

22. ADVERSE REACTIONS General adverse reactions CNS inhibitory symptoms
Anticholinergic effects： Urinary retention, Dry mouth,
Constipation, blurred vision
Antiadrenergic effects：Orthostatic hypotension,
cardiopalmus, nasal obstruction
Neuroendocrine effects：amenorrhea (闭经),
galactorrhea (泌乳)
Antihistaminergic effects：sedation（antagonism of H1
receptor in CNS).

24. Extrapyramidal reactions
① Parkinson's syndrome
② Akathisia (静坐不能)
③ Acute dystonia (急性肌张力障碍)
④ Tardive dyskinesia
Allergic response
skin rash, photosensitive dermatitis（光敏性皮炎）, hepatic
injury, agranulocytosis (粒细胞缺乏)
Emotional disturbance induced by drugs
Convulsion and epilepsy induced by drugs
Acute toxic reaction

25. CONTRAINDICATION Lower the convulsion threshold, and induce epilepsy.
Enhance the CNS-depressant effects.
Chlorpromazine should not given to the patients with serious hepatic functional lesion.
Chlorpromazine should cautiously used in the elder with cardiovascular diseases, and sudden death may happen in patients with coronary artery disease （CAD）.

26. Other Antipsychotic Drugs
Clozapine (氯氮平）
Selective inhibit D4 and 5-HT2-receptors
> Rapid onset (1 week) and potent antipsychotic effects, hanving low risk of extrapyramidal syndrom.
> Mainly used in psychosis that the other drugs are not effective, effective on both positive and negative syndroms.
Risperidone （利培酮）
Selective inhibit D2 and 5-HT-receptors
> Effective on both positive and negative syndroms.
> Rapid onset, less extrapyramidal syndrom, convenient for
use, effective on cognition and depression

27. ANTIDEPRESSANTS Tricyclic Antidepressants
imipramine (丙米嗪)，amitriptyline (阿米替林）
Monoamine Oxidase Inhibitors（MAOI）
moclobemide （吗氯贝胺）, tranylcypromine （反苯环丙胺）
Other Antidepressants
> selective NA reuptake inhibitor
desipramine（地昔帕明）; maprotilin （马普替林）
> selective 5-HT reuptake inhibitor
fluoxetine （氟西汀）
> Atypical Antidepressants
mirtazapine （米他扎平）, mianserin (米安色林）

28. History of depressants

29. Pharmacologic Effects
Imipramine(米帕明,丙米嗪）
Pharmacologic Effects
Central nervous system
Normal subjects: drowsiness, dizziness, dry mouth, blurred vision, impaired concentration, difficult of thinking and a fall in blood pressure.
Depressed patients: improve mood, antidepression
Charicteristics: The onset of the antidepressant effect is very slow, taking 2~3 weeks to develop.

31. Mechanisms of Action
Blocking 5-HT and NA uptake into the presynaptic terminal from the synaptic cleft.
Receptors desensitize
Blocking the presynaptic adrenergic (a2)-receptor, decreasing the number of presynaptic adrenergic recptors (regulating the release of adrenergic neurotransmitter via a feedback mechanism.
Inhibit MAO
prolongs the duration of the amine neurotransmitters (5-HT, NA, DA)

34. Pharmacologic Effects
Autonomic Nervous System
Anticholinergic effects at therapeutic dose: blurred vision, dry mouth, urinary retention, constipation
Cardiovascular System
Fall in blood pressure and arrhythmias at therapeutic dose
Orthostatic hypotension
Prominent ECG changes: inversion or flattening of the T waves
Producing quinidine-like effect on myocardium, decreasing the autorhythmicity of myocardium

35. Therapeutic Uses Treating major depression
Control childhood enuresis (bed-wetting in children)
Severe anxiety disorders
panic-agoraphobia syndrome, and in obsessive-compulsive disorder, severe anxiety disorders

36. Adverse Effects Central nervous system Antimuscarinic effects
Weakness, fatigue, muscle tremors, transition from depression to manic state, confusion, tonic-clonic seizures
Antimuscarinic effects
dry mouth, constipation, dizziness, tachycardia, palpitations （心悸）, blurred vision, and urinary retention
Cardiovascular system
Orthostatic hypotension
Others
jaundice (黄疸）, agranulocytosis (粒细胞减少）, rashes （皮疹）

37. Monoamine Oxidase Inhibitors

38. Selective 5-HT reuptake inhibitors (SSRIs)

39. Anti-manic Drugs Lithium Carbonate
Decrease NA and DA release
Promote reuptake of NA
Inhibit the reactions modulated by cAMP and PLC
Lithium Carbonate is the only specific anti-manic drug for the prophylaxis and the treatment bipolar disorder, especially in the manic phase.

40. Effect of lithium on the IP3 and DAG Second-Messenger System.

41. Study questions Choose the ONE best answer
1 All of the following are observed in patients taking neuroleptic agents EXCEPT:
A. sexual dysfunction.
B. increased blood pressure.
C. altered endocrine function.
D. constipation.
E. orthostatic hypotension.

42. A. They are caused by btockade of dopamine receptors
2. All of the following statements about the extra-pyramidal effects of neuroleptics are correct EXCEPT
A. They are caused by btockade of dopamine receptors
B. They are less likely to be produced by clozapine than by
fluphenazine.
C. They can be countered to some degree by antimuscarinic
drugs.
D. Haloperidol does not cause extrapyramidal disturbances.
E. Neuroleptics may cause tardive dyskinesia.

43. 3. The neuroleptic drugs:
A. are equally effective against the positive and
negative symptoms of schizophrema.
B. can cause blurred vision, urinary retention and other
signs of muscarinic blockade.
C. bind selectively to D2-dopaminergic receptors.
D. have antiparkinsonism effects similar to levodopa.
E. have a rapid onset of antipsychotic action.

44. 4. Which one of following is an appropriate therapeutic use for imipramine?
A Insomnia
B Epilepsy
C Bed-wetting in children
D Glaucoma (青光眼）
E Mania

45. 5. MAO inhibitors are contraindicated with all of the following EXCEPT
A indirect adrenergic agents, such as ephedrine.
B tricyclic antidepressants.
C beer and cheese.
D aspirin
E dopamine

46. 6. Which of the following statements concerning
tricyclic antidepressants is correct?
A All of the tricycllic antidepressants show similar therapeutic
efficacy.
B Hypertension is a common adverse effect.
C The tricyclic antidepressants selectively inhibit uptake of
norepinephrine into the neuron.
D These drugs show an immediate therapeutic effect.
E These drugs must be administered intramuscularly.

47. 7. Which of the following is common to the
tricyclic antidepressants and MAO inhibitors?
A They can produce sedation.
B They produce physical dependence.
C They show strong interaction with certain foods.
D They can produce postural hypotension.
E They decrease availability of epinephrine and serotonin in
the synaptic cleft

48. 8. A very upset mother brings in her 10 year old son to ask help in dealing with his bed-wetting. Which of the following drugs might alleviate this problem?
A Fluoxetine
B Imipramine
C Tranylcypromine
D Trazodone (曲唑酮）

49. 9. Side effects of chlorpromazine dministration may include
A Hallucinations
B Movement disorders
C Hyperactivity and insomnia
D Endocrine irregularities
E Dry mouth, blurred vision, and constipation