Chapter 25 Drugs and Treatment of Psychiatric Disorders

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

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

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

Dopamine Hypothesis

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

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）

PHENOTHIAZINES

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.

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.

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

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

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）

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).

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

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）.

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

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）

History of depressants

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.

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)

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

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

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）

Monoamine Oxidase Inhibitors

Selective 5-HT reuptake inhibitors (SSRIs)

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.

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

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.

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.

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.

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

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

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.

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

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）

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