ANTIPSYCHOTICS

ANTIDEPRESSANTS
LITHIUM
 Dopaminergic neural pathways
Nigrostriatal tract-
Substantia nigra 
striatum
Mesolimbic and
mesocortical tracts-
Midbrain  limbic and
cerebrocortical structures
Tuberoinfundibular
pathway- hypothalamus 
anterior pituitary
Chemoreceptor trigger
zone- activation of DA
receptors
 Dopaminergic actions in brain

DA agonists  nausea and vomiting

DA antagonists  antiemetics
Hyperprolactinemia causes amenorrhea, galactorrhea,
infertility, gynaecomastia
ANTIPSYCHOTICS
Psychoses- serious distortion of thought, behavior, capacity to
recognize reality and of perception (hallucinations, delusions)
Schizophrenia
 Positive symptoms- hallucinations, delusions, thought dysfunction
(due to excess dopamine in mesolimbic pathway)
 Negative symptoms- social withdrawal, apathy (due to deficiency in
dopamine in mesocortical pathway)
Phenothiazines
 Low potency- Chlorpromazine, thioridazine
 High potency- fluphenazine
Butyrophenones- haloperidol (high potency)
Thioxanthenes- Thiothixene (high potency)
Others- pimozide, molindone, reserpine
Atypical antipsychotics- clozapine, olanzapine, risperidone
NEUROLEPTICS
 Block D2 receptors to reduce positive symptoms of schizophrenia
 Low potency drugs- CPZ, thioridazine
block D2 receptors with low affinity (worsen apathy, cause EPS side
effects, hyperprolactinemia)
block M receptors (dry mouth, blurring of vision, block extrapyramidal
system EPS effects, parkinsonism)
α adrenergic blockade (postural hypotension, sexual dysfunction)
antihistaminic (sedation)
 High potency drugs- Fluphenazine,
thiothixene, haloperidol
 Block D2 receptors strongly- EPS
symptoms and hyperprolactinemia
more severe
 Autonomic dysfunction less as
other receptors not blocked much
 Adverse effects
 Behavioral- sedation, mental confusion (low potency drugs), pseudodepression
 Seizures- CPZ, clozapine
 α adrenergic blockade- postural hypotension, sexual dysfunction (impaired
ejaculation) with CPZ and thioridazine
 Anticholinergic- dry mouth, blurring of vision, urinary retention, constipation
(thioridazine mainly, also CPZ)
 Hyperprolactinemia- amenorrhea, galactorrhea, infertility in women; loss of
libido, impotence, infertility in men (high potency drugs)
 Retinal deposits and browning of cision- thioridazine. CPZ can cause deposits
in corneal and lens.
 Hypersensitivity reactions- Skin rashes, photosensitivity, cholestatic jaundice-
CPZ
 Thioridazine, pimozide prolong QT interval (quinidine-like effect) 
ventricular arrhythmias, sudden death
 Adverse effects
 Extrapyramidal system adverse effects- (high potency drugs)
 Parkinsonism- rigidity, tremor, bradykinesia, shuffling gait  benztropine
 Akathisia (uncontrollable restlessness)  benztropine, diphenhydramine
 Acute dystonias- grimacing, spastic retrocollis or torticollis, locked jaw 
botulinum toxin, benztropine, promethazine, pramipexole,
 Tardive dyskinesia- late occurring, sometimes even after withdrawal of
drug. May subside after months or years after withdrawal or may be
lifelong.
 Involuntary facial movements tongue thrusting, lip smacking, lip pursing,
grimacing and chewing
 Choreoathetoid movements of limbs
 Discontinue or reduce dose of neuroleptic, switch to atypical antipsychotic,
reduce drugs with anticholinergic properties, Diazepam may be useful.
Neuroleptic malignant syndrome- rare but can be fatal
 Marked muscle rigidity, immobility, fever, fluctuating BP and HR
 Neuroleptic stopped. Bromocriptine, diazepam/ dantrolene useful.
 USES
 Psychoses- schizophrenia, schizoaffective states like drug induced psychoses,
delusions, psychosis with Alzheimer’s disease, organic brain syndromes
 Symptoms may take several weeks to respond to drug treatment. Parenteral
formulations of high potency drugs in case of non-compliance
 Positive symptoms (hallucinations, delusions, disorganized thought) improved
 Negative symptoms might be worsened(apathy, social withdrawal). Atypical
antipsychotics preferred to reduce negative symptoms and if EPS is severe.
 CPZ good for controlling agitation, violent behavior
 Mania, bipolar disorder- i.m for rapid control. Lithium/ carbamazepine started,
neuroleptic withdrawn gradually.
 Preanesthetic medication- promethazine acts through H1 receptors to produce
sedation. CPZ can be given to potentiate anesthetics, to allay anxiety but not
preferred.
 Anesthesia- droperidol + fentanyl
 Anti-emetic- drug or radiation induced emesis- prochlorperazine. Promethazine
for motion sickness.
 Intractable hiccough, tetanus, tourette’s syndrome
ATYPICAL ANTIPSYCHOTICS
D2 and 5-HT blockade, also weak muscarinic, α adrenergic and
H1blockade
 extrapyramidal symptoms, tardive dyskinesia, Neuroleptic
Malignant Syndrome rare .
 Suppresses both positive and negative symptoms of
schizophrenia due to D2 and 5HT2 blockade respectively.
 All agents show varying degree of postural hypotension,
weight gain
Clozapine- Agranulocutosis may be fatal, can cause seizures,
sialorrhea.
 Used in refractory schizophrenia, or if TD is present.
Risperidone- more incidence of EPS, hyperprolactinemia among
atypical antipsychotics, TD lower risk
Olanzapine- glucose intolerance
 ANTI DEPRESSANTS
Reserpine, an antihypertensive depletes brain amines -
causes depression.
Actions of antidepressant drugs  increase NE and/or 5HT
actions
 Amine hypothesis of depression- Depression may arise from
deficiency in NE and/or 5HT
But, antidepressant shows effects in 2 weeks and optimal
response in 4 weeks . Beneficial effects may be due to
compensatory responses to initial increase in levels of
biogenic amines.
Some drugs do not appear to have significant effects on brain
amines.
 Classification
 MAO inhibitors
 Non-selective (MAO type A and B)-
phenelzine, tranylcypromine
 Selective (MAO type A)- moclobemide
 Tricyclic antidepressants (TCAs)
 NE and 5-HT reuptake inhibitors- imipramine,
amitriptyline, clomipramine, doxepin
 NE > 5HT reuptake inhibitors- desipramine,
nortriptyline, amoxapine
 Selective serotonin reuptake inhibitors
(SSRIs)- fluoxetine, paroxetine, sertraline,
fluvoxamine, citalopram
 Heterocyclics/ Atypical antidepressants-
bupropion, nefazodone, trazodone,
mirtazapine, venlafaxine
 MAO inhibitors
 Monoamine oxidase type A metabolizes NE & 5-HT, tyramine. Type B
metabolizes DA.
 Non-selective- tranycypromine
 Side effects- anticholinergic, orthostatic hypotension, impotence, weight gain
 Overdose- agitation, confusion, hallucinations, mania
 Interactions-
 Cheese reaction- foods like cheese, beer etc contain tyramine  not

degraded  large amounts of NE released  not degraded  hypertensive

crisis
 Hypertensive crises with L-DOPA, TCAs , reserpine, guanethidine

 Pethidine, dextromethorphan- hyperthermia, HTN, seizures

 Serotonin syndrome with SSRIs

 Moclobemide- selective type A inhibitor, mild interactions, safer in overdose

 Tricyclic antidepressants
 Extensive first pass metabolism in liver. Imipramine  desipramine, amitriptyline 
nortriptyline
 Adverse effects
 M block, α block  dry mouth, blurred vision, urinary retention, constipation, postural
hypotension, tachycardia, sexual dysfunction
 May induce mania/ hypomania in patints with bipolar disorder
 Sedation, decrease seizure threshold, weight gain
 Also cause quinidine-like effects  cardiotoxicity, ventricular arrhythmias
 Withdrawal syndrome- malaise, vertigo, muscle pain, nightmares. Gradual withdrawal
recommended.
 Uses-
 Major depressions, phobic and panic anxiety states
 Obsessive-compulsive disorder (OCD)- specially clomipramine
 Neuropathic pain, enuresis- imipramine
 Other uses Migraine- amitriptyline, Pruritis- doxepin
 TCAs- Drug interactions
Hypertensive crisis, hyperthermia, coma, convulsions and death with
MAOIs
Marked motor impairment with alcohol, additive sedation with other
CNS depressants.
Prevent anti-HTN effect of guanethidine and clonidine.
Treatment of poisoning-
Symptoms- autonomic side effects, muscle spasms, excitement,
delirium. Triad C- coma convulsions, cardiotoxicity (arrhythmias)
Physostigmine to reverse anticholinergic symptoms
Propranolol or lidocaine to treat arrhythmias
Diazepam to control convulsions, delirium
 Selective serotonin reuptake
inhibitors (SSRIs)
 Extensive metabolism in liver. Fluoxetine (t ½ - 2days)  norfluoxetine
(longer t ½ - 1 week). Once daily dosing possible.
 Adverse effects-
 Anxiety, insomnia (may need sedative)
 Sweating, tremors, bruxism (grinding teeth)
 Nausea, diarrhea, weight loss
 sexual dysfunction (anorgasmia), seizures
 Withdrawal syndrome - vertigo, malaise
 Uses-
 Major depressions, anxiety states (panic, phobias, social)
 Bulimia
 OCD, and alcoholism.
SSRIs
Drug interactions
 Serotonin syndrome includes muscle rigidity, myoclonus,
hyperthermia, ANS instability, mental changes and seizures.
Has been reported for SSRIs when used with MAOIs, TCAs
 Paroxetine, fluvoxamine, fluoxetine inhibit CYP 450 liver
enzymes elevating plasma levels of opioids, beta-blockers
calcium channel blockers, antifungals, alprazolam, oral
contraceptives. Sertraline, citalopram have less propensity to
inhibit liver enzymes.
Deaths due to overdose rare.
 2nd and 3rd generation drugs
(Heterocyclics)
 Mechanism of action
 Mirtazapine blocks presynaptic a2 receptors, preventing feedback inhibition
of transmitter release.
 Nefazodone and trazodone block 5HT reuptake, 5HT antagonists.

 Venlafaxine enhances 5HT activity at low doses and NE at higher doses

 Bupropion- NE/DA reuptake inhibitor
 Adverse Effects
 Mirtazapine- sedation, weight gain
 Trazodone, nefazodone- sedation, liver failure (nefazodone)
 Venlafaxine- sedation, sexual dysfuncton, hypertension
 Bupropion- nausea, insomnia, seizures, aggravation of psychoses,
contraindicated in eating disorders.
Drug choice
TCAs, venlafaxine- greater efficacy than SSRIs
SSRIs preferred over TCAs because tolerated better
Sedation greatest with amitriptyline, doxepin, trazodone,
mirtazapine
Autonomic side effects in amitriptyline, doxepin
Sexual dysfunction with SSRIs, venlafaxine
SSRIs safe in overdose, once daily dosing
Choice of drug depends on patient acceptance (toleration
of side effects)
MAOI in atypical depression
BIPOLAR DISORDER
A mental illness characterized by mood instability
Also known as manic-depressive illness — manic
behavior is one extreme and depression is the other.
Lithium is a mood stabilizer, drug of choice. May
need as adjunts antidepressants to improve
depression phase and sedative drugs initially during
mania.
Slow onset (2 weeks), narrow therapeutic index
Back-up drugs- valproate, carbamazepine. In
pregnancy- gabapentine, lamotrigine.
 Mechanism of action
• Lithium inhibits
recycling of inositol to
form PIP2.

• This second
messenger system is
involved in ACh, NE,
and 5HT receptors.

• Uncouples receptors
from G proteins eg
renal V2 receptors of
ADH (vasopressin) 
polyuria, TSH
receptors 
hypothroidism
Adverse effects, Drug interactions
 Tremor, ataxia, choreoathetosis, motor incoordination, nystagmus- monitor
serum levels (0.5-1.5 mEq/L).
 Serum levels- 2 mEq/L  toxicity
 muscle twitchings, delirium, coma, convulsons
 Hemodialysis, osmotic diuretics effective
 Acne, edema, visual dysfunction, seizures
 Hypothyroidism, goiter, inhibits
 Nephrogenic diabetes insipidus – polydipsia, polyuria(responds to amiloride)
 Teratogenicity-fetal goiter, lethargy, cyanosis, and possible hepatomegaly in
infant. Cardiac anomalies rare.
 Diuretics like thiazides cause compensatory reabsorption of Li+ due to
similarity with Na+  lithium toxicity.
 Neuroleptics combined with Li+ can cause more EPS symptoms
Clinical problems
 A 38-year-old patient with paranoid schizophrenia is discovered by his
Department of Mental Health caseworker during a routine home visit
lying in his bed with a temperature of 103 degrees. The patient is
disoriented and so rigid the caseworker is unable to stand him up.
Which of the following is the most likely cause of such a presentation?
 a. An increase in the dose of haloperidol received three days earlier
 b. Minor surgery two days earlier
 c. Patient stopped taking his medications for two weeks
 d. Patient has been drinking four to five beers every night
 e. Patient has been in close contact with a a friend who has
pneumococcal
 Clinical problems
 A 45-year-old woman with a chronic mental illness seems to be constantly chewing. Her
tongue darts in and out of her mouth and occasionally she smacks her lips. She also
grimaces, frowns, and blinks excessively.
 These abnormal movements are seen, characteristically, in
 a. Tourette’s syndrome
 b. Akathisia
 c. Tardive dyskinesia
 d. Parkinson’s disease
 e. Wilson’s disease
 What medication has she received for the past 25 years?
 a. Diazepam
 b. Phenobarbital
 c. Clozapine
 d. Perphenazine
 e. Amitriptyline