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ANTIPSYCHOTIC DRUGS. Martin Štěrba, PharmD., PhD. Associate professor 2012. Psychotic disorders (psychosis): are severe mental disorders that cause abnormal thinking and perceptions. Classification of psychotic disorders Schizophrenia – see below

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Martin Štěrba, PharmD., PhD.

Associate professor



Psychotic disorders (psychosis):

  • are severe mental disorders that cause abnormal thinking and perceptions.
  • Classification of psychotic disorders
    • Schizophrenia– see below
    • Schizoaffective disorder– disorder of both thought and mood
    • Delusional disorder– incl. paranoid psychosis
    • Substance-induced psychotic disorder– use/withdrawal of amphetamines, cocaine, alcohol, LSD, psilocybe…
    • Psychotic disorder due to a medical condition(organic psychosis) - disturbances caused by head injury or tumor
    • others
  • Definition:
    • Chronic (relapsing and remitting) disorder of though
    • characterised by acute psychotic episodes
    • periods of impaired psychosocial functionality and residual symptoms in between
  • Typical feature – is a loss of touch with reality
  • Life-time prevalence– 1% of population
  • Onset in adolescence/early adulthood
  • Etiology – unclear
    • significant genetic component
    • neurodevelopmental theory – aberrant intrauterine brain development (infections, hypoxia?)  abnormal neuronal shape, position and connections
  • Highly disabling – strong medical, social and economical implications
schizophrenia pathophysiology
  • Morphological changes
  • brain asymmetry with decreased cortical/hyppocampal size and increased ventricular size
  • Neurotransmitter changes
  • theories were derived from pharmacological observations
  • unfortunately nodetail understanding to the neurochemistry
    • Dopamine theory– central and most important one, it will be discussed further in detail
    • Glutamate theory
      • Psychotic-like symptoms induced by administrations of NMDA-antagonists (ketamine and phencyclidine
      • Reduction of glutamatergic and increased dopaminergic neurotransmission
      • → impairment of gating fucntion of GABA neurons
    • Serotonin theory
      • schizophrenia-like symptoms induced by LSD,psilocybine
      • many atypical antipsychotics block also 5-HT receptors (! 5-HT2A)
dopamine theory of schizophrenia
Dopamine theory of schizophrenia
  • Symptoms of schizophrenia - hyperactivity of dopaminergic pathways in mesolimbic/mesocortical system
  • Psychotic symptoms and related behavioural changes can be
    • Induced by
      • Drugs causing dopamine release – e.g., amphetamines
      • D-agonists (e.g., bromocryptine) and dopamine precursors (like L-DOPA)
    • Inhibited by
      • Drugs blocking dopamine storage (e.g., reserpine)
      • D-antagonists
  • Dopamine receptors – D1 type(D1 and D5) and D2-type (D2, D3, D4)
      • D2-receptors
        • Are evidently involved
        • correlation between D2-antagonistic effects and antipsychotic action
        • Clinical response in occupancy of 60-80% of D2 receptors
        • for atypical drugs 30-50% is enough
      • Some theories suggest
        • overactivation of D2 receptors in subcortical regions (positive symptoms)
        • Deficient activation of D1 receptors (negative symptoms)
symptom clusters in schizophrenia
Symptom clusters In schizophrenia
  • Positive symptoms
    • Delusions(fixed false beliefs, often paranoid/conspirative in nature)
    • Hallucinations(usually hearing of voices, typically spurring)
    • Incoherent thought(disconnection - loosing of associations, inability of logical analysis of the situation, ambivalence – contradictory thoughts)
    • Suspiciousness, hostility and potentially aggression
    • Disorganized speech
    • Stereotype/abnormal movements
  • Negative symptoms
    • Affective flattening– poor emotional experience
    • Anhedonia– loss of the capacity to experience pleasure
    • Avolition- lack of desire, drive, or motivation to pursue goals
    • Withdrawal from social contacts
  • Cognitive symptomes
    • Impaired attention, working memory and executive function
  • Clinical picture may vary considerably, especially according to the positive/negative symptoms balance
goals and means of treatment
Goals and means of treatment
  • Goals
    • To suppress any acute psychotic episode
    • To prevent relapses and progression of the disease
    • To restore/keep the psychosocial functionality (family, job and social networks)
  • Therapy
    • should be complex
    • is not causal
      • Pharmacologic– the mainstay of the treatment
        • Common mechanism of action: D2-antagonism
        • Additional mechanisms: antagonism on 5-HT2A/C.α1, M, H1,
        • Adverse effects
        • Therapeutic effects
pharmacotherapy of schisophrenia general aspects
Pharmacotherapy of Schisophreniageneral aspects
  • Response in 70% of patients
    • 30% are treatment resistant forms = big clinical issue!!!
  • Negative symptomsrespond much less than positive symptoms
    • improved in atypical drugs
  • The full antipsychotic effect deserve weeks (3-4 weeks).
    • only non-specific sedative and aggression controlling effects can be induced immediately
  • Monotherapy is preferable
    • combinations only in resistant forms
pharmacotherapy of schisophrenia general aspects1
Pharmacotherapy of Schisophreniageneral aspects
  • Long-term treatment
      • is usually initiated with newer atypical drugs
  • Compliance– often big issue, i.m. injection (acute episode) or „depot“ i.m. forms (to avoid chronic non-compliance)
  • Dose is usually gradually titrated, adverse effects should be closely monitored
  • Typical antipsychotics
    • useful in acute psychotic episode with strong aggression (sedative effects, injectable forms are available)
pharmacokinetics of antipsychotics
Pharmacokinetics of antipsychotics
  • Route ofadministration
    • oral or by i.m. injection
    • once or twice a day.
  • Generally highly lipophilic drugs
    • highly bound on plasma proteins
    • large distribution into the tissues (high Vd), risk of accumulation
  • T1/2 of most antipsychotics
    • is long (15-30 hours)
  • CL depends entirely on hepaticbiotransformation
    • mostly CYP 450-dependent (exception ziprasidone)
    • genetic polymorphisms (e.g., in CYP 2D6 - substrates risperidon)
  • Slow- release („depot“) preparations
    • flupentixoldecanoat, fluphenazinedecanoat
    • active drug is esterified with heptanoic or decanoic acid
    • dissolved in oil.
    • Given as an i.m. inj., the drug acts for 2-4 weeks.

Classification of antipsychotic drugs:

I. typical antipsychotics

a) basal (sedative):

-chlorpromazine(typical example, a phenothiazine structure)

- chlorprotixene,thioridazine

b) incisive:

-haloperidol(typical example, a butyrophenone structure)

- fluphenazine, flupenthixol, clopenthixol

II. atypical antipsychotics:

a) Multi Acting Receptor Targeted Antipsychotics (MARTA)

-olanzapine, zotepin, quetiapine, clozapine

D1/2, 5-HT2A,α, H1, M and receptor antagonists

b) Dopamine and serotonin receptor antagonists

-risperidone, ziprasidone, aripiprazole

c) D2-selective antagonists

-sulpiride, amisulpiride

classification of antipsychotics
  • Incisive vs. sedative (typical) antipsychotics
    • Incisive - more potent and selective D2-antagonits than sedative (basal) drugs
      • Incisive drugs are more effective

however, they induce significant problems with extrapyramidal adverse effects

      • Sedative drugs are weaker D2-antagonists,but block also H1,α1, M (which explain sedative effects as well as some adverse effects)
  • Atypical vs. typical antipsychotics
    • Atypical drugs
      • less extrapyramidal complications
      • Have improved efficacy against negative symptoms
      • Might be useful in treatment-resistant groupof patients

(especially clozapine)

      • Difference in overal efficacy ?
adverse effects a type dose dependent
Adverse effects - A- type(dose dependent)

I. Extrapyramidal motor disturbances

- result from D2 blockade in the nigrostriatal pathways

- more frequent in typical (especially incisive) antipsychotics

  • Acute (reversible)
    • Parkinson-like symptoms(further details on next seminar)
      • Tremor
      • Rigidity
      • Bradykinesia/akinesia:
    • Acute dystonias
      • - severemuscle spasms, very painful (occur within initial 24-96h)
        • Orofacialmuscles(e.g., blepharospasm - eye lid spasm, oculogyric crisis – turning of eye bulbi upward),
        • Neck muscle spasms (torticollis – „wry neck“)
        • Tongue protrusion

Can be life-threatening – pharyngeal-laryngeal forms

    • Akathasia
      • motor restlessness (restless leg syndrome)
      • „inner restlessness“
      • Treatment: benzodiazepines, beta-blockers

Adverse effects - A- type(dose dependent)

I. Extrapyramidal motor disturbances

  • Slowly developing (often irreversible)
    • Tardive dyskinesia
      • involuntary movements in face/tongue and limbs appearing after months or years of antipsychotic treatment.
      • Includes: tongue thrusting, rolling and „fly catching“,
      • Chewing and „rabbit lip syndrome“ (impaired speech, eating)
      • Grimassing, blinking… + choreiform movements of extremities (caused by up-regulation of D-receptors in striatum?)

Mechanisms of EPS

Dopamine (-)


pathway (+)



GABA (-)


Adverse effects – A -type

II. Decreased seizure threshold

- in predisposed persons may induce seizures (convulsions)!!!

- mainly in high doses

III. Sedation and cognitive deficit

- occurs with many antipsychotics

- antihistamine (H1) activity significantly contributes to this effects

(especially sedative typical drugs but also others)

IV. Antimuscarinic activity

- blurring of vision

- increased intraocular pressure (glaucoma!)

- dry mouth and eyes

- constipation

- urinary retention


Adverse effects – A -type

V. Cardiovascular adverse reactions

- Orthostatic hypotension - α-adrenoreceptorsblockade

- Drug induced QT syndrome (e.g., thioridazine)

VI. Weight gain + dyslipidemia

- probably related to 5-HT blockade and apetite stimulation

VII. Diabetes

- atypical, esp. olanzapine and clozapine


Adverse effects

B –typeunpredictable

  • - neuroleptic malignant syndrome
    • Muscle rigidity, rapid rise in body temp. and mental confusion,
      • instable blood pressure and tachycardia.
    • Death rate 10-20%(renal or cardiovascular failure)
    • Discontinuation of therapy
    • Supportive care is essential (cooling!).
    • It is more frequent with typical antipsychotics.
  • - jaundice(with older drugs, mainly phenothiazines)
    • Usually mild cholestatic hepatitis (obstructive origin), disappears quickly
    • when the drug is stopped
  • - leukopenia and agranulocytosis
    • rare but potentially fatal complication occurring in clozapine – its use requires
    • regular monitoring of blood cell counts
adverse effects others
Adverse effects Others

-urticarial skin reactions

  • mainly phenothiazines

- depositions

- in skin in complex with melanine

gray discolorations of skin and excessive UV light sensitivity

- in cornea/lens(vision disturbances)

selected typical drugs
  • Chlorpromazine
    • 1st classic neuroleptic drug, inexpensive
    • Strong autonomic effects (blocks also ,M, H1)
    • Route: p.o., i.m., i.v.
    • Ind.:
      • schizophrenia (against positive symptoms)
      • Bipolar disorder (against mania)
    • Not to be used: in patients with dementia, treated by IMAO
    • Slow discontinuation after longer treatment
    • Be careful about combination with: sedative drugs, QT-prolonging drugs, hypotensives
  • Haloperidol
    • Prototype incisive neuroleptic drug
    • Butyrophenone (not phenothiazine)
    • Ind.:
      • Schizophrenia (both acute and chronic)
      • Korsakov syndrome (in alcoholics – acute amnesia, confusion, delusions, apathy)
      • Delusional disorders (like paranoid disorders)
      • Psychomotoriccalm-down
      • Antiemetics
    • Lessvegetativesymptoms, more extrapyramidalsymptoms
selected atypical drugs
  • Olanzapine
      • MARTA – much less antiD2 and more anti5-HT2A
      • IND
        • Schizophrenia
        • Manic phase of bipolar disorder (acute treatment and prophylaxis)
      • Superior to haloperidol in overall efficacy in schizophrenia
      • Good response of positive and negative symptoms
      • Response in partial resistance and failure of other atypical drug
      • Adverse reactions: body weight gain, dyslipidemia, diabetes (monitoring!), slight sedation…minimal problems with EPS
  • Clozapine
    • Developed in 70s, but not introduced into clinical practice
    • Adverse effect: leukopenia and agranulocytosis (monitoring), epileptic seizures, anticholinergic effects,
    • The only drug clearly effective in pharmacoresistant forms of disease!!!
    • Very good response in negative symptoms
    • Drug of 3rd choice due to the safety concerns