2. Psychosis
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).
•2
4. 1. Acute and chronic organic brain syndromes (cognitive disorders)
such as, Delirium and dementia, prominent features of confusion,
disorientation, defective memory and disorganized behavior.
2. Functional disorders such as, memory and orientation mostly
retained by emotion, thought, reasoning and behavior are altered.
3. Schizophrenia (split mind) i.e. splitting of perception and
interpretation from reality- hallucination, inability to think
coherently. Schizophrenia is often described in terms of positive or
negetive (deficit) symptoms.. Schizophrenia is a particular kind of
psychosis characterized mainly by a clear sensorium but a marked thinking
disturbance.
4. Paranoid state i.e. fixed delusions (false beliefs) and loss of insight in
to abnormality. •4
5. Schizophrenia
• Onset of schizophrenia is in the late teens -
early ‘20s.
• 0.7-1% population
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• May or may not be present with anatomical
changes.
•5
10. Etiology of Schizophrenia
Characterized by several structural and
functional abnormalities in the brains of
schizophrenic patients:
1) Enlarge cerebral ventricles.
2) Atrophy of cortical layers.
3) Reduced volume of the basal ganglia.
•10
11. Brain Morphology & Schizophrenia
Some schizophrenia patients exhibit
morphological changes in the brain like
enlargement of fluid-filled ventricles.
•11
13. DSM V Diagnosis of Schizophrenia
• Two or more of the following, including 1, 2, or 3
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly abnormal psychomotor behavior
5. Negative symptoms
• Duration: 1 month during last 6
• Social/occupational dysfunction
• Exclusion: medical condition or drug
•13
14. •14
Early treatments of psychosis
•Bethlehem Asylum 'Bedlam‘, one of the first asylums
(1403) •18
th
century asylum
•National Library of Medicine
•Jerrold & Quenzer, Psychopharmacology,
•Sinauer, c2005, p. 445
15. History of Antipsychotic treatments
Schizophrenia has been around perhaps, since the
beginning of humankind, however, it was not until
the last century that it was established as a
separate entity amongst other mental disorders.
Many treatments have been devised:
Hydrotherapy:
“The pouring of cold water in a stream, from a height of
at least four feet onto the forehead, is one of the most
certain means of subsiding violent, maniacal excitement
that we have ever seen tried”... wrote an anonymous
physician in the early 1800’s.
•15
16. Prefrontal lobotomy, Electroconvulsive therapy
• Dr. Egas Moniz –Developed prefrontal lobotomy
technique
• 1935 – heard about work on a chimp “Becky” –
Performed surgery on many patients
• they were just calmer, but also more sluggish and
apathetic
• Awarded the Nobel Prize in Physiology and Medicine
• Next 15 years - 50,000 lobotomies
•16
18. HISTORY OF ANTIPSYCHOTICS
• Anti-psychotics were discovered accidentally by a French
naval surgeon, Henri Laborit. Laborit was interested in
circulatory shock, not schizophrenia.
• Laborit experimented with a variety of drugs to combat shock
syndrome.
• One of the drugs was an agent called Pomethazine. His
primary reason for using the drug was for its effects on the
ANS, however, he discovered the secondary properties of the
drug
– The drug made patients drowsy, reduced pain, and created
a feeling of euphoric quietude.” This drug had
psychological effects.
• Laborit’s observation were used to modify the formula of
Promethazine into the first effective anti-psychotic
medication, Chloropromazine (Thorazine).
• Heinrichs, R. W., (2001). In Search of Madness: Schizophrenia and Neuroscience. Oxford University Press:
New York.
•18
20. Pharmacodynamics
Anatomic Correlates of Schizophrenia...
Areas Associated with Mood and Thought Processes:
Frontal cortex
Amygdala
Hippocampus
Nucleus accumbens
Limbic Cortex
•20
21. Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway.
II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.
•21
22. •22
•Anatomy of dopamine neurons
•Brody, Larner & Minneman, Human Pharmacology, Mosby, c1998, p. 343
23. •23
Functional neuroanatomy of DA in the CNS
• Nigrostriatal pathway: motor planning and execution, habit
formation, learning, habituation, memory
• Mesolimbic: complex target-oriented behavior, integrating
emotional responses, motor and sensory processing
• Mesocortical: cognition; orchestration of thoughts and actions in
accordance with internal goals
• Tuberoinfundibular: tonic inhibition of prolactin release, increase
growth hormone release
• Chemoreceptor trigger zone: emesis & nausea
24. Dopamine System
• DOPAMINE RECEPTORS
– There are at least 5 subtypes of receptors:
– D1 and D5: mostly involved in postsynaptic
inhibition.
– D2, D3, and D4: involved in both pre-and
postsynaptic inhibition.
D2: the predominant subtype in the brain:
regulates mood, emotional stability in the limbic
system and movement control in the basal
ganglia.
•25
28. Schizophrenia - Dopamine Hypothesis
Repeated administration of stimulantslike amphetamines and
cocaine, which enhance central dopaminergicneurotransmission, can
cause a psychosis that resembles the positive symptoms of
schizophrenia
Low doses of amphetamine can induce a psychotic reaction in
schizophrenics in remission
Stress, a major predisposing factor in schizophrenia, can produce a
psychotic state in recovered amphetamine addicts.
Carlsson and Lindqvist (1963) first proposed that drugs such as
chlorpromazine and haloperidol alleviate schizophrenic symptoms by
blocking DA receptors and thereby reduce DA function.
Thess antipsychotic medications, which have been the main stay for
treatment for nearly 50 years, have in common their ability to block
dopamine D2 receptors
•29
29. A strong correlation between the affinity of antipsychotic drugs
for DA receptors and their clinical potency
But no clear and consistent abnormality in DA function has been
detected in schizophrenic patients.
Some early studies with postmortem tissue revealed increased
numbers of DA receptors (in particular D2-like) in schizophrenic
patients, but there are serious problems with these findings. But
long-term administration of antipsychotics produces increases in
D2 receptors in animals.
The reduction in cortical dopamine transmission (both at the pre-
and postsynaptic level) in the chronic Phencyclidine model seems
to be consistent with some findings in schizophrenic patients
Reduced cortical dopamine transmission induced by long-term
PCP exposure may be associated with a hyperactivity of
subcortical dopamine systems
Schizophrenia - Dopamine Hypothesis
•30
30. Dopamine Theory of Schizophrenia
Dopamine Correlates:
• Antipsychotics reduce dopamine synaptic activity.
• These drugs produce Parkinson-like symptoms.
• Drugs that increase DA in the limbic system cause
psychosis.
• Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.
• Increased DA receptor density (Post-mortem, PET).
• Changes in amount of homovanillic acid (HVA), a DA
metabolite, in plasma, urine, and CSF.
•31
31. Dopamine Theory of Schizophrenia
Evidence against the Theory?
• Antipsychotics are only partially effective in most
(70%) and ineffective for some patients.
• Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in non-
schizophrenic subjects than DA agonists.
• Atypical antipsychotics have low affinity for D2
receptors.
• Focus is broader now and research is geared to
produce drugs with less extrapyramidal effects.
•32
32. Other transmitter systems involved..
• Glutamatergic system dysfunction
• e.g. effect of phencyclidine – blocker of NMDA type of
glutamate receptors
• G-protein signaling abnormalities
• Serotoninergic system abnormalities
• most antipsychotics also affect serotonin receptors
Dopamine and serotonin theory of schizophrenia
•33
33. correlation between DA affinity and antipsychotic efficacy has
become weaker as a result of recently developed atypical
antipsychotic medications that also show substantial affinity for
5HT2 receptors
Alteration of 5-HT transmission in the brains of schizophrenics
patients have been reported in post-mortem studies and serotonin-
agonists challenge studies
There are widespread and complex changes in the 5-HT system in
schizophrenics patients
These changes suggest that 5-HT dysfunction is involved in the
pathophysiology of the disease
Schizophrenia - Serotonin Hypothesis
•35
34. •Prefrontal Cortex
•Limbic
System
•GABA/ACh
•Striatum
•Ventral Tegmental Area
(A10)
•Substantia Nigra
(A9)
•Dorsal
Raphe
•Median
Raphe
•5-HT2A antagonists release
dopamine from inhibition and decrease
EPS
•Blockade of D2 receptors
by conventional APDs
causes EPS
•Motor Outputs
•GABA
Glutamate
•Dopamine (DA)
•Serotonin (5-HT)
•Serotonin-Dopamine Interactions
•36
35. • Preclinical as well as clinical studies provide evidence of
hypofunction of NMDA receptors as a contributory process in
the pathophysiology of schizophrenia
• Several clinical trials with agents that act at the glycine
modulatory site on the NMDA receptor have revealed consistent
reductions in negative symptoms andvariable effects of cognitive
and positive symptoms
• These studies also provide evidence that suggests the effects of
clozapineon negative symptoms and cognition may be through
activation of the glycine modulatory site on the NMDA
receptor.
Schizophrenia - Glutamate Hypothesis
•38
36. •Limbic
System
•Ventral Tegmental Area
(A10)
•Substantia Nigra
(A9)
•Dorsal
Raphe
•Median
Raphe
•Prefrontal
Cortex
•Striatum
•NMDA antagonists elevate extracellular brain levels of 5-HT in the
prefrontal cortex
•NMDA antagonists reduce burst
firing of VTA DA neurons
•NMDA antagonists
increase the firing of DA
in limbic areas
•5-HT2A antagonists restore dopaminergic
function in the prefrontal cortex
•5-HT2 antagonists block the
effects of NMDA antagonists
•Dopamine
(DA)
•Glutamate
•Serotonin
(5-HT)
•GABA
•Serotonin-Glutamate-Dopamine Interactions
•39
38. •41
NMDA Hypothesis of Schizophrenia
• Reducing glutamate worsens psychotic symptoms
– Competitive NMDA antagonists induce both positive and negative
symptoms in healthy and schizophrenic subjects
– NMDA antagonists worsen symptoms in unmedicated patients with
schizophrenia
– Chronic treatment with antipsychotic drugs can block effects of NMDA
antagonists
– Decreased levels of glutamate in CSF, prefrontal cortex and
hippocampus of schizophrenics
• NMDA agonists improve symptoms in schizophrenia
39. ANIMAL MODEL OF SCHIZOPHRENIA
• High doses of amphetamine produce a syndrome of repetitive
behaviours (sniffing, head movements, gnawing and licking)
known as stereotypy or stereotyped behaviour.
• Because stereotyped behaviour also occurs in humans after
higher doses of amphetamine and is similar to the repetitions of
meaningless behaviour seen in schizophrenia, the amphetamine-
induced stereotypy has been used as an animal model of
schizophrenia.
• DA receptor antagonists block amphetamine stereotypy and
there is a strong correlation between their potency in this model
and in ameliorating schizophrenic symptoms.
• Other more complicated models are based on attentional and
cognitive abnormalities observed in schizophrenia.
•42
40. Schizophrenia Pathophysiology
Schizophrenia Pharmacologic
Pathophysiology Profile of APDs
Past Excess dopaminergic Dopamine D2-receptor
activity antagonists
Present
Renewed interest in the Combined 5-HT2/D2
role of serotonin (5-HT) antagonists
Future
Imbalance in cortical More selective antagonists
communication and Mixed agonist/antagonists
cortical-midbrain Neuropeptide analogs
integration, involving
multiple neurotransmitters
•43
41. Antipsychotics treatment
Antipsychotics/Neuroleptics
• Antipsychotics are the drugs currently used in
the prevention of psychosis.
• They have also been termed neuroleptics,
because they suppress motor activity and
emotionality.
** These drugs are not a cure **
• Schizophrenics must be treated with
medications indefinitely, in as much as the
disease in lifelong and it is preferable to
prevent the psychotic episodes than to treat
them.
•44
42. Antipsychotic treatments
In 1940’s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly
were adopted by psychiatrists to calm down their
mental patients.
In 1955, chlorpromazine was developed as an
antihistaminic agent by Rhône-Pauline Laboratories
in France. In-patients at Mental Hospitals dropped
by 1/3.
•45
43. Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are drugs
used mainly in the treatment of schizophrenia,
they are also used in the treatment of other
psychoses associated with depression and
manic-depressive illness, and psychosis
associated with Alzheimer’s disease. These
conditions are life-long and disabling.
•46
48. Antipsychotics/Neuroleptics
• It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.
• The affinities of most older “classical” agents
for the D2 receptors correlate with their
clinical potencies as antipsychotics.
•51
49. •52
•The potency of antipsychotic drugs in binding to the D2 family of
receptors is proportional to the potency of the drugs in treating
schizophrenia
•This is not true for the potency
of the drugs in blocking histamine
H1, serotonin or α-adrenergic
receptors
•Adapted from Nestler Hyman & Malencka, Molecular Neuropharmacol.ogy, McGraw Hill, c2001, p. 402
50. Antipsychotics/Neuroleptics
• Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.
• Clozapine has a higher affinity for the D4 receptors
than for D2.
• Recently it has been found that most antipsychotic
drugs may also bind D3 receptors (therefore, they
are non-selective).
•53
51. Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor
activity).
– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors
(increased locomotion and stereotyped behavior).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of
prolactin release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
•54
52. Pharmacokinetics
Absorption and Distribution
• Most antipsychotics are readily but incompletely
absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65%.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98%).
• High volumes of distribution (>7 L/Kg).
• Slow elimination.
**Duration of action longer than expected, metabolites are present
and relapse occurs, weeks after discontinuation of drug.**
•55
53. Pharmacokinetics
Metabolism
• Most antipsychotics are almost completely
metabolized.
• Most have active metabolites, although not
important in therapeutic effect, with one
exception. The metabolite of thioridazine,
mesoridazine, is more potent than the parent
compound and accounts for most of the
therapeutic effect.
•56
60. Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain
why their therapeutic effects are not evident until
4-8 weeks of treatment.
Possible reasons are…
•63
61. Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors
Compensatory Effects
Firing rate and activity of nigrostriatal and mesolimbic DA
neurons.
DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.
Receptor Supersensitivity •64
62. Adverse Effects Summary
• Sedation - initially considerable; tolerance usually develops
after a few weeks of therapy; dysphoria
• Postural hypotension - results primarily from adrenergic
blockade; tolerance can develop
• Anticholinergic effects - include blurred vision, dry mouth,
constipation, urinary retention; results from muscarinic
cholinergic blockade
• Endocrine effects - increased prolactin secretion can cause
galactorhea; results from antidopamine effect
• Hypersensitivity reactions - jaundice, photosensitivity,
rashes, agranulocytosis can occur
• Idiosyncratic reactions - malignant neuroleptic syndrome
• Weight gain
• Neurological side effects - see next
•65
63. Antipsychotics & Tardive Dyskinesia
•Chronic blockade of D2 receptors leads
•them to up-regulate.
•This may cause involuntary
movements.
•tardive: slow or belated onset
•dyskinesia: presence of involuntary movements, tongue thrusts, lip smacking,
• eye blinking
•Potentially permanent! •66
73. REACTION FEATURES TIME OF
MAXIMAL RISK
PROPOSED
MECHANISM
TREATMENT
Acute dystonia Spasm of muscles of tongue,
face, neck, back; may mimic
seizures; not hysteria
1 to 5 days Unknown Antiparkinsonian agents are
diagnostic and curative
Akathisia Motor restlessness; not
anxiety or "agitation"
5 to 60 days Unknown Reduce dose or change drug:
antiparkinsonian agents,b
benzodiazepines or
propranololc may help
Parkinsonism Bradykinesia, rigidity,
variable tremor, mask facies,
shuffling gait
5 to 30 days Antagonism of
dopamine
Antiparkinsonian agents
helpful
Neuroleptic
malignant
syndrome
Catatonia, stupor, fever,
unstable blood pressure,
myoglobinemia; can be fatal
Weeks; can persist for
days after stopping
neuroleptic
Antagonism of
dopamine may
contribute
Stop neuroleptic
immediately: dantrolene or
bromocriptined may help:
antiparkinsonian agents not
effective
Perioral tremor
("rabbit" syndrome)
Perioral tremor (may be a
late variant of parkinsonism)
After months or years
of treatment
Unknown Antiparkinsonian agents
often help
Tardive dyskinesia Oral-facial dyskinesia;
widespread choreoathetosis
or dystonia
After months or years
of treatment (worse on
withdrawal)
Excess function of
dopamine
hypothesized
Prevention crucial; treatment
unsatisfactory
a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg
intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to
perhaps several weeks thereafter. b. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less
effective. c. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects,
bromocriptine may be tolerated in large doses (10-40 mg per day).
Neurological Side Effects of antipsychotics
•77
74. FGA Side effects
Weight gain – 40% - weight gain now attributed to ratio of binding to D2
and 5-HT2 receptors; possibly also histamine (for newer antipsychotics
anyway)
Sexual dysfunction
result from NE and SE blockade
erectile dysfunction in 23-54% of men
retrograde ejaculation in
loss of libido and anorgasmia in men and women
Seizures - <1% for generalized grand mal
•78
75. •ESTIMATED MEAN WEIGHT GAIN AT 10 WEEKS
•Allison DB, •Mentore •JL, •Heo •M, et al: Weight gain associated with conventional
•and newer •antipsychotics •: a meta•- •Analysis. AJP, 1999.
•0
•1
•2
•3
•4
•5
•-1
•Meanchangeinbodyweight(kg)
•A comprehensive literature search identified 78 studies that included data on weight change in patients treated with a specific antipsychotic.
•For each agent a meta-analysis and random effects regression estimated the change in weight at 10 weeks of treatment.
•79
76. Summary: Pros & Cons
• FGAs have strong efficacy against + symptoms.
• FGAs either do not help – symptoms or exacerbate them.
• The primary concern with FGAs is long-term development of
tardive dyskinesia although acute EPS impair the quality of
life of schizophrenics.
•Stahl, S. (2008). Essential Psychopharmacology, p. 369.
•80
77. ARRIVAL OF THE ATYPICAL ANTIPSYCHOTIC
• “German psychiatrists working with G. Stille at
Wander Pharmaceuticals in Bern, Switzerland, in the
early 1960s worked to refute that EPS and
antipsychotic efficacy were linked. Their work led to
the introduction of Clozapine, an antipsychotic with
no EPS.”
• Clozapine was briefly marketed and quickly
withdrawn for two reasons:
– The embarrassment of not having any EPS, and
– Agranulocytosis
•81
80. NEUROBIOLOGY OF CLOZAPINE
•Here you can see that Clozapine will not bind to any Dopamine
receptor, it is selective, it has an affinity for the D4 receptor subtype.
•84
81. Atypical (Second Generation)
• Mechanism of Action
– Dissociate more rapidly from the D2 receptor
•Stahl, S. (2008). Essential Psychopharmacology, p. 369-370.
•85
82. MOA of Atypical Antipsychotics
• Dissociate more rapidly from the D2 receptor
– ↓ acute EPS, ↓ hyperprolactinemia
•Stahl, S. (2008). Essential Psychopharmacology, p. 371. •86
83. MOA of Atypicals
• Atypicals
– Dissociate more rapidly from the D2 receptor
– Block the 5-HT2A (and so many other!) receptors
•Stahl, S. (2008). Essential Psychopharmacology, p. 384.
•87
85. Risks with long-term Atypicals
•Mechanism: 5-HT2C
•Mechanism: X
•$515 Million
•89
86. • SGAs produce less acute EPS than FGA but
also cause diabetes.
• No clear consensus exists in the choice
between FGA and SGA.
• Using agents at above recommended doses or
combining drugs are common clinically but are
not well studied.
•90
88. Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic
(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of
treatment and shows no predilection for age,
duration of treatment, antipsychotic
medication, or dose.
•94
89. Neuroleptic Malignant Syndrome
• Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
• Due to excessively rapid blockade of postsynaptic
dopamine receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with
this syndrome may be mistaken for an infection.
• Autonomic instability with altered blood pressure
and heart rate is another midbrain manifestation.
• Creatine kinase isozymes are usually elevated,
reflecting muscle damage. •95
93. • The most important are those on the
cardiovascular,
• central and autonomic nervous systems, and
endocrine system. Other dangerous
• effects are seizures, agranulocytosis, cardiac
toxicity, and pigmentary degeneration of the
retina, all
• of which are rare
TOXIC REACTIONS AND ADVERSE
EFFECTS
•99