Schizophrenia and

antipsychotics
 Schizophrenia
 Characterized by psychosis, hallucinations,
delusions, cognitive defects, occupational
and social dysfunction
 Chronic psychotic illness
 Episodic exacerbations and remissions with residual symptoms
 Complete remission is not common
 Schizophrenia
 Positive symptoms Negative symptoms
 Hallucinations Social withdrawal
 Delusions Emotional
 Disordered thinking withdrawal
 Disorganized Lack of motivation
speech
Poverty of speech
 Combativeness
Blunted affect
 Agitation
Poor insight
 Paranoia
Poor judgement
Poor self-care
 The Criteria of
Diagnosis
For the diagnosis of schizophrenia is necessary
• presence of one very clear symptom - from point 1 to 4
• or the presence of the symptoms from at least two groups -
from point 5 to 9 for one month or more:

1. the hearing of own thoughts, the feelings of thought

withdrawal, thought insertion, or thought broadcasting
2. the delusions of control, outside manipulation and influence,
or the feelings of passivity, which are connected with the
movements of the body or extremities, specific thoughts,
acting or feelings, delusional perception
3. hallucinated voices, which are commenting permanently the
behavior of the patient or they talk about him between
themselves, or the other types of hallucinatory voices,
coming from different parts of body
4. permanent delusions of different kind, which are
inappropriate and unacceptable in given culture
 The Criteria of
Diagnosis
5. the lasting hallucination of every form
6. blocks or intrusion of thoughts into the flow of thinking and
resulting incoherence and irrelevance of speach, or
neologisms
7. catatonic behavior
8. „the negative symptoms”, for instance the expressed
apathy, poor speech, blunting and inappropriatness of
emotional reactions
9. expressed and conspicuous qualitative changes in
patient’s behavior, the loss of interests, hobbies,
aimlesness, inactivity, the loss of relations to others and
social withdrawal

• Diagnosis of acute schizophorm disorder (F23.2) – if the

conditions for diagnosis of schizophrenia are fulfilled, but
lasting less than one month
• Diagnosis of schizoaffective disorder (F25) - if the
schizophrenic and affective symptoms are developing
together at the same time
 Schizophrenia
 Epidemiology
 Incidence is about 1% of population,
with a strong, but not invariable,
hereditary component
 Onset in late teens or early 20s in
males; sometime later in females
 Suicide rate comparable to depressive
illness (approx 10%)
 Schizophrenia
 Etiology
 Exact etiology unknown
 Genetic predisposition
 Intrauterine, birth or postnatal complications
 Viral CNS infections
 Environmental stressors (biochemical or social)

 No evidence of association with poor parenting

 cont….
 Stress such as relationship problems, financial difficulties,
social isolation, bereavement, etc.
 A viral infection during the mother's pregnancy, or in early
childhood.
 A lack of oxygen at the time of birth that may damage a
part of the brain.
 Illegal or street drugs may trigger the condition in some
people. For example, those who use cannabis heavily are
six times more likely to develop schizophrenia than
nonusers. Many other drugs of abuse such as amfetamines,
cocaine, ketamine, and lysergic acid diethylamide (LSD) can
trigger a schizophrenia-like illness.
 Schizophrenia
 Pathophysiology
 No consistent neuropathology or biomarkers for schizophrenia
 ? Increased dopamine in mesolimbic pathways causes
delusions and hallucinations
 ? Dopamine deficiency in mesocortical and nigrostriatal
pathways causes negative symptoms (apathy, withdrawal)
 Hallocinogens produce effect through action on 5-HT2
receptors
 Etiology of Schizophrenia - Dopamine Hypothesis
• The most influential and plausible are the
hypotheses, based on the supposed disorder of
neurotransmission in the brain, derived mainly from
1. the effects of antipsychotic drugs that have in common the
ability to inhibit the dopaminergic system by blocking
action of dopamine in the brain
2. dopamine-releasing drugs (amphetamine, mescaline,
diethyl amide of lysergic acid - LSD) that can induce state
closely resembling paranoid schizophrenia

• Classical dopamine hypothesis of schizophrenia:

Psychotic symptoms are related to dopaminergic
hyperactivity in the brain. Hyperactivity of
dopaminergic systems during schizophrenia is result
of increased sensitivity and density of dopamine D2
receptors in the different parts of the brain.
 Schizophrenia -
Contemporary Models
• Dopamine hypothesis revisited: various
neurotransmitter systems probably takes place in the
etiology of schizophrenia (norepinephric, serotonergic,
glutamatergic, some peptidergic systems); based on
effects of atypical antipsychotics especially.

• Contemporary models of schizophrenia conceptualize

it as a neurocognitive disorder, with the various signs
and symptoms reflecting the downstream effects of a
more fundamental cognitive deficit:
o the symptoms of schizophrenia arise from “cognitive
dysmetria” (Nancy C. Andreasen)
o concept of schizophrenia as a neurodevelopmental disorder
(Daniel R. Weinberger)
 Etiology of Schizophrenia -
Neurodevelopmental Model
• Neurodevelopmental model supposes in
schizophrenia the presence of “silent lesion” in
the brain, mostly in the parts, important for the
development of integration (frontal, parietal and
temporal), which is caused by different factors
(genetic, inborn, infection, trauma...) during very
early development of the brain in prenatal or early
postnatal period of life.
• It does not interfere too much with the basic brain
functioning in early years, but expresses itself in
the time, when the subject is stressed by
demands of growing needs for integration, during
formative years in adolescence and young
adulthood.
Antipsychotic Agents

• Antipsychotic drugs are able to reduce psychotic

symptoms in a wide variety of conditions, including
schizophrenia, bipolar disorder, psychotic depression,
senile psychoses, various organic psychoses, and
drug-induced psychoses. They are also able to
improve mood and reduce anxiety and sleep
disturbances, but they are not the treatment of choice
when these symptoms are the primary disturbance in
nonpsychotic patients.
 Treatment of
Schizophrenia
• The acute psychotic schizophrenic patients will
respond usually to antipsychotic medication.
• According to current consensus we use in the first
line therapy the newer atypical antipsychotics,
because their use is not complicated by appearance
of extrapyramidal side-effects, or these are much
lower than with classical antipsychotics.
chlorpromazine, chlorprotixene, clopenthixole,
conventional levopromazine, periciazine, thioridazine
antipsychotics droperidole, flupentixol, fluphenazine,
(classical fluspirilene, haloperidol, melperone,
neuroleptics) oxyprothepine, penfluridol, perphenazine,
pimozide, prochlorperazine, trifluoperazine
atypical amisulpiride, clozapine, olanzapine,
antipsychotics quetiapine, risperidone, sertindole, sulpiride
 Antipsychotics
• Main categories are:
• Typical antipsychotics
• Phenothiazines (chlorpromazine,
perphenazine, fluphenazine,
thioridazine et al)
• Thioxanthenes (flupenthixol,
clopenthixol)
• Butyrophenones (haloperidol,
droperidol)
• Atypical antipsychotics (e.g. clozapine,
risperidone, sulpiride, olanzapine)
 Classification of
Antipsychotic drugs
• Distinction between ‘typical’ and
‘atypical’ groups is not clearly defined,
but rests on:
• -Incidence of extrapyramidal side-
effects(EPS) (less in ‘atypical’ group)
• -Efficacy in treatment-resistant group
of patients
• -Efficacy against negative symptoms.
 Modes of action
• - All anti-psychotic drugs have inhibitory
effects on the D2 receptor
• - Some have actions against the D1, D4
receptors
• - All have other effects - to varying degrees:
• Serotonin 5HT2 blockade (may improve negative
symptoms)
• Histamine H1 blockade (drowsiness)
• Alpha adrenoceptor blockade (postural hypotension)
• Muscarinic receptor blockade ( dry mouth,
hypothension, blurred vision, constipation)
 Typical /
conventional
antipsychotics
 Chlorpromazine( Fenactil)
 Flupenthixol (Fluanxol®)
 Haloperidol
 Perazinum (Perazin)
 Trilafon
 Sulpiride
 Thioridazine
 Trifluoperazine (Apo-trifluoperazine)
 Thiothixene
 Typical /
conventional
antipsychotics
 Refers to agents introduced in US
before 1990
 Also known as
 “Dopamine receptor antagonists”
 Pharmacologic activity at blocking central
dopamine receptors (esp. D2 receptors)
 “Neuroleptics”
 Due to tendency to cause neurologic adverse
effects
 “Major tranquilizers”
 Inappropriate as these agents (esp. high
potency) can improve psychosis without
sedating or making patients tranquil
 Typical /
conventional
antipsychotics
Dopamine receptors in various tracks
Track Origin Innervation Function Antipsychotic
s effect
Mesolimbic Midbrain, Limbic Emotional Hallucinations
Ventral structure, and , deulsions,
nucleus intellectual disordered
tegmental cognition
accumbens

Mesocortic Ventral Frontal

al tegmental cortex
Nigrostriat Substantia Basal Extrapyramid Motor
al nigra ganglia al system symptomatolo
movement gy

Tubero- Hypothalam Pituitary Regulate Plasma

infundubul us gland endocrine prolactin levels
ar functions
 Typical /
conventional
antipsychotics
 Mechanism of action
 Blocks receptors for dopamine, acetylcholine, histamine and
norepinephrine
 Current theory suggests dopamine (D2) receptors suppresses
psychotic symptoms
 All typical antipsychotics block D2 receptors
 Close correlation between clinical potency and potency as
D2 receptor antagonists
 Typical /
conventional
antipsychotics
 Properties
 Effective in reducing positive symptoms
during acute episodes and in preventing
their reccurrence
 Less effective in treating negative
symptoms
 Some concern that they may exacerbate
negative symptoms by causing akinesia
 Higher incidence of EPS / sedation /
anticholinergic Adverse effects
 Typical /
conventional
antipsychotics
 Potency
 All have same ability to relieve symptoms of psychosis
 Differ from one another in terms of potency
 i.e. size of dose to achieve a given response
 When administered in therapeutically equivalent doses, all drugs
elicit equivalent antipsychotic response
 Typical /
conventional
antipsychotics
 Low potency
 Chlorpromazine, thioridazine
 Medium potency
 Perphenazine
 High potency
 Trifluoperazine, thiothixene, fluphenazine, haloperidol, pimozide
 Typical /
conventional
antipsychotics
Potency Drug Equiv EPS Sedation Anticholinergic
oral s/e
dose
(mg)
Low Chlorpromazi 100 Moderat High Moderate
ne e
Pericyazine NA Low High Low
Thioridazine 100 Low High High
Moderat Perphenazine 10 Moderat Moderate Low
e e
High Trifluoperazin 5 High Low Low
e
Thiotheixene 2 High Low Low
Fluphenazine 2 High Low Low
Haloperidol 2 High Low Low
Pimozide 0.5 High Moderate Moderate
 Typical /
conventional
antipsychotics
Comparison of representative antipsychotics
Drug Advantages Disadvantages
Chlorpromazin Generic, Many adverse
e inexpensive effects (esp.
autonomic)
Thioridazine Slight EPS, generic Cardiotoxicity (QT
prolongation)
Fluphenazine Generic, depot (?) increased
available tardive dyskinesia
Thiothixene (?) decreased Uncertain
tardive dyskinesia
Haloperidol Generic, injection Prominent EPS
and depot A/V, few
autonomic s/e
 Differences among
Antipsychotic Drugs
• Chlorpromazine and thioridazine
• block α1 adrenoceptors more potently than D2
receptors
• block serotonin 5-HT2 receptors relatively strongly
• affinity for D1 receptors is relatively weak
• Haloperidol
• acts mainly on D2 receptors
• some effect on 5-HT2 and α1 receptors
• negligible effects on D1 receptors
• Pimozide and amisulpride†
• act almost exclusively on D2 receptors
 Typical / conventional
antipsychotics
Receptor blockade and Adverse effects
Receptor type Consequence of blockade
D2 dopaminergic Extrapyramidal symptoms;
prolactin release
H1 histaminergic Sedation
Muscarinic Dry mouth, blurred vision,
cholinergic urinary retention, constipation,
tachycardia
Alpha1-adrenergic Orthostatic hypotension; reflex
tachycardia
5-HT2 serotonergic Weight gain
 Typical / conventional
antipsychotics
 Adverse effects
 Extrapyramidal symptoms (EPS)
 Early reactions – can be managed with drugs
 Acute dystonia
 Parkinsonism
 Akathisia
 Late reaction – drug treatment unsatisfactory
 Tardive dyskinesia (TD)
 Early reactions occur less frequently with low
potency drugs
 Risk of TD is equal with all agents
 Typical / conventional
antipsychotics
 Adverse effects
 Acute dystonia
 Develops within a few hours to 5 days after first dose
 Muscle spasm of tongue, face, neck and back
 Oculogyric crisis (involuntary upward deviation of
eyeballs)
 Opisthotonus (tetanic spasm of back muscles,
causing trunk to arch forward, while head and lower
limbs are thrust backwards)
 Laryngeal dystonia can impair respiration
 Management
 Anticholinergics (Benztropine, diphenhydramine IM/IV)
 Lower or split dosing
 Switch agent
 Add scheduled benztropine / diphenhydramine with
antipsychotic
 Typical / conventional
antipsychotics
 Adverse effects
 Parkinsonism (neuroleptic induced)
 Occurs within first month of therapy
 Bradykinesia, mask-like facies, drooling, tremor,
rigidity, shuffling gait, cogwheeling, stooped
posture
 Shares same symptoms with Parkinson’s disease
 Management
 Centrally acting anticholinergics (scheduled
benztropine / diphenhydramine / benzhexol with
antipsychotics) and amantadine
 Avoid levodopa as it may counteract antipsychotic
effects
 Switch to atypical antipsychotics for severe
symptoms
 Typical / conventional
antipsychotics
 Adverse effects
 Akathisia
 Develop within first 2 months of therapy
 Compulsive, restless movement
 Symptoms of anxiety, agitation
 Management
 Beta blockers (propranolol)
 Benzodiazepines (e.g. lorazepam)
 Anticholinergics (e.g. benztropine, benzhexol)
 Reduce antipsychotic dosage or switch to low
potency agent
 Typical /
conventional

antipsychotics
Adverse effects
 Tardive dyskinesia (TD)
 Develops months to years after therapy
 Involuntary choreoathetoid (twisting, writhing, worm-like)

rhytmical movements of tongue and face, but also of trunk and

limbs, appearing after months or years of antipsychotic
treatment. It may be associated with proliferation of dopamine
receptors (possibly presynaptic) in corpus striatum
 Can interfere with chewing, swallowing and speaking
 Symptoms are usually irreversible
 Typical /
conventional
antipsychotics
 Adverse effects
 Tardive dyskinesia (TD)
 Management
 Some manufacturers suggest drug withdrawal at
earliest signs of TD (fine vermicular movements
of tongue) may halt its full development
 Gradual drug withdrawal (to avoid dyskinesia)
 Use lowest effective dose
 Atypical antypsychotic for mild TD
 Clozapine for severe, distressing TD
 Inconsistent results with
 Diazepam, clonazepam, valproate
 Propranolol, clonidine
 Vitamin E
 Typical /
conventional
antipsychotics
 Other Adverse effects
 Neuroleptic malignant syndrome (NMS)
 Rare but serious reaction, 0.2% of patients on
neuroleptics
 High fever, autonomic instability, mental status
changes, leaden rigidity, elevated CK, WBC,
myoglobinuria
 Management
 Discontinue antipsychotic
 Paracetamol for hyperthermia
 IV fluids for hydration
 Benzodiazepines for anxiety
 Dantrolene for rigidity and hyperthermia
 Bromocriptine for CNS toxicity
 Typical /
conventional
antipsychotics
 Other Adverse effects
 Neuroleptic malignant syndrome (NMS)
 After symptom resolution
 Some suggest to wait for at least 2 weeks before
resuming
 Use lowest effective dose
 Avoid high potency agents
 Consider atypical antipsychotics
 However, NMS has been reported from patients
taking clozapine, risperidone, olanzapine and
quetiapine
 Typical /
conventional
antipsychotics
 Other Adverse effects
 Prolactinemia
 D2 receptor blockade decreases dopamine
inhibition of prolactin
 Results in galactorrhea, amenorrhea, loss of
libido
 Managed with bromocriptine
 Sedation
 Administer once daily at bedtime
 Seizures
 Haloperidol has a lower risk of seizures
 Anticonvulsants (beware or possible interaction
with antipsychotic)
 Atypical
antipsychotics
 Refers to newer agents
 Also known as
 “Serotonin-dopamine antagonists”
 Postsynaptic effects at 5-HT2A and D2 receptors
 Atypical
antipsychotics
 Amisulpiride (Solian®)
 Quetiapine (Seroquel®)
 Ziprasidone (Zeldox®)
 Risperidone (Risperdal®)
 Olanzapine (Zyprexa®)
 Clozapine (Clozaril®)
 Aripiprazole (Abilify®)
 Atypical
antipsychotics
 Mechanism of action
 Similar blocking effect on D2 receptors
 Seem to be a little more selective,
targeting the intended pathway to a larger
degree than the others
 Also block or partially block serotonin
receptors (particularly 5HT2A, C and
5HT1A receptors)
 Aripiprazole: dopamine partial agonist
(novel mechanism)
 Atypical
antipsychotics
 Properties
 Available evidence to show advantage for some (clozapine,
risperidone, olanzapine) but not all atypicals when compared
with typicals
 At least as effective as typicals for positive symptoms
 May be more efficacious for negative and cognitive symptoms
(still under debate)
 Atypical
antipsychotics
 Properties
 Less frequently associated with EPS
 More risk of weight gain, new onset diabetes, hyperlipidemia
 Novel agents, more expensive
 Atypical
antipsychotics
 Potency
 All atypical antipsychotics are equally effective at therapeutic
doses
 Except clozapine
 Most effective antipsychotic
 For resistant schizophrenia
 2nd line due to life-threatening side effect
 Atypical
antipsychotics
Relative receptor-binding of atypical
antipsychotics
Drug D1 D2 5- 1 M1 H1
HT2
Clozapine ++ ++ +++ ++ ++ +
+ +
Risperidone - ++ +++ ++ - +
+ +
Olanzapine ++ ++ +++ ++ ++ ++
+
Quetiapine - + ++ ++ + +
+
 Atypical
antipsychotics
Comparison of representative atypical antipsychotics
Drug Advantages Disadvantages
Clozapine For treatment-resistant Risk of fatal agranulocytosis
cases, little EPS
Risperidone Broad efficacy, little or no EPS and hypotension at high
EPS at low doses doses
Olanzapine Effective with positive and Weight gain
negative symptoms, little
or no EPS
Quetiapine Similar to risperidone, Dose adjustment with
maybe less weight gain associated hypotension, bd
dosing
Ziprasidone Perhaps less weight gain QT prolongation
than clozapine, Inj A/V
Aripiprazole Less weight gain, novel Uncertain
mechanism potential
 Atypical
antipsychotics
Relative incidence of Adverse effects

Drugs Sedatio EP Anticholinerg Orthostas Seizur Prolacti Weight

n S ic is e n gain
elevatio
n
Clozapine ++++ + ++++ ++++ ++++ 0 ++++

Risperidon +++ + ++ +++ ++ 0 to ++ ++

e ++

Olanzapin +++ + +++ ++ ++ + +++

e
Quetiapin +++ + ++ ++ ++ 0 ++
e
Ziprasidon ++ + ++ ++ ++ 0 +
e
Aripiprazo ++ + ++ ++ ++ 0 +
le
 Atypical
antipsychotics
 1st line atypical antipsychotics
 All atypicals except clozapine
 NICE recommendations
 Atypical antipsychotics considered when
choosing 1st line treatment of newly diagnosed
schizophrenia
 Treatment option of choice for managing acute
schizophrenic episode
 Considered when suffering unacceptable Adverse
effects from a conventional antipsychotic
 Changing to an atypical not necessary if typical
controls symptoms adequately and no
unacceptable Adverse effects
 Atypical
antipsychotics
 2nd line atypical antipsychotic
 Clozapine
 Most effective antipsychotic for reducing
symptoms and preventing relapse
 Use of clozapine effectively reduce suicide risk
 1% risk of potentially fatal agranulocytosis
 Acute pronounced leukopenia with great
reduction in number of neutrophil
NICE(National Institute for Health and Clinical Excellence)
recommendations
 Clozapine should be introduced if schizophrenia
is inadequately controlled despite sequential
use of 2 or more antipsychotic (one of which
should be an atypical) each for at least 6-8
weeks)
 Atypical
antipsychotics
 Clozapine
 Rare cases of myocarditis and
cardiomyopathy
 Fatal
 Most commonly in first 2 months
 Recommendations
 Physical exam and medical history before starting
 Persistent tachycardia esp. in first 2 weeks should
prompt observation for cardiomyopathy
 If myocarditis or cardiomyopathy, stop clozapine
 Inform patients for unexplained fatigue, dyspnea,
tachypnea, chest pain, paipitation and ask them
to report these signs and symptoms immediately
 Atypical
antipsychotics
 Clozapine
 Contraindication
 History of clozapine-induced agranulocytosis
 Bone marrow suppression
 On myelosuppressive drugs

 Caution
 Seizure disorders
 Diabetes
 dispersible and
solution
preparations
 Oral-dispersible preps available for
 2 atypicals
 Risperidone (Risperdal Quicklet®)
 Olanzapine (Zyprexa Zydis®)
 Carefully peel off packing, allow tablet to dissolve on
tongue and swallow
 Do not break the tablet
 Some may be dispersed in fluids (consult manufacturer
literature)
 Solutions available for
 1 typical
 Haloperidol (Haldol® drops)
 1 atypical
 Risperidone (Risperdal® solution)
 Very concentrated, avoid from contact with skin
(dermatitis)
 Antipsychotic
injections
 Available for
 2 typicals
 Chlorpromazine
 Haloperidol (Haldol®)

 2 atypicals
 Olanzapine (Zyprexa®)
 Ziprasidone (Zeldox®)

 Useful for acutely agitated patients

 Antipsychotic depot
injections
 Available for
 4 typicals
 Haloperidol decanoate (Haldol Decanoate®)
 Fluphenazine decanoate (Modecate®)
 Flupenthixol (Fluanxol®)
 Zuclopenthixol (Clopixol Depot®)
 1 atypical
 Risperidone (Risperdal Consta®)
 Used for chronic illness and history of
noncompliance
 Trial of oral meds first to assess tolerability
 Non-antipsychotic
agents
 Benzodiazepines
 Useful in some studies for anxiety, agitation,
global impairment and psychosis
 Schizophrenic patients are prone to BZD
abuse
 Limit use to short trials (2-4 weeks) for
management of severe agitation and anxiety
 Lithium
 Limited role in schizophrenia monotherapy
 Improve psychosis, depression, excitement,
and irritability when used with antipsychotic
in some studies
 Non-antipsychotic
agents
 Carbamazepine
 Weak support when used alone and with antipsychotic
 Alters metabolism of antipsychotic
 NOT to be used with clozapine (risk of agranulocytosis)
 Valproate
 Concurrent administration with risperidone and
olanzapine resulted in early psychotic improvement in
recent investigation
 Propranolol
 Research showed improvement in chronic aggression
 Treat aggression or enhance antipsychotic response
 Reasonable trial  240mg/day
 Antipsychotics in
schizophrenia
 Selection of typical antipsychotics
 Equally efficacious
 Chosen by side effect profile
 Atypical antipsychotics may be
appropriate if
 Adverse effect is a particular concern
 Additional benefits for negative and cognitive
symptoms required
 Clozapine
 2nd line treatment when other agents are
ineffective or not tolerated
 Antipsychotics in
schizophrenia
 Depot antipsychotic preparations
 Useful for noncompliant patients with poor
insight
 Antidepressents and mood stabilisers
 In schizoaffective disorders
 Patients with secondary mood symptoms
or aggressivity
 Differentiate between adverse effects
and signs of disease progression
 E.g. Parkinsonism vs. psychotic hysteria,
Akathisia vs. exacerbation of psychosis
 Antipsychotics in
schizophrenia
 Oral administration
 Divided daily doses at initial phase
 Once daily at bedtime when stabilized
 Promoting sleep and reducing daytime sedation
 Smallest effective dose employed
 Oral-dispersible and solution preparations
 For unreliable patients
 Injections
 Usually deltoid or gluteal muscle (or according to
manufacturer)
 Depot injections
 At intervals of 1 to 4 weeks
 Generally not more than 2-3ml oily injection at one site
 Correct injection technique (z-track) and injection site
rotation
 Antipsychotics in
schizophrenia
 Treatment response
 First 7 days
 Decreased agitation, hostility, combativeness,
anxiety, tension and aggression
 Normalization of sleep and eating habits
 First 2-3 weeks
 Increased socialization, improvement in self-
care
 6-8 weeks
 Improvement in formal thought disorder
 Antipsychotics in
schizophrenia
 Acute phase
 Initiate therapy
 Titrate as tolerated to average effective dose
 Stabilization phase
 Dose titration within the therapeutic range
 Maintenance phase
 Therapy should be continued for at least 12 months
after remission of 1st episode
 Good treatment responders should be treated for
at least 5 years
 Continuous lifetime maintenance required in the
majority of patients to prevent relapse
 Lowest effective and tolerable dose
 drugs
used in
affective
disorders
 DEPRESSION
• Types
• Symptoms
• Diagnosis
• Causes
• Treatment
 Definitions
• Affective disorders - mental illnesses
characterized by pathological changes in mood
(not thought – compare with schizophrenia)
1. Unipolar disorders
• Depression – pathologically depressed mood (life time
prevalence up to 17%)
• Mania – excessive elation and accelerated psychomotoric activity
(rare)

2. Bipolar disorder (manic-depressive illness) – „cycling mood“

• = severe highs (mania, event. hypomania) and lows (major
depressive episodes)
• prevalence 1-5%, life-time illness, stronger genetic background
 Depression
 Epidemiology
 Life prevalence 3-17%(US 2008)
 Onset in late 20’s
 Highest in
 25-44 years
 Elderly in community
 Female vs male = 2:1
 Female 10-25% lifetime risk
 Male 5-12% lifetime risk
 Depression
 Epidemiology
 4th most common reason to visit family
physician
 Most common in elderly and difficult to
diagnose
 Coexists with dementia or delirium frequently
 Recurrence rate of major depression
 After single episode = 50%
 After second episode = 70%
 After third episode = 90%
 Approx 10-15% of patients with major
depressive or bipolar disorder complete
suicide
 Depression
• common mental disorder that presents with depressed mood, loss of
interest or pleasure, feelings of guilt or low self-worth, disturbed
sleep or appetite, low energy, and poor concentration (WHO def.)
• Major Depressive Episode Criteria/Core symptoms
o Five (or more) of the following symptoms have been
present during the same 2-week period and represent
a change from previous functioning
o (1) depressed mood or (2) loss of interest or pleasure
must be present
• significant weight loss /gain
• insomnia or hypersomnia
• psychomotor agitation or retardation, fatigue or loss of
energy
• feelings of worthlessness or excessive or inappropriate guilt
• diminished ability to think or concentrate, or indecisiveness
• recurrent thoughts of death or suicidal ideation without a
specific plan or a suicide attempt (!)
 Additional Signs include
Feeling empty
Inability to enjoy anything
Hopelessness
Loss of sexual desire
Loss of warm feelings for family or friends
Loss of self esteem
Inexplicable crying spells, sadness or irritability
Unexplained headaches or backaches
Stomachaches, indigestion or changes in bowl
habits
 What is not depression
• it is not the same as a passing „blue
mood“.
• It is not a sign of personal weakness or a
condition that can be wished away.
• people with a depressive disease can not
merely "pull themselves together" and get
better.
- no effect of encouraging to do so!
• without treatment, symptoms can last for
weeks, months, or years.
• appropriate treatment, however, can help most
people with depression.
 Common Types of Depression

Major Depression
Dysthymia
Bipolar Disorder
Seasonal Affective Disorder (SAD)
 Major Depression
This type causes symptoms that
may:
Begin suddenly, possibly triggered by a
loss, crisis or change
Interfere with normal functioning
Continue for months or years
It is possible for a person to have only
one episode of major depression. It is
more common for episodes to be long
lasting or to occur several times
during a person’s life
 Dysthymia
People with this illness are mildly depressed
for years. They function fairly well on a
daily basis but their relationships suffer
over time.
 Bipolar Disorder
People with this type of illness change back
and forth between periods of depression
and periods of mania (an extreme high).
Symptoms of mania may include:
Less need for sleep
Overconfidence
Racing thoughts
Reckless behavior
Increased energy
Mood changes are usually gradual, but can be
sudden
 Season Affective Disorder
This is a depression that results from
changes in the season. Most cases begin
in the fall or winter, or when there is a
decrease in sunlight.
Professional treatment is
necessary for all these
types of depression.
 Depression
 Etiology (What causes deprresion??)
 Etiology unknown
 Uncertain with heredity
 History of child abuse or other major life
stresses
 Changes in neurotransmitter/neurohormone
levels
 Cholinergic, noradrenergic/dopaminergic and
serotonergic neurotransmission
 Deregulation with hypothalamic-pituitary-adrenal
axis, hypothalamic-pituitary-thyroid axis and
growth hormone
 Life stresses (e.g. Separation and losses)
 Positive or negative events can trigger
depression. Examples include the death of a
loved one or a promotion.
Major illnesses such as heart attack, stroke or
cancer may trigger depression.
Certain medications used alone or in
combination can cause side effects much like
the symptoms of depression.
Use of Alcohol or other Drugs can lead to or
worsen depression.
Depression can also occur for no apparent
reason!
 Neurobiological theory of depression
• Monoamine (catecholamine) theory (1965)
o =underlying biological basis for depression is a
deficiency of central noradrenergic and/or
serotonergic transmission in the CNS
Supported by:
• pharmacological effects of antidepressants (TCA, MAOI)
• In the past, medication of hypertension with reserpine induced
depression
Contradiction:
• several drugs (e.g., cocaine) increase the amount of these
neurotransmitters in the CNS, but are unable to treat
depression
• antidepressants induce rapid change in neurotransmitters,
but onset of antidepressant action is significantly delayed
• „Receptor theory“
o the problem is in up-regulation of post-synaptic receptors and
alterations in their sensitivity
o The antidepressant treatment increases the amount of monoamines in
CNS and gradually normalize the density/sensitivity of their
receptors
• The precise pathophysiology of depression remains unsolved
 Depression
 Pathophysiology
 neurotrophic and endocrine factors play a major role (the
neurotrophic hypothesis)?-role of BDNF (brain-derived
neurotrophic factor)
 Changes in receptor-neurotransmitter relationship in limbic
system
 Serotonin, norepinephrine, sometimes dopamine
 Increased pump uptake of neurotransmitter
 Reabsorption into neuron
 Destroyed by monoamine oxidase in mitochondria
 Lack of neurotransmitters
 Therapy of depression
Pharmacotherapy
• Tricyclic antidepressants (TCA)
• Monoamine oxidase inhibitors (MAOI)
• Selective Serotonin Re-uptake Inhibitors
(SSRI)
• Other and atypical antidepressant
• Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)
• Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
• Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)
• Noradrenaline Reuptake Inhibitors (NaRI)
• Noradrenergic/Specific Serotonergic Antidepressants (NaSSA)

Duration of treatment – 6 months after recovery (1st epizode), may be even

life-long treatment in recurrent depression

Non-pharmacological treatment
• Psychotherapy
• Light therapy
• Electroconvulsive therapy (ECT)
 Antidepressants
 Tricyclic and related antidepressants (TCA)
 E.g. amitriptyline, imipramine, doxepin,
mianserin, trazodone
 Monoamine-oxidase inhibitors (MAOI)
 E.g. moclobemide, phenelzine, isocarboxazid,
tranylcypromine
 Selective serotonin reuptake inhibitors
(SSRI)
 E.g. fluoxetine, paroxetine, sertraline,
citalopram
 Other antidepressants
 E.g. mirtazapine, venlafaxine, duloxetine,
flupentixol
All available antidepressants appear to
work via 1 or more of the following
mechanisms:
(1) presynaptic inhibition of uptake of 5-HT or
NE;
(2) antagonist activity at presynaptic inhibitory
5-HT or NE receptor sites, thereby enhancing
neurotransmitter release;
(3) inhibition of monoamine oxidase, thereby
reducing neurotransmitter breakdown.
 How Antidepressants Work
Most of the important clinical actions of
antidepressant drugs cannot be fully
accounted for on the basis of “synaptic
pharmacology”.
• There are two important observations
that contribute to this rationale.
• Many drugs require long term administration
to be effective.
• Drugs of abuse require repeated
administration to produce tolerance and
physical dependence.
Clinical effects would appear to result
from the slow onset adaptive changes
that occur within neurons, not within the
synapse.
That is, activation of intraneuronal
messenger pathway and regulation of
neural gene expression play a central
role. (drug-induced neural plasticity)
Tricyclic and related
antidepressants
(TCA)
 Amitriptyline (Saroten®)
 Clomipramine (Anafranil®)
 Dothiepin (a.k.a. dosulepin,
Prothiaden®)
 Doxepin (Sinequan®)
 Imipramine (Tofranil®)
 Mianserin (Tolvon®)
 Nortriptyline (Nortrilen®)
 Trazodone (Trittico®)
 Trimipramine (Surmontil®)
 Tricyclic Antidepressants (TCAs)
• Chemical structure with characteristic
three-ring nucleus – lipophilic nature
• Originally developed as antipsychotics
(1949), but were found to have no effect in
this indication.
• Principal mechanism of action:
o blockade of re-uptake of monoamine imipramine
neurotransmitters noradrenaline (NA) and
serotonin (5-HT)
o by competition for binding site of the carrier
protein (NET and SERT)
• NET vs SERT inhibition – variable within the group
• 5HT and NA neurotransmission is similarly affected but the
effect on the dopamine system is much less important
(compare with cocaine)
o in most TCA, other receptors (incl. those outside the
CNS)
• blockade of H1-receptor, -receptors, M-receptors
Tricyclic and related
antidepressants
(TCA)
 Initial response develops in 1-3 weeks
 Maximal response develops in 1-2 months
 Older tricyclics
 Marked anticholinergic Adverse effects
 Risk of cardiotoxicity
 Tricyclic-related drugs (e.g. trazodone)
 Fewer anticholinergic Adverse effects
 Sedation, dizziness, priapism (persistent penile
erection accompanied by pain and tenderness)
 Most important TCAs
• imipramine (a representative)
• desimipramine
o demethylated form, the active metabolite of imipramine
• amitriptyline
• nortriptyline
o demethylated form, the active metabolite of amitriptyline)

• Clinical use and efficacy is relatively similar within

the group
• The more significant difference is in their adverse
effects
Tricyclic and related
antidepressants
(TCA)
 Properties
 Inexpensive, generic
 Some with off-label use, e.g.
 Neuropathy with amitriptyline
 Refractory skin diseases with doxepin
 Very dangerous in overdose
 Life threatening
 Lethal dose only 8 times average daily dose
 Acutely depressed patients should not be given
more than 1-week TCA supply at one time
• Administered orally
Pharmacokinetics
o rapid absorption, extensive first pass effect  low
and inconsistent BAV
• Strong binding
o to plasma proteins (90-95% bound).
o in tissues + wide distribution (high
lipophilicity) = large distribution volumes
(ineffectiveness of dialysis in acute intoxications).
• Biotransformation
o in the liver (CYP450, N-demethylation and tricyclic ring
hydroxylation)
o most of these metabolites are active! CYP450
polymorphisms
o Glucuronidation  inactive metabolites excreted in the urine.
o Elimination half-lives
o generally LONG (T1/2 =10-80h).
o Elderly patients – even longer T1/2  risk of accumulation.
 Adverse effects
• TCA are effective antidepressants
• their use is complicated by numerous troublesome adverse
effects
o Anticholinergic (atropine-like) due to M-
blockade
• Dry mouth, blurred vision
• Constipation, urinary retention (more in amitriptyline,
less in imipramine)
• Palpitations, tachycardia
o Postural (orthostatic) hypotension + reflex
tachycardia
• -blockade of adrenergic transmission (frequent in
elderly)
o Sedation - H1-blockade
• drowsiness, difficulty
 Possible in concentration
problems with compliance ?!!!
(amitriptyline,)
Tricyclic and related
antidepressants
(TCA)
 Adverse effects
 Orthostatic hypotension
 Reduced by moving slowly when assuming upright
posture
 Sit or lie down if symptoms (dizziness,
lightheadedness) occur
 Divided doses and slow titration
 Anticholinergic effects
 Tolerance may develop as treatment persists
 Divided doses and slow titration
 Sedation
 Dose at bedtime
 Acute intoxication with TCA
• Very dangerous and relatively frequent
o patients with depression often have suicidal tendencies

• Precautions
• patient education - remind him/her that 2-4 week
delay in the effect is anticipated and that it is NOT a
failure of medication)
• therapy of concomitant anxiety/agitation
• prescription of limited quantities of TCA
• high risk patient should be treated under
supervision of specialists or treated as inpatients
 Acute intoxication
• TCA - low therapeutic index
• Target systems – the CNS and heart

• CNS - pronounced atropine-like effects.

• Excitement, hallucinations, delirium, convulsions.
• Coma and respiratory depression may follow.
• Cardiac dysrrhythmias
• very common
• tachycardia (antimuscarine action)
• atrial or ventricular extrasystoles, QRS complex widening, QT interval
elongation.
• ventricular fibrillation and sudden death may occur.
• Hypotension
• Treatment- diazepam (seizures),
physostigmine???
• No effect of haemodialysis and hemoperfusion is
Tricyclic and related
antidepressants
(TCA)
 Adverse effects
 Cardiac toxicity
 ECG recommended before initiation
 Do not use in heart block
 Seizures
 Lowered seizure threshold
 Hypomania (mild mania)
 Elevated mood
 Patient should be evaluated to determine dose
reduction or bipolar disorder
 Diaphoresis
 Paradoxical effect
Tricyclic and related
antidepressants
(TCA)
 Drug interactions
 CNS depressants
 Narcotics, benzodiazepines
 Additive CNS depression

 Anticholinergics
 Additive anticholinergic effects

 P450 enzyme inducers/inhibitors

 MonoAminoOxidase Inhibitors
(MAOI)
• The first compounds (iproniazide derivatives) - originally
developed as antimycobacterial drugs by chemical
modification of isoniazid molecule (1950s).

• Principal mechanism of action:

• Inhibition of intracellular enzyme MAO in CNS
neurons (= decrease in
degradation of catecholamines and serotonin).
• antidepressant action - MAO-A enzyme isoform inhibition
 increased cytoplasmic pool of monoamines leading among other(s) to
spontaneous leakage of monoamines.

• when given to normal non-depressed subjects they

increase a motor activity and cause euphoria +
excitements  risk of abuse!
 MAOI drugs
• Irreversible non-selective inhibitors
(hydrazides)
long lasting inhibition (up to 1-2 weeks) despite of the
elimination rate of a drug
• phenelzine
• tranylcypromine

• Reversible Inhibitors of MAO-A (RIMA)

• moclobemide

Great difference in adverse reactions between these

groups
Note: Reversible inhibitors of MAO-B (e.g. selegiline) are used in
the
treatment of Parkinson's disease.
 Adverse reactions and toxicity
• Hypertension
• Postural hypotension (in up to 1/3 patients)
• CNS stimulation – tremor, excitement,
insomnia, convulsions in overdose.
• Weight gain (increased appetite)
• Rare severe hepatotoxicity (hydrazine
MAOI)
 Interaction with food
• The most serious problem of this class of drugs
• Much less important in novel RIMA drugs like moclobemide
• Tyramine „cheese and wine“ reaction
o tyramine
o a natural indirect sympathomimetic produced by
fermentation
• some food contain high amounts
• normally metabolized by MAO in the gut and liver.
o After MAOI treatment bioavailability of tyramine is significantly
higher
o pharmacodynamic synergism
o hypertensive crisis, severe headache and potentially fatal
intracranial hemorrhage or other organ damage.
o Dietary restrictions: maturing cheeses, wine, beer, yogurts,
bananas etc.
• This risk is minimal with modern RIMA drugs.
 Interaction with drugs
• Hypertension & hypertensive crisis
o TCA wash-out period (2 weeks) when switching
these antidepressants! Lower risk in RIMA.
o levodopa (catecholamine precursor),
sympathomimetics

• Serotonin syndrome (SSRI, TCA, opioids e.g.

pethidin)
o confusion, agitation and excitation, tremor, fever,
sweating, nausea, diarrhea, sleep disruption

• prolongs and profounds the effect of:

o benzodiazepines, antihistamines, alcohol (inhibition
 Monoamine-oxidase
inhibitors (MAOI)
 Properties
 Useful in atypical depression (somnolence and weight gain),
refractory disorders and certain types of anxiety disorders
 Less prescribed than tricyclics, SSRIs and other antidepressants
 Danger of dietary and drug interactions
 Selective Serotonin Re-uptake
Inhibitors (SSRI)
• More modern (1st drug fluoxetine available in
1988) and safe antidepressants
• Principal mechanism of action:
o selective inhibition of 5-HT (serotonin)
reuptake (SERT)
o  gradual complex changes in the density and/or
sensitivity
o both autoreceptors (5-HT1A) and postsynaptic
receptors (important subtype 5-HT2A )
• Other indications of SSRI
o anxiety disorders
• generalized anxiety, panic disorder, social anxiety disorder,
obsessive-compulsive disorder
o bulimia nervosa, gambling, drug withdrawal
 Most important SSRI
• Fluoxetine
• Fluvoxamine
• Paroxetine Enantioselective forms e.g.
• Sertraline escitalopram (S-enantiomer)
• Citalopram
 Pharmacokinetics
• Good absorption after oral administration
• Important biotransformation in the liver
• CYP450 - 2D6 and 2C19 isoforms
polymorphism  interindividual variability in the clinical effect) and active
metabolites (e.g., fluoxetine)
o CYP450 inhibitors!
• Fluoxetine, fluvoxamine -1A2, 2C19, 2D6, 3A4
• Paroxetine and duloxetine – 2D6
• Possible Interactions – TCA, clozapine, venlafaxine, haloperidol,
warfarine, b-blockers, Ca2+ channel blockers….

• Long half-lives of elimination(s)

• fluoxetine (T1/2=50h) + active metabolite (T1/2
=240h)
• Drug interaction
• based on plasma protein binding and CYP blockade
• increased effect of co-administered TCA, -
blockers, benzodiazepines etc.
 Adverse effects
•Relative improvement to other antidepressants (mostly
mild)
•GIT
• nausea, vomiting, abdominal cramps, diarrhea
• relatively frequent, higher doses?
• Headache
• Sexual dysfunctions (loss of libido, erectile
dysfunction…)
• Restlessness (akathisia)
• Anxiety - an increase in anxiety or agitation during
early treatment
• Insomnia and fatigue
• Serotonin syndrome upon intoxication or drug
interactions
 Other and atypical antidepressants
• Serotonin and Noradrenaline Reuptake Inhibitors
(SNRI)
• venlafaxine
• pharmacodynamics like in TCA
• improved profile of adverse reactions
• Very effective, better remission rate than SSRI
• Adverse reactions: nauzea, vertigo (both frequent and may improve),
hypertension, manic reactions
• Used in: depression and depression with anxiety, generalized anxiety
disorders, social fobias, neuropathic pain
• Liver metabolism and active metabolite

• Noradrenaline and Dopamine Reuptake Inhibitors

(NDRI)
• Bupropion
rather CNS activating effects (low sedation),
•

• use: severe depression + smoking cessation

treatment.
• adverse reactions: insomnia, excitation, restless,
siezures
• Noradrenaline Reuptake Inhibitors (NaRI)
• Reboxetine
• also rather activating
• severe depression prophylaxis and treatment
 Other and atypical
antidepressants
• Serotonin (5HT2A) Antagonists/Reuptake
Inhibitors (SARI)
o In depression with significant anxiety and sleep
disturbances
o Inhibits select. SERT, antagonist on H1 and 1 and 2-
receptors
o Trazodone
o nefazodone (newer and improved)

• Miscellaneous
o St John´s wort (Hypericum perforatum)
o a herb containing number of active compounds (among
other hyperforin a MAOI)
o clinically effective and well tolerated
o but it induces CYP450
• risk of drug interactions! E.g. it decreases the effect of
ciclosporin which may result even in transplant rejection in
transplanted patients)
 Mixed serotonin
norepinephrine
effects
 Mirtazapine (Mirtazon®, Remeron®,
Remeron SolTab®), mianserin
 Mechanism of action
 Presynaptic α2-antagonist
 Increases central noradrenergic and serotonergic
neurotransmission
 Mixed serotonin
norepinephrine
effects
 Mirtazapine (Mirtazon®, Remeron®,
Remeron SolTab®), mianserin
 Properties and Adverse effects
 Fewer anticholinergic effects
 Marked sedation during initial treatment
 Stimulating as dose increases
 Increased appetite and weight gain
 Constipation, dry mouth
Second generation
antidepressants Other atypical
•Trazodone antidepressants:
- SSRI, Ø NA and 5-HT receptors  Mianserine
- may be used in presynaptic α2
schizophrenic patients blocker
A: sedative,
•Maprotiline anxiolytic
- selective noradrenaline reuptake inhibitor  Tianeptine
(NARI)  5-HT reuptake
(???)
•Bupropion (Wellbutrin) (+) few ADEs
ADE: hepatitis
- selective dopamine reuptake inhibior, (rare)
antinicotine treatment  Viloxazine
•Venlafaxine  NE reuptake
o Serotonin-noepinephrine reuptake (+) not cardiotoxic
or cholinolytic
inhibitors (SNRIs)
o clinical profile like SSRIs, quick onset of
action
•Mirtazapine
- noradrenergic and specific serotonergic
antidepressant (NaSSA)
- Ø presynaptic NA and 5-HT receptors
 Serotonin syndrome
• upon intoxication or drug interactions
o SSRI, IMAO, TCA, venlafaxine, nefazodone, pethidine,
tramadol
o Drugs inhibiting SSRI metabolism (erytromycine…)
• Serotonine system overstimulation
• Symptoms
o Psychiatrical: anxiety, confusion, hypomania, agitation
o Neurological: tremor, myoclonus, hyperreflexia, ataxia
o GIT: nauzea, vomiting
o Cardiovascular: hypertension tachycardia
o Fever, sweating!
• Managment – benzodiazepines (lorazepam),
supportive care,
o 5-HT blockers, such as methysergid,
cyproheptadine, and propranolol may be given
 Other
antidepressants
 Flupenthixol (Fluanxol®)
 Typical antipsychotic
 Antidepressant effect at low doses
 Antipsychotic dose: 3-9mg twice daily
 Antidepressant dose: 1-3mg daily
 Combined with another antidepressant as Deanxit®
 Flupenthixol 0.5mg + melitracen 10mg
 For depression and anxiety
Non-antidepressants
 Anxiolytics
 Antipsychotics
 Use may mask the true diagnosis
 Used with caution
 But are still useful adjuncts in agitated
patients
 Lithium and thyroid
 To potentiate effect of antidepressants in
refractory cases
 Lithium: plasma level 0.4-0.8mEq/L
 Thyroid supplement: 25mcg/day
 Antidepressants in
depression
 Choice of agents
 All are equally efficacious for depression
 Selection based on
 Side effect profile
 Potential drug interaction

 Response failure to an antidepressant does not predict response

to another drug class or another drug within class
• The right drug Drug choice
and the right dose for the
individual patient must be accomplished
empirically and depends on:
•the clinical characteristics of the patient`s illness
•the drug`s adverse effect profile
•toxicity in overdosage and dosing schedules
•the past history of the patient`s drug experience
• The greater tolerability of the SSRIs and SNRIs,
NaSSAs make them the preferred agents for most
patients
• If there are no medical contraindications or no
risk of suicide, a TCA can be used
 Antidepressants in
depression
 Geriatrics
 Reduce initial dose by half
 Gradual dose titration
 Risk of dizziness and syncope
 Hyponatremia
 Pediatrics
 Decrease initial dose by half
 Recent evidence links SSRIs with suicide in
adolescents
 Antidepressants in
depression
 Treatment response
 Weeks 1-2
 Physical responses
 Improvement in appetite and sleep
 Weeks 3-4
 Energy and cognitive responses
 Improvement in energy
 Improvement in guilt, concentration
 Weeks 5-6
 Emotional responses
 Improvement in mood
 Antidepressants in
depression
 Continuation therapy
 To prevent relapse
 4-9 months after complete remission of
symptoms
 At therapeutic doses
 Lifelong maintenance therapy
 Recommended by some investigators for
patients at greater risk or reoccurrence
 < 40 years with ≥ 2 prior episodes
 Any age with ≥ 3 prior episodes
• MainTherapy
aim: of bipolar disorder
• to eliminate mood episodes
• maximize adherence to therapy
• improve functioning of the patients
• eliminate adverse effects

„MOOD STABILIZERS“
• Lithium
• Valproate
• Carbamazepine
• Lamotrigine
• Adjunctive agents (antidepressants and
benzodiazepines)
 Lithium
• Since 1949 - indication as a prophylactic treatment in bipolar
disorder. Effective also in 60-80% patients with mania or
hypomania.
• Principle mechanism of action
o remains elusive though profound effects on second messenger systems
(mainly IP3) is supposed.
• Pharmacokinetics
• administered orally (readily and almost completely
absorbed)
• distribution - extracellular, then gradually accumulates
in various tissues
• elimination – 95% in urine (T1/2= 20-24h; when the
treatment is abruptly stopped - slow 2nd phase of
excretion /1-2 weeks/ representing Li+ taken up by cells
occurs)
• only 20% of Li+ filtered by GF is excreted (80%
reabsorbed)
 Lithium – toxicity and adverse reactions
• Acute intoxication, symptoms:
o GIT: vomiting, profuse diarrhea
o CNS: confusion, tremor, ataxia, convulsions,
coma.
o
Heart: arrhythmias, hypotension
Unfortunately there is no specific antidote  supportive treatment
• Toxicity of long-term therapy
o Renal toxicity – the kidney's ability to concentrate the urine is decreased
• Adverse reactions: polyuria and polydipsia, weight gain,
GIT disturbances (vomiting, nausea, dyspepsia), alopecia
• Drug interactions: thiazides – increased Li reabsorption
 intoxication Critical importance of TDM to reach desirable
effects without risk of toxicity!
The effects as well as toxicity correlates much more better with
plasma concentrations than with dose. The range of plasma
concentrations is narrow:
0.5-1.0 mmol/L (above 1.5 mmol/L toxic effects appear)
• Thank You
 End
Questions & Answers