Lecture 4, Antipsychotics, Antidepressants

Antipsychotic Drugs Russell Crowe in “A Beautiful Mind”

Psychotic Disorders Definition: Psychotic disorders are defined as mental disorders in which the personality is severely altered and a person’s contact with reality is impaired. Characteristics: delusions, hallucinations, odd behavior, and incoherent or disorganized speech

Causes: Traumatic Experience, Stressful Event, and Drug Use

Major Psychotic Disorders Brief Psychotic Disorder  Delusional Disorder  Schizoaffective Disorder  Schizophreniform  Shared Psychotic Disorder  Schizophrenia 

x

D1

x

D2

Frontal

x

X

x

Caudat/ Putamen

X

x

D3

x

Amigdala

x

Accumbens

X

x

x

Pallidus

x

x

x

Hippocamp

X

Hipotalamus

x

Subst neagra Bulb Punte

D4

x x

Psychosis: Schizophrenia – split between thought and emotion. Diagnostic criteria for Schizophrenia A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): (1) delusions (2) hallucinations (3) disorganized speech (e.g., frequent derailment or incoherence) (4) grossly disorganized or catatonic behavior (5) negative symptoms, i.e., affective flattening, alogia, or avolition Note: Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.

Criteria for Manic Episode DSM – IV A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: (1) inflated self-esteem or grandiosity (2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep) (3) more talkative than usual or pressure to keep talking (4) flight of ideas or subjective experience that thoughts are racing (5) distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) (6) increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (7) excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

Names - Antipsychotic Antipsychotic drugs were initially called neuroleptics because they were found to cause neurolepsy, which is an extreme slowness or absence movement Major tranquilizer – as opposed to minor tranquilizer (benzodiazepines). Refers to sedating property, but is not a “stronger” version of minor tranquilizer. Antipsychotic effect is not achieved through sedation.

Traditional Antipsychotics 

Phenothiazines        



chlorpromazine (Chlorpromazine Mixture, Chlorpromazine Mixture Forte, Largactil) fluphenazine (Anatensol, Modecate) flupenthixol (Fluanxol) pericyazine (Neulactil) pimozide (Orap) thioridazine (Aldazine) trifluoperazine (Stelazine) zuclopenthixol (Clopixol)

Butyrophenones  

droperidol (Droleptan Injection) haloperidol (Haldol, Serenace)

Newer Antipsychotics 

Atypical agents       

aripiprazole (Abilify) clozapine (CloSyn, Clopine, Clozaril) risperidone (Risperdal) quetiapine (Seroquel) amisulpride (Solian) olanzapine (Zyprexa) ziprazidone (Zeldoxx)

Typical antipsychotics were developed before 1975, they have Parkinsonian side effects and are only effective against positive symptoms. Atypical antipsychotics were developed after 1990. They have minimal parkinsonian effects and are effective against both positive and negative symptoms.

Neurophysiology Dopamine hypothesis: schizophrenia is caused by an excess of dopamine activity in the brain. In the 1970s it was noted that the clinical potency of a drug was correlated with its affinity for D2 receptors

Philip Seeman

Dopamine pathways 

Mentation & Mood  



Extrapyramidal Function 



Nigrostriatal

Prolactin release 



Mesocortical Mesolimbic

Tuberoinfundibular

Emesis 

Chemoreceptor trigger zone

3

3

Dopamine systems in the brain Mesolimbic DA system from the VTA to the Nucleus Accumbens and frontal cortex - Reward system and schizophrenia Nigrostriatal system from the Substantia Nigra to the basal ganglia. - extrapyramidal motor system.

Antipsychotic drugs block DA receptors in both systems and therefore Parkinsonian symptoms are side effects.

Dopamine Hypothesis today: Drugs like amphetamine and cocaine cause psychotic behavior, but so do other drugs like PCP and LSD suggesting that serotonin and NMDA receptors for glutamate are involved as well. Drugs that block DA receptors block psychotic behavior, but there is a delay in effectiveness of antipsychotic drugs suggesting an adaptation in a brain mechanism

Typical and Atypical Antipsychotics Typical antipsychotics have a high affinity for D2 receptors. Atypical antipsychotic drugs have high affinity for D3 and D4 receptors and low affinity for D2 receptors. D3 receptors are found in the n. acc. and D4 receptors in the cortex amygdala and hippocampus. There are few D3 and D4 receptors in the motor system. Atypicals also have a higher affinity for the 5HT2A receptor than the D2 receptor while typicals have a lower affinity for the 5HT2A receptor than the D2 receptor. This has the effect of counteracting the D2 blockade in the motor system

Mechanism of Action

2

Blockade of serotonin receptors also causes diminished response of glutamanergic neurons in the cortex. (oppostie effect of LSD). This may reduce hallucinations Atypical antipsychotic drugs are also more effective in treating the negative symptoms of schizophrenia like alogia and avoilition. Other neurotransmitters known to be involved are acetylcholine, histamine, GABA, and NE. Different drugs have different profiles if relative activity of different transmitters.

New Era in Psychiatric Medicine Chlorpromazine was the first anti-psychotic drug developed • Initially this drug was administered to patients before a surgery because it produced anti- anxiety effects. • It was then tried on patients with mental illnesses and it was discovered that it relieved psychotic episode symptoms. •

Phenothiazines Chlorpromazine belongs to this class of drugs.  Other examples include: 

Perphenazine Fluphenazine Trifluoperazine

Mechanism of Action of Phenothiazines The drugs found in this class are antagonists.  They work by blocking the D2 receptors in the dopamine pathways of the brain; thus, decreasing the normal effect of dopamine release.  Blocking the D2 receptors in the mesolimbic pathway results in the antipsychotic effect. 

Side Effects Associated with Phenothiazines •

Pharmacological Side Effects • Constipation • Retention of urine • Increased heart rate • Dry mouth • Dilated pupils



Serious Side Effects • Parkinsonian-like syndrome • Dystonia • Diskinesia • Neuroleptic Malignant Syndrome (NMS)

Butyrophenones 

Butyrophenones are high-potency antipsychotics (potency refers not to effectiveness but rather to the ability to bind to dopamine receptors)



Haloperidol (Haldol) is the most common of the butyrophenones:

Other Butyrophenones  Droperidol

 Benperidol

Mechanism of Action  All the butyrophenones work in the same manner as the phenothiazines. 

They block the D2 receptors in the dopamine pathways, thus, thwarting any possible over excitation of the dopamine receptors.

Side Effects of Butyrophenones Pharmacological   

effects include:

Dry mouth Urinary retention Dimmed sight

 More

Serious Side effects include: -Dystonia -Tardive Dyskinesia - Akathisia

Comparisons Between the Two Classes of Drugs 

Phenothiazines  Low potency  Are sedative  Block D2 receptors  metabolism and removal of phenothiazines is complex and among the slowest of any group of drugs  cause extra pyramidal symptoms



Butyrophenones  High potency  Non-sedative  Block D2 receptors  Metabolism and removal is quicker  Cause extra pyramidal symptoms

Typical Antipsychotics Phenothiazines and Butyrophenones are typical antipsychotics  These drugs are no longer regarded as the best practice for treating psychotic disorders, even though they are still commonly utilized in emergency treatments.  The reason for this is that they are not very selective. They do not only block the D2 receptors of the mesolimbic pathway but also block the D2 receptors in the nigrostriatal pathway, mesocortical zone, and tuberoinfundibular pathway.  The fact that they are not very selective causes the extra pyramidal symptoms such as tardive diskinesia 

clozapine

Atypical Anti-psychotics  Were

developed in an attempt to minimize the side effects of typical anti-psychotics  They have proven to cause fewer extra pyramidal symptoms (EPS) when compared to typical anti-psychotics.  They produce fewer EPS because they are more selective.

Common Atypical Antipsychotics 

Clozapine



Risperidone



Olanzapine

Other Atypical Antipsychotics 

Quetiapine:



Ziprasidone:

Mode of Action Antagonists  Atypical antipsychotic drugs have a similar blocking effect on D2 receptors but appear to be more selective in targeting the intended pathway to a larger degree than typical antipsychotics.  They also interact with other neurotransmission systems, particularly with the serotonergic and noradrenergic pathways. 

Side Effects Associated with Atypical Antipsychotics Glucose Metabolism Disorders such as hyperglycemia, onset of diabetes type 2, and worsening of pre-existing diabetes ( This was particularly seen with patients treated with olanzapine and clozapine)  Weight Gain has been seen with patients taking Olanzapine; the increase of weight gain can result in other heart diseases such as hypertension and coronary heart disease.  QTc prolongation which occurs when there is an abnormally long delay between the electrical excitation and relaxation of the ventricles of the heart which can cause death 

Differences among Antipsychotic Drugs  

All effective antipsychotic drugs block D2 receptors Chlorpromazine and thioridazine   



Haloperidol   



block α1 adrenoceptors more potently than D2 receptors block serotonin 5-HT2 receptors relatively strongly affinity for D1 receptors is relatively weak 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

Differences among Antipsychotic Drugs 

Clozapine 



Risperidone 



about equally potent in blocking D2 and 5-HT2 receptors

Olanzapine  



binds more to D4, 5-HT2, α1, and histamine H1 receptors than to either D2 or D1 receptors

more potent as an antagonist of 5-HT2 receptors lesser potency at D1, D2, and α1 receptors

Quetiapine 

lower-potency compound with relatively similar antagonism of 5-HT2, D2, α1, and α2 receptors

Differences among Antipsychotic Drugs 

Clozapine, olanzapine and quetiapine  



potent inhibitors of H1 histamine receptors consistent with their sedative properties

Aripiprazole 

partial agonist effects at D2 and 5-HT1A receptors

Differences among Antipsychotic Drugs 

Chlorpromazine: α1 = 5-HT2 > D2 > D1



Haloperidol: D2 > D1 = D4 > α1 > 5-HT2



Clozapine: D4 = α1 > 5-HT2 > D2 = D1

Metabolic effects Weight gain over 1 year (kg) aripiprazole

1

amisulpride

1.5

quetiapine

2–3

risperidone

2–3

olanzapine

>6

clozapine

>6

Most Common Problems Associated with Antipsychotic Treatment The slow onset of antipsychotic efficacy • The development of antipsychotic-induced side effects • Patients’ vulnerability to relapse following antipsychotic drug discontinuation. •

Current and Future Work in Antipsychotic Treatment •

•

•

Synthesis of compounds acting on N-Methyl-DAspartate (NMDA) sub-group of glutamate receptors, which are believed to be involved in the pathogenesis of psychotic symptomatology. Aripiprazole is a new atypical antipsychotic drug that shows both partial agonist activity at the D2 and 5HT1A receptors and potent antagonism activity at the 5HT2A receptors. Individualized treatment based on genetic profile in attempts to eliminate side effects

•

Antidepressants

Definitions 

Affective disorders - mental illnesses

characterized by pathological changes in mood (not thought – compare with schizophrenia) 1.

Unipolar disorders 



2.

Depression – pathologically depressed mood (life time prevalence up to 17%) Mania – excessive elation and accelerated psychomotoric activity (rare)

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 



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 

Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.        

depressed mood most of the day… markedly diminished interest or pleasure 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 (!)

Neurobiological theory of depression 





Monoamine (catecholamine) theory (1965) = the underlying biological or neuroanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic transmission in the CNS Supported by:  pharmacological effect 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  the effect of antidepressants on neurotransmitter levels is relatively quick but onset of antidepressant action is significantly delayed „Receptor theory“ = the problem is in up-regulation of postsynaptic receptors and alterations in their sensitivity The antidepressant treatment increases the amount of monoamines in CNS and thereby gradually normalize the density/sensitivity of their receptors The precise pathophysiology of depression remains unsolved

Traditional Antidepressants 

Tricyclic antidepressants       



Tetracyclic antidepressants 



amitriptylline (Endep, Tryptanol) clomipramine (Anafranil, Chem mart Clomipramine, GenRx Clomipramine, Placil, Terry White Chemists Clomipramine) doxepin (Deptran, Sinequan) dothiepin (Dothep, Prothiaden) imipramine (Tofranil) nortriptylline (Allegron) trimipramine (Surmontil) Mianserin (Lumin, Tolvon)

MAOIs (monoamine oxidase inhibitors)  

Phenelzine (Nardil) Tranylcypromine (Parnate)

Newer antidepressants 



SSRIs (specific serotonin reuptake inhibitors)  citalopram (Celapram, Chem mart Citalopram, Ciazil, Cipramil, GenRx Citalopram, Talam, Talohexal, Terry White Chemists Citalopram)  escitalopram (Lexapro)  fluoxetine (Auscap 20 mg Capsules, Chem mart Fluoxetine, Fluohexal, Fluoxebell, Fluoxetine-DP, GenRx Fluoxetine, Lovan, Prozac, Terry White Chemists Fluoxetine, Zactin)  fluvoxamine (Faverin, Luvox, Movox, Voxam)  paroxetine (Aropax, Chem mart Paroxetine, GenRx Paroxetine, Oxetine, Paxtine, Terry White Chemists Paroxetine)  sertraline (Chem mart Sertraline, Concorz, Eleva, GenRx Sertraline, Sertraline-DP, Terry White Chemists Sertraline, Xydep, Zoloft) RIMA (reversible inhibitor of monoamine oxidase A)  moclobemide (Arima, Aurorix, Chem mart Moclobemide, Clobemix, GenRx Moclobemide, Maosig, Mohexal 150 mg, Terry White Chemists Moclobemide)

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: 



imipramine

blockade of re-uptake of monoamine neurotransmitters noradrenaline (NA) and serotonin (5-HT) by competition for binding site of the carrier protein. 5HT and NA neurotransmission is similarly affected but the effect on the dopamine system is much less important (compare with cocaine) in most TCA, other receptors (incl. those outside the CNS) are also affected: blockade of H1-receptor, α -receptors, M-receptors

Pharmacokinetics 



Administered orally – rapid absorption, however extensive first pass effect ⇒ low and inconsistent BAV Strong binding to plasma proteins (90-95% bound). They are also bound in tissues + wide distribution (high lipophilicity) = large distribution volumes (ineffectiveness of dialysis in acute intoxications).



Biotransformation – in the liver (CYP450, Ndemethylation and tricyclic ring hydroxylation) – most of these metabolites are active! CYP450 polymorphisms ! Glucuronidation → inactive metabolites excreted in the urine.



Elimination half-lives - generally LONG (T1/2 =10-80h). Elderly patients – even longer T1/2, risk of accumulation.

Adverse effects 



TCA are effective antidepressants but their use is complicated by numerous troublesome adverse effects Anticholinergic (atropine-like) due to M-blockade Dry mouth, blurred vision, constipation, urinary retention (more in amitriptyline, less in imipramine) Palpitations,



tachycardia Postural (orthostatic) hypotension + reflex tachycardia - α -blockade of adrenergic transmission in the vasomotor center (frequent in elderly)



Sedation, drowsiness, difficulty in concentration (amitriptyline, H1-blockade)



Sexual dysfunction (loss of libido, impaired erection)

Acute intoxication   



  

low therapeutic index Target systems – the CNS and heart excitement, hallucinations, delirium, convulsions, coma and respiratory depression - Pronounced atropine-like effects. Cardiac dysrrhythmias – 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 practically ineffective

Newest antidepressants SNRI

(serotonin noradrenergic reuptake inhibitors)

venlafaxine

(Efexor-XR)

NaSSA

(noradrenergic and specific serotonergic antidepressant) mirtazapine

Remeron)

(Avanza, Avanza SolTab, Axit, Mirtazon,

SaSRI

(serotonine antagonist and serotonine reuptake inhibitor)  trazodone

NaRI

(Trittico, Desyrel)

(selective noradrenaline reuptake inhibitor )

reboxetine

(Edronax)

Serotonin receptors 

5–HT1 

subtypes 





5–HT1A , 5–HT1B , 5–HT1D , 5– HT1E , 5–HT1F

primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin

5–HT2 

subtypes 



5–HT2A , 5–HT2B , 5–HT2C

primarily responsible for the toxic effects of increased intrasynaptic serotonin

Serotonin receptors  5–HT1  subtypes 5–HT

HT1F

1A

, 5–HT1B , 5–HT1D , 5–HT1E , 5–

 5–HT2  subtypes 5–HT

2A

, 5–HT2B , 5–HT2C

Serotonin receptors  5–HT3  5–HT4

(rat)

 5–HT5

(rat)

5–HT

 5–HT6

, 5–HT5

5A

(rat)

 5–HT7 (rat

and human)

Selective Serotonin Re-uptake Inhibitos (SSRI) 

More modern (1st drug fluoxetine available in 1988) and safe antidepressants



Principal mechanism of action:  selective inhibition of 5-HT (serotonin) reuptake → gradual complex changes in the density and/or sensitivity both autoreceptors (5-HT1A) and postsynaptic receptors (important subtype 5-HT2A )



Other indications of SSRI - anxiety disorders: generalized anxiety, panic disorder, social anxiety disorder, obsessive-compulsive disorder + bulimia nervosa, gambling

Most important SSRI     

Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram

Enantioselective forms e.g. escitalopram (S-enantiomer)

Selectivity of antidepressants

NAselective

Nonselective

5-HTselective

Ratio NA: 5-HT uptake inhibition

1000

100

10 1

0.1

0.01

0.001

Nisoxetine Nomifensine Maprotiline (approx)

Desipramine Imipramine Nortriptyline Amitriptyline Clomipramine Trazodone Zimelidine Fluoxetine Citalopram (approx)

NaSSA

NaRI SSRI

NaSSA

Pharmacokinetics  

Good absorption after oral administration Important biotransformation in the liver 



Long half-lives of elimination(s) 



CYP450 - 2D6 and 2C19 isoforms (polymorphism → interindividual variability in the clinical effect) and active metabolites (e.g. fluoxetine) 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 but also β blockers, benzodiazepines etc.

Adverse effects 

Relative improvement to other antidepressants (mostly mild)

     



GIT – nausea, vomiting, diarrhea Headache Sexual dysfunctions Restlessness (akathisia) Insomnia and fatigue Few patients experience an increase in anxiety or agitation during early treatment Serotonin syndrome upon intoxication or drug interactions

Serotonin excess 

Primary neuroexcitation (5–HT2A) 

mental status 



agitation/delirium

motor system clonus/myoclonus  inducible/spontaneous/ocular  tremor/shivering  hyperreflexia/hypertonia 



autonomic system 



diaphoresis/tachycardia/mydriasis

Other responses to neuroexcitation  

fever rhabdomyolysis

Severe serotonin toxicity 

Combination therapy 

multiple different mechanisms of serotonin elevation

Rapidly rising temperature  Respiratory failure 





hypertonia/rigidity

Spontaneous clonus

Treatment options 

Supportive care   



symptom control control of fever ventilation

5–HT2A antagonists 

ideal safe  effective  available 

Cyproheptadine 

blockade of brain 5–HT2 receptors

Chlorpromazine 

5–HT2 antagonist

Therapy 

Oral therapy 



Oral therapy unsuitable or fails 



cyproheptadine 12 mg stat then 4–8 mg q 4–6h chlorpromazine 25–50 mg IVI stat then up to 50 mg orally or IVI q6h

Ventilation impaired and/or fever > 39oC  

anaesthesia, muscle relaxation ± active cooling chlorpromazine 100–400 mg IMI/IVI over first two hours

Other and atypical antidepressants 









Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)  trazodone (sedative effects)  nefazodone (newer and improved) decreased some SSRI adverse reactions Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)  venlafaxine - pharmacodynamic like in TCA however improved profile of adverse reactions Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)  bupropion – rather CNS activating effects (low sedation), usage: severe depression + smoking cessation treatment. Adverse reactions: insomnia, excitation, restlessness, lowers epilepsy threshold Noradrenaline Reuptake Inhibitors (NaRI)  reboxetine – also rather activating  maprotiline Noradrenergic/Specific Serotonergic Antidepressants (NaSSA)  mirtazapine – increased NA and 5-HT neurotransmission through blockade of their autoreceptors (low 5-HT adverse effects – blocks also postsynaptic 5-HT receptors)

MonoAmine Oxidase Inhibitors (MAOI) 

Principal mechanism of action: 



Inhibition of intracellular enzyme MAO in CNS neurons (= decrease in degradation of catecholamines and serotonin).

In contrast to other antidepressants, when given to normal non-depressed subjects they increase a motor activity and cause euphoria + excitements (while TCA would cause only sedation and/or confusion). ⇒ risk of abuse!

MAOI drugs 

Irreversible non-selective inhibitors (hydrazides)  



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.

Interaction with foods 

Tyramine „cheese and wine“ reaction 





some kind of foods contain high amounts of tyramine (natural indirect sympathomimetic produced during fermentation), which is however normally metabolized by MAO in the gut and liver. In depressed patients treated with MAOI, these enzymes are also inhibited → bioavailability of tyramine is significantly higher which together with pharmacodynamic synergism → strikingly increased noradrenaline transmission results in hypertensive crisis, severe headache and potentially fatal intracranial hemorrhage or other organ damage.

Dietary precautions: restriction in the consumption of some maturing cheeses, wine, beer, yogurts, bananas etc.

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) Atropine-like adverse effects – like in TCA but less common Rare severe hepatotoxicity (hydrazine MAOI)

Therapy of bipolar disorder 

Main aim: to eliminate mood episodes, maximize adherence to therapy, improve functioning of the patients and 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 

remains elusive though profound effects on second messenger systems (mainly IP3) is supposed.

Lithium 

Pharmacokinetics administered orally (readily and almost completely absorbed)  distribution - extracellular, then gradually accumulates in various tissues  elimination – 95% in urine (T = 20-24h; when the 1/2 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:

GIT: vomiting, profuse diarrhea  CNS: confusion, tremor, ataxia, convulsions, coma.  Heart: arrhythmias, hypotension Unfortunately there is no specific antidote → supportive treatment 



Toxicity of long-term therapy 

Renal toxicity – the kidney's ability to concentrate the urine is decreased

Lithium – toxicity and adverse reactions 

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)