an update on psychopharmacology
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AN UPDATE ON PSYCHOPHARMACOLOGYProf. Dr. Haroon Rashid Chaudhry
FACHARZT (Psych & Neurology) MRCPsych (London), FACP (USA), FAPA (USA), FRCP (Ireland)
Head Department of PsychiatryFJMC & SGRH
Zonal Representative World Psychiatric Association (WPA)
Vice President World Federation for Mental Health (WFMH)
Honorary Executive DirectorFountain House, Lahore
President Elect Pakistan Psychiatric Society (PPS)
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• Anti-depressants
• Mood stabilizers
• Anti-anxiety drugs
• Anti-psychotic drugs
• Anti-epileptic drugs
• Anti-dementia drugs
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ANTI-DEPRESSANTS
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Imipramine (Kuhn 1957) 1st TCA
Iproniazide (Loomer
Saunders & Kline 1957) 1st MAOA
HISTORY
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TRICYCLIC ANTI- DEPRESSANTS (TCAS)
NEUROTRANSMITTERS ADDRESSED
Imipramine Amitryptiline Clomipramine Dothiepin Nortriptyline
Serotonin
Norepinephrine
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Time Tested Established Efficacy
BUT HIGH RISK FOR Cardiac Pts Epileptic Pts Glaucoma Pts Patients with Enlarged Prostate Overdose
ADDITIONAL RISK FOR Cancer Pts Hepatitis pts Old Age
TCAs
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SIDE EFFECTS Dryness of mouth Constipation Blurring Urine Retention Tachycardia Postural Hypotension Conduction Contractility
TCAs
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Maprotiline Mianserin
SEARCH FOR SAFER ANTIDEPRESSANTS
EFFICACY vs. SAFETY=± TCAs >TCAs
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Irreversible MAOIs Phenelzine Tranylcypromine
Precautions Dietary Restrictions Serious Interactions
MONOAMINE OXIDASE INHIBITORS (MAOIs )
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IMPROVED SAFETY
Reversible MAOIs
Moclobamide
Befloxatone
MAOIs
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SINGLE NEUROTRANSMITTER
ADDRESSED
SEROTONIN
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Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIs)
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SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
FluoxetineFluvoxamineCitalopramSertralineParoxetine
Major Depression Prophylaxis of Recurrent
Major Depression Treat. Of Secondary
Depression e.g., Schizophrenia, Dementia
Bulimia OCD Phobic Disorder Panic Disorder Alcohol /Sub. Abuse
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SSRIs
EFFICACY vs. SAFETY
= TCAs >TCAs
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Fluoxetine Weekly
Escitalopram
Paroxetine SR
IMPROVED EFFICACY
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SINGLE RECEPTOR SELECTIVITY
SEROTONIN-REUPTAKE INHIBITORS/ RECEPTOR BLOCKERS
TRAZODONE
NEFAZODONE
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EFFICACY vs SAFETY
=TCAs >>TCAs
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Readdressed
Norepinephrine
Reboxetine
SINGLE NEUROTRANSMITTER
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SELECTIVE DOPAMINE REUPTAKE INHIBITORS (SDRIs)
BUPROPION
Major Depression Prophylaxis of Recurrent Major
Depression Bipolar Depression ADHD Alcohol, Nicotine Dependence
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Venlafaxine
Milancipran
Duloxetine
DUAL ACTION READDRESSED SNRIs
Serotonin
Norepinephrine (Dopamine)
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EFFICACY vs SAFETY
(=/>?TCAs (>>TCAs)
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Mirtazepine
NASSA
EFFICACY vs. SAFETY
(=/> TCAs (>>>TCAs)
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MOOD STABLIZERS
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HOW SHOULD WE DEFINE A “MOOD STABILIZERS”?
No common definition exists today
Debate about key features
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MOOD STABILIZERS: POSSIBLE FEATURES
Acute antimanic effects Prevention of manic episodes Acute antidepressant effects in mixed patients Prevention of depressive episodes Prevention of rapid cycling amelioration of residual symptoms Do not precipitate manic episodes Do not precipitate depressive episodes
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EFFECTIVENESS OF POSSIBLE MOOD STABLIZERS
Acute Acute Acute Maint-Mania Mixed Rapid enance
States Cyclers
Lithium Yes No? No? Yes
Valproate Yes Yes Yes Yes
Carbamazepine (Yes) Yes Yes Yes
Olanzapine/ Yes Yes Yes Pending*Clozapine
* Open extension data positive for olanzapine
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VALPROATE: AD EFFICACY
Open study1 (N=55)
Moderate to Marked Improvement = 47%
Open study2 (N=103)
Moderate improvement = 22%
1 calabrese JR, Delucchi GA, Am J Psychiatry. 1990; 147(4)431-434.
Lambert, 1984.
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PRECIPITATION OF MOOD EPISODES
Mania Depression
Lithium No No
Valproate No No
Carbamazepine No No
Olanzapine/ No NoClozapine
Antidepressants Yes No
Typial antipsychotics No Probable
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EASE OF USE OF MOOD STABILIZERS
Simple Frequent Lab Prescribing Monitoring
Lithium No Yes
Valproate Somewhat Somewhat
Carbamazepine No Yes
Olanzapine/ Yes No
Clozapine No Yes
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SIDE EFFECTS OF MOOD STABILIZERS
Lithium Weight gain, tremor, Gl symptoms,
thyroid function, cognitive complaints
Valproate Weight gain, (thyroid function),
Gl upset, pancreatitis, ? Polycystic ovaries
Carbamazepine WBC, rashes, nausea
Olanzapine/ Weight gain, sedation ? Hyperglycemia
Clozapine Weight gain, sedation, agranulocytosis,
salivation, ? hyperglycemia
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OPTIMAL WORKING DEFINITION OF MOOD STABILIZER
Primary considerations Effective in acute mania Effective in acutely reducing depressive symptoms in mixed
states Prevents episodes of both mania and depression Does not precipitate mania or depression
Secondary considerations Efficacy in rapid cycling Reduction of residual symptoms
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PUTATIVE/INNOVATIVE MOOD STABILIZERS
FOR REFRACTORY BIPOLAR PATIENTS
Anticonvulsants Ca2+Channel Blockers
Gabapentin Verapamil
Lamotrigine Nifedipine
topiramate Nimodipine
Tiagabine
Acetazolamide
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Atypical Antipsychotics Hormonal
Clozapine thyroxine
Risperidone Estrogen/progesterone
Olanzapine Tamoxifen
Quetiapine
(Ziprasidone) Other
Tryptophan
Choline
Donepezil
Omega-3 fatty acids
PUTATIVE/INNOVATIVE MOOD STABILIZERS
FOR REFRACTORY BIPOLAR PATIENTS
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MOOD STABILIZER: MANIA
Mania with psychosis: * Divalproex - * Lithium (Olanzapine, Risperidone, High potency conventional)
Dysphoric mania: * Divalproex - * Lithium
Epuphoric mania: * Lithium - * Divalproex
Hypomania: * Lithium - * Divalproex
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MOOD STABILIZER: DEPRESSION
Without an AD: * Lithium * Divalproex
*Lamotrigine * Carbamazepine
With an AD: * Lithium - * Divalproex
* Lamotrigine * Caramazepine
With psychosis: * Olanzapine - * Risperidone
* Quetiapine * Conventional
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LithiumDivalproexCarbamazepine
First Line
Lamotrigine ? Gabapentin
Olanzapine Topiramate
Efficacy in Depression Clinical Features
?
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BIPOLAR DISORDERS:RELAPSE PREVENTION
Bipolar disorders are recurrentRecurrence has clinical, medical, psychosocial,
and economic effects.
Recurrence results in hospitalization Mania or depression (Bipolar I)
Depression (Bipolar II)
Recurrence results in cycle shortening
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BIPOLAR RECURRENCE: CLINICAL EFFECTS
Rate of substance abuse comorbidity
Rate of alcoholism comorbidity
Rate of suicide
Possible treatment refractoriness
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BIPOLAR RECURRENCE: MEDICAL EFFECTS
Risk of cardiac disease
Risk of drug interactions
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BIPOLAR RECURRENCE: PSYCHOSICAL EFFECTS
Rates of divorce, separation
Possibility of jail/prison or hospitalization
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BIPOLAR RECURRENCE: ECONOMIC EFFECTS
Job performance
Medical treatment costs
Psychiatric treatment costs
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BIPOLAR DISORDERS:RELAPSE PREVENTION
Bipolar disorders are recurrentRecurrence has clinical, medical, psychosocial,
and economic effects.
Recurrence results in hospitalization Mania or depression (Bipolar I)
Depression (Bipolar II)
Recurrence results in cycle shortening
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PREDICTORS OF POOR LONG-TERM RESPONSE WITH LITHIUM
Psychosis
Substance abuse
Rapid cycling
More than 3 episodes
Mixed mania (depression and mania)
Poor compliance
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PROBLEMS OF CURRENT MOOD STABILIZERS
Limited efficacy Toxicity Side effects: renal, thyroid, hematologic, hepatic Monitoring Interactions Teratogenicity Weight gain Poor compliance Refractoriness
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BIPOLAR DISORDERS:TREATMENTS THAT DECREASE RISK
OF RECURRENCE
Lithium
Anticonvulsant mood stablizers
(carbamazepine, divalproex, Lamotrigine)
Possibly benzodiazepines (clonazepam)
Possibly ECT
Possibly clozapine
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Tricyclic antidepressants
“Typical” neuroleptics
Gabapentin
Nonmood stablizing anticonvulsants
Alprazolam
BIPOLAR DISORDERS:TREATMENTS THAT INCREASE
RISK OF RECURRENCE
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“Atypical” neuroleptics
Risperidone
Olanzapine
Quetiapine
Ziprasidone
BIPOLAR DISORDERS:Treatments Being Studied to Determine Risk of
Recurrence
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Improve illness awareness
Early identification of new episodes
Enhance compliance
Stress management
Avoid substance abuse
GOALS OF PSYCHOEDUCATION IN BIPOLAR PATIENTS
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Treat the illness, not just the episodes
Help the patient learn about destabilizing factors
Be empathetic, but blunt, about illness and denial
Work to achieve recovery, not limited improvement.
Use regimens that yield excellent tolerability and adherence
Acute episode drug needs are often different from
maintenance, but they interact significantly
PRINCIPLES OF BIPOLAR DISORDER
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Case Vignette Ms. X is an attractive 21 year old final
semester engineering student, an active member of her college literary and drama club presented with a 10 day history of excessive cheerfulness, over talkativeness, spending sprees, endless partying, insomnia, and suspicions of being teased and harmed.
She has no past history of medical/ mental illness/ no substance use.
Family history revealed an episodic illness in mother stabilized on lithium.
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Case Vignette Psychiatric examination revealed
Increased PMA Flight of ideas Elated mood Inflated self esteem Delusions of persecution and reference
Detailed medical evaluation, investigations ruled out any organic / systemic dysfunction
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Case Vignette
A consultant Psychiatrist made a
diagnosis of Mania with psychotic
symptoms (ICD 10) [DSM IV TR Bipolar
I disorder Single manic episode severe
with psychotic features] and she was
hospitalized.
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• What will be your drug regimea) Mood stabilizers alone (LI/DVX)
b) Antipsychotics alone (AAP/TAP)
c) Mood stabilizers (Li/DVX) + Antipsychotics (AAP/TAP)
d) Mood stabilizers + Benzodiazepines
e) Mood stabilizers + Antipsychotics + Benzodiazepines
MANIA WITH PSYCHOTIC SYMPTOMS
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Rapid cycling10 – 20%
Mixed (dysphoric)30 – 50%
Pure mania30 – 50%
VPA
VPA
Li, VPA
Olanz, VPA
? GB
BP IIDep
Lamotrigine
Not listed in DSM IV TR.
Anxiety, Hostility, Impulsivity,Poor insight, Confusion,
Memory impairment Sensory hyper acuity
Mania with psychotic Features 25 – 75%
Mood Stabilizer
Combinations
Phenomenological Domains
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ANTI-ANXIETY DRUGS
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a) BENZODIAZEPINES• Short Acting• Intermediate• Long Acting
b) NON BENZODIAZEPINES
• Buspirone
• Etifoxine HCI
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BENZODIAZEPINES PROS / CONS
• Established Efficacy• Safety in Over Dose• Withdrawal Effects• Dependence• Tolerance• Memory Disturbance• Rebound Anxiety
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BENZODIAZEPINES
A FRIEND FOE ?OR
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History of Anxiolytic DevelopmentHistory of Anxiolytic Development
ALCOHOL
1903 - BARBITURATES
1950’s – NON BARBITURATES (Meprobamate)
LATE 50’s - BENZODIAZEPINES
NONBENZODIAZEPINE HYPNOTICS
GABA MIMETICS
SELECTIVE GABA A TARGETS
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SIX ISSUESSIX ISSUES
1. Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex?
2. Wouldn’t a world without benzodiazepines make the patients anxious, the psychiatrists restless, the pharma industry insomniacs, and the society bewildered?
3. Don’t we think that the ‘GOOD’ that benzodiazepines have provided, are providing and will provide far outweigh the questionable ‘BAD’ about benzodiazepines?
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4. Do we have enough evidence on– BZD and cognitive dysfunction?– BZD and oversedation?– BZD and dependence potential?– BZD withdrawal?
5. Are we aware of what we are talking about?
6. Can we balance the options?
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• Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex?
ISSUE 1ISSUE 1
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GABA BZD IN NEUROPSYCHIATRYGABA BZD IN NEUROPSYCHIATRY
• Anxiety
– Preclinical and clinical evidence is robust
– BZD are effective anxiolytics
• Depression
– Behavioural models have shown depression in
animal can be manipulated by GABA agents
– Stress is key to depression and stress induced
changes occur in GABAergic function
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• Schizophrenia
– Several lines of evidence support the role of an
epigenetic-induced GABAergic cortical dysfunction
in schizophrenia psychopathology
• Addiction
– Decreased GABAergic function is a major etiologic
step in the maintenance of addictive state
GABA BZD IN NEUROPSYCHIATRYGABA BZD IN NEUROPSYCHIATRY
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• Other disorders
– Epilepsy
– Catatonia
– ADHD
– PMDD
– Dyskinesias/Akathisia
– Tourettes
– Parkinsons
– Huntington’s disease
GABA BZD IN NEUROPSYCHIATRYGABA BZD IN NEUROPSYCHIATRY
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ISSUE 2ISSUE 2
Wouldn’t a world without benzodiazepines
make the patients anxious, the psychiatrists
restless, the pharma industry insomniacs,
and the society bewildered?
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• Benzodiazepines have often been called the most widely prescribed group of drugs in the world and the biggest selling drugs in the history of medicine.
• Worldwide sales of benzodiazepines are estimated at in excess of $21 billion.
• 1980’s 1 billion alprazolam prescription worldwide
• Non psychiatric prescriptions account for 70% of benzodiazepine – Physicians
– Cardiologists
– Gastroenterologists etc
BENZODIAZEPINE IN PRACTICEBENZODIAZEPINE IN PRACTICE
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ISSUE 3ISSUE 3
Don’t we think that the ‘GOOD’ that
benzodiazepines have provided, are
providing and will provide far
outweigh the questionable ‘BAD’ about
benzodiazepines?
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• Do we have enough evidence on
– BZD and cognitive dysfunction?
– BZD and oversedation?
– BZD and dependence potential?
– BZD withdrawal?
ISSUE 4ISSUE 4
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Cognitive effects of long-term benzodiazepine use:
a meta-analysis
• Moderate-to-large weighted effect sizes were found for
all cognitive domains suggesting that long-term
benzodiazepine users were significantly impaired,
compared with controls, in all of the areas that were
assessed. However, this study has several limitations, one
being that it includes a relatively small number of
studies.
Barker et al, (2004), CNS Drugs, 18(1) 37-48
BENZODIAZEPINE AND COGNITIONBENZODIAZEPINE AND COGNITION
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The effects of benzodiazepines on cognition.
• Neuroimaging studies have found transient changes in the brain after benzodiazepine administration but no brain abnormalities in patients treated long term with benzodiazepines.
• Such findings suggest that patients should be advised of potential cognitive effects when treated long term with benzodiazepines, although they should also be informed that the impact of such effects may be insignificant in the daily functioning of most patients.
Stewart SA (2005) J Clin Psychiatry, 66 Suppl 2: 9-13
BENZODIAZEPINE AND COGNITIONBENZODIAZEPINE AND COGNITION
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Benzodiazepine use, abuse, and dependence.• It is important to distinguish between addiction to and normal
physical dependence on benzodiazepines.
• Few cases of addiction arise from legitimate use of benzodiazepines.
• Pharmacologic dependence, a predictable and natural adaptation of a body system long accustomed to the presence of a drug, may occur in patients taking therapeutic doses of benzodiazepines.
• Due to the chronic nature of anxiety, long-term low-dose benzodiazepine treatment may be necessary for some patients; this continuation of treatment should not be considered abuse or addiction.
O'brien CP. (2005)J Clin Psychiatry,66 Suppl 2:28-33.
BENZODIAZEPINE DEPENDENCEBENZODIAZEPINE DEPENDENCE
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Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance dependence.• There is much ambiguity over appropriate definitions for
benzodiazepine abuse and dependence• Furthermore, benzodiazepines do not appear to induce relapse
of substance abuse in these patients. • The position that benzodiazepines are contraindicated in former
substance abusers appears to lack empirical justification. • Benzodiazepines may be indicated in certain patients with
anxiety disorders and a history of substance abuse or dependence.
Posternak MA (2001) Am J Addict, 10(1):48-68.
• The presence or absence of a history of alcohol use disorders is not a strong predictor of the use of benzodiazepines in subjects with anxiety disorders over 12 months of prospective follow-up.
Mueller TI (1996) J Clin Psychiatry, 57(2):83-9.
BENZODIAZEPINE DEPENDENCEBENZODIAZEPINE DEPENDENCE
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• In 1990, the APA task force on BZD’s concluded that BZD are not drugs of abuse though it is common among people actively abusing alcohol, opiates, sedative hypnotics.
Selzman C (1991) Am. J Psychiatry, 148:151-52
• In early 1980’s studies indicated that long term administration of BZD at therapeutic doses produce physical dependence. So in 1990’s it was recommended that these agents should (esp. short t1/2) be tapered gradually when discontinuing them
Rosenbaum JR (2005) J. Clin. Psychiatry, 66 Suppl 2: 4-8
• By 1999 International group of experts recommended the use of BZD for anxiety disorders even for long periods
Uhlenhuth EH (1999) J Clin. Psychopharmacol, 19 (6): 23S-
29S
BENZODIAZEPINE DEPENDENCEBENZODIAZEPINE DEPENDENCE
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• Retrospective analysis of hypnotic overdose in 1989-90 found a decrease in BZD overdose and a statistically significant rise in non BZD sedative overdose
Hofman RS (1991) NY State J Med, 91:436-439
• BZD are less toxic in overdose than alternatives, are safe, and have little liability for abuse among patients without history of abuse
Rosenbaum JR (2005) J. Clin. Psychiatry, 66 Suppl 2: 4-8
BENZODIAZEPINE OVERDOSEBENZODIAZEPINE OVERDOSE
CHANGING ATTITUDE TO BZDCHANGING ATTITUDE TO BZD
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• Don’t we have antipsychotics that produce cognitive
dysfunction
• Don’t we have antidepressants that produce cognitive
dysfunction
• Doesn’t anxiety produce cognitive dysfunction
• Don’t we read about cognitive dysfunction in
schizophrenia and bipolar
• Haven’t we heard of withdrawal of antipsychotics,
antidepressants and anticonvulsants
CRITIQUECRITIQUE
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• Is it not therefore a question of
– Rational/irrational use ?
– Use/misuse/abuse ?
– Combinations that are useful and dirty?
– And what of useful and dirty combinations in
neurobiology
CRITIQUECRITIQUE
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Are we aware of what we are talking about?
ISSUE 5ISSUE 5
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BZDs allosterically modulate GABA neurotransmission by potentiating GABA’s ability to increase conductance of chloride through its channel
BASICSBASICS
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• 19 different sub units grouped into 5 classes according to
the degree of amino acid identity
• Alpha 1-6, Beta 1-3, gamma1-3,Delta, Theta, epsilon, pi
and Rho1-3
• Alpha subunits, especially 1 ,2 and 5 are important for
receptor activation by GABA
• Most GABA A receptor complexes are α1β2γ2
• Specifically α and γ subunits are thought to determine
GABA A-BZD receptor pharmacology
GABA RECEPTORGABA RECEPTOR
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• BDZ1 (Omega - 1) -preferentially labelled by
triazolopyridazines, imidazolopyridine and
pyrazoloqinolines. Also, beta carbolines.
• BDZ1 rich areas - lamina IV of cerebral cortex, cingulate
cortex , globus pallidus, nucleus basalis, substantia nigra
pars reticulata, molecular layer of the cerebellum,
Amygdaloid nucleus , periaqueductal gray matter, ventral
pallidum and inferior colliculus.
• Implicated in sleep wakefulness mechanism
BENZODIAZEPINE RECEPTORBENZODIAZEPINE RECEPTOR
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BZD-2 receptors (Omega-2) - caudate putamen,
olfactory bulb, cerebral cortex, hippocampus and
dentategyrus
Related to cognitive, memory and psychomotor
function.
BZD-3(Omega-3) are not directly associated with
GABA receptors or with chloride channels . They
may regulate the synthesis of neuroactive steroids.
BENZODIAZEPINE RECEPTORBENZODIAZEPINE RECEPTOR
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BDZ
GABACl
Channel
GABA BENZODIAZEPINE RECEPTORGABA BENZODIAZEPINE RECEPTOR
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• 1 – Sedative, amnestic, ataxic and partly anticovulsant• 2 and 3 – Anxiolytic• 3 – DA system receives GABAergic inhibitory input• 5 – Cognitive• 3 – Immobilisation action of propofol and etomidate. • 2 - Hypnotic and respiratory depression GABA A receptor subtype selective anxiolytics
L-838417SL 651498 (Full agonist at 2 and 3, partial agonist at 1 and 5)GLB139- 3 selective BZ agonist
GABA RECEPTOR - SELECTIVITYGABA RECEPTOR - SELECTIVITY
Whiting PJ (2006) Curr Opinion Pharmacol 6: 24-29 Rudolf U & Mohler H (2006) Curr Opinion Pharmacol, 6:18-23
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GABA RECEPTORGABA RECEPTOR
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GABAergic SystemGABAergic System
Morris B et al (2005) Current Opinion in Pharmacology 5 : 101 - 106
2 CCK/VIP+
1
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GABAergic SystemGABAergic System
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• Prescribing is not carefree but requires monitoring to obtain optimal risk benefit ratio
• Benzodiazepines are therefore ‘GOOD’ and are here to stay
ISSUE 6ISSUE 6BALANCING THE OPTIONSBALANCING THE OPTIONS
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• So Benzodiazepine is a friend not a foe
• However it is maybe an evil albeit
necessary if not rationally prescribed
CONCLUSIONCONCLUSION
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“Apply your breaks”
CONCLUSIONCONCLUSION
Don’t blame the machine If the driver is at fault
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The most deserving six-The most deserving six-letter word.......letter word.......
““THANKSTHANKS""
for your for your patient patient
listening.listening.