An update on psychopharmacology part i 22 june 2007 fountain house

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)

• Anti-depressants

• Mood stabilizers

• Anti-anxiety drugs

• Anti-psychotic drugs

• Anti-epileptic drugs

• Anti-dementia drugs

ANTI-DEPRESSANTS

Imipramine (Kuhn 1957) 1st TCA

Iproniazide (Loomer

Saunders & Kline 1957) 1st MAOA

HISTORY

TRICYCLIC ANTI- DEPRESSANTS (TCAS)

NEUROTRANSMITTERS ADDRESSED

Imipramine Amitryptiline Clomipramine Dothiepin Nortriptyline

Serotonin

Norepinephrine

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

SIDE EFFECTS Dryness of mouth Constipation Blurring Urine Retention Tachycardia Postural Hypotension Conduction Contractility

TCAs

Maprotiline Mianserin

SEARCH FOR SAFER ANTIDEPRESSANTS

EFFICACY vs. SAFETY=± TCAs >TCAs

Irreversible MAOIs Phenelzine Tranylcypromine

Precautions Dietary Restrictions Serious Interactions

MONOAMINE OXIDASE INHIBITORS (MAOIs )

IMPROVED SAFETY

Reversible MAOIs

Moclobamide

Befloxatone

MAOIs

SINGLE NEUROTRANSMITTER

ADDRESSED

SEROTONIN

Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

(SSRIs)

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

SSRIs

EFFICACY vs. SAFETY

= TCAs >TCAs

Fluoxetine Weekly

Escitalopram

Paroxetine SR

IMPROVED EFFICACY

SINGLE RECEPTOR SELECTIVITY

SEROTONIN-REUPTAKE INHIBITORS/ RECEPTOR BLOCKERS

TRAZODONE

NEFAZODONE

EFFICACY vs SAFETY

=TCAs >>TCAs

Readdressed

Norepinephrine

Reboxetine

SINGLE NEUROTRANSMITTER

SELECTIVE DOPAMINE REUPTAKE INHIBITORS (SDRIs)

BUPROPION

Major Depression Prophylaxis of Recurrent Major

Depression Bipolar Depression ADHD Alcohol, Nicotine Dependence

Venlafaxine

Milancipran

Duloxetine

DUAL ACTION READDRESSED SNRIs

Serotonin

Norepinephrine (Dopamine)

EFFICACY vs SAFETY

(=/>?TCAs (>>TCAs)

Mirtazepine

NASSA

EFFICACY vs. SAFETY

(=/> TCAs (>>>TCAs)

MOOD STABLIZERS

HOW SHOULD WE DEFINE A “MOOD STABILIZERS”?

No common definition exists today

Debate about key features

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

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

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.

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

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

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

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

PUTATIVE/INNOVATIVE MOOD STABILIZERS

FOR REFRACTORY BIPOLAR PATIENTS

Anticonvulsants Ca2+Channel Blockers

Gabapentin Verapamil

Lamotrigine Nifedipine

topiramate Nimodipine

Tiagabine

Acetazolamide

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

MOOD STABILIZER: MANIA

Mania with psychosis: * Divalproex - * Lithium (Olanzapine, Risperidone, High potency conventional)

Dysphoric mania: * Divalproex - * Lithium

Epuphoric mania: * Lithium - * Divalproex

Hypomania: * Lithium - * Divalproex

MOOD STABILIZER: DEPRESSION

Without an AD: * Lithium * Divalproex

*Lamotrigine * Carbamazepine

With an AD: * Lithium - * Divalproex

* Lamotrigine * Caramazepine

With psychosis: * Olanzapine - * Risperidone

* Quetiapine * Conventional

LithiumDivalproexCarbamazepine

First Line

Lamotrigine ? Gabapentin

Olanzapine Topiramate

Efficacy in Depression Clinical Features

?

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

BIPOLAR RECURRENCE: CLINICAL EFFECTS

Rate of substance abuse comorbidity

Rate of alcoholism comorbidity

Rate of suicide

Possible treatment refractoriness

BIPOLAR RECURRENCE: MEDICAL EFFECTS

Risk of cardiac disease

Risk of drug interactions

BIPOLAR RECURRENCE: PSYCHOSICAL EFFECTS

Rates of divorce, separation

Possibility of jail/prison or hospitalization

BIPOLAR RECURRENCE: ECONOMIC EFFECTS

Job performance

Medical treatment costs

Psychiatric treatment costs

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

PREDICTORS OF POOR LONG-TERM RESPONSE WITH LITHIUM

Psychosis

Substance abuse

Rapid cycling

More than 3 episodes

Mixed mania (depression and mania)

Poor compliance

PROBLEMS OF CURRENT MOOD STABILIZERS

Limited efficacy Toxicity Side effects: renal, thyroid, hematologic, hepatic Monitoring Interactions Teratogenicity Weight gain Poor compliance Refractoriness

BIPOLAR DISORDERS:TREATMENTS THAT DECREASE RISK

OF RECURRENCE

Lithium

Anticonvulsant mood stablizers

(carbamazepine, divalproex, Lamotrigine)

Possibly benzodiazepines (clonazepam)

Possibly ECT

Possibly clozapine

Tricyclic antidepressants

“Typical” neuroleptics

Gabapentin

Nonmood stablizing anticonvulsants

Alprazolam

BIPOLAR DISORDERS:TREATMENTS THAT INCREASE

RISK OF RECURRENCE

“Atypical” neuroleptics

Risperidone

Olanzapine

Quetiapine

Ziprasidone

BIPOLAR DISORDERS:Treatments Being Studied to Determine Risk of

Recurrence

Improve illness awareness

Early identification of new episodes

Enhance compliance

Stress management

Avoid substance abuse

GOALS OF PSYCHOEDUCATION IN BIPOLAR PATIENTS

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

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.

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

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.

• 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

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

ANTI-ANXIETY DRUGS

a) BENZODIAZEPINES• Short Acting• Intermediate• Long Acting

b) NON BENZODIAZEPINES

• Buspirone

• Etifoxine HCI

BENZODIAZEPINES PROS / CONS

• Established Efficacy• Safety in Over Dose• Withdrawal Effects• Dependence• Tolerance• Memory Disturbance• Rebound Anxiety

BENZODIAZEPINES

A FRIEND FOE ?OR

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

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?

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?

• Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex?

ISSUE 1ISSUE 1

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

• 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

• Other disorders

– Epilepsy

– Catatonia

– ADHD

– PMDD

– Dyskinesias/Akathisia

– Tourettes

– Parkinsons

– Huntington’s disease

GABA BZD IN NEUROPSYCHIATRYGABA BZD IN NEUROPSYCHIATRY

ISSUE 2ISSUE 2

Wouldn’t a world without benzodiazepines

make the patients anxious, the psychiatrists

restless, the pharma industry insomniacs,

and the society bewildered?

• 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

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?

• Do we have enough evidence on

– BZD and cognitive dysfunction?

– BZD and oversedation?

– BZD and dependence potential?

– BZD withdrawal?

ISSUE 4ISSUE 4

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

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

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

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

• 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

• 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

• 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

• 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

Are we aware of what we are talking about?

ISSUE 5ISSUE 5

BZDs allosterically modulate GABA neurotransmission by potentiating GABA’s ability to increase conductance of chloride through its channel

BASICSBASICS

• 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

• 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

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

BDZ

GABACl

Channel

GABA BENZODIAZEPINE RECEPTORGABA BENZODIAZEPINE RECEPTOR

• 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

GABA RECEPTORGABA RECEPTOR

GABAergic SystemGABAergic System

Morris B et al (2005) Current Opinion in Pharmacology 5 : 101 - 106

2 CCK/VIP+

1

GABAergic SystemGABAergic System

• 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

• So Benzodiazepine is a friend not a foe

• However it is maybe an evil albeit

necessary if not rationally prescribed

CONCLUSIONCONCLUSION

“Apply your breaks”

CONCLUSIONCONCLUSION

Don’t blame the machine If the driver is at fault

The most deserving six-The most deserving six-letter word.......letter word.......

““THANKSTHANKS""

for your for your patient patient

listening.listening.