PHRM-512 L.S.No-8 v-2(Final)

Evidence Based:PSYCHOPHARMACOLOGICAL ISSUES

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Key Questions

1. How to implement a rational pharmacotherapy in specific syndromes?

2. Which strategies can be followed to distinguish behavioural disturbances from (atypical) psychiatric symptoms?

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Criteria for psychopharmacotherapy

• -Pharmacokinetic variables • (CYP 1A2, 3A4, 2Cfamily, 2D6 iso-enzymes)• -Plasmaconcentrations psychotropics• (not much information available)• -Side effects depend on receptor binding profile• -Epileptogenic side effects of psychotropics• -Recently marketed drugs are contra-indicated• (efficacy/side effects unknown)

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Criteria for psychopharmacotherapy

• -Metabolic syndrome (dyslipidemia, diabetes, weight gain)• (atypical antipsychotics e.g. olanzapine, risperidone and

clozapine) • -Withdrawal syndrome and (tardive) motor side effects • (SSRI’s [paroxetine and sertraline] and venlafaxine)

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Evidence based pharmacotherapy?

• All studies use as inclusion criterion ‘challenging behaviour’ (aggressive, self-injurious, destructive stereotyped and disturbing behaviours)

• No evidence for beneficial effect of antipsychotics, including risperidone, or antidepressants on challenging behaviours • (Deb et al., JIDR:766-777, 2007; Sohanpal et al., JIDR:750-

765, 2007)•

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ANTIPSYCHOTIC MEDICATION FOR CHALLENGING BEHAVIOURS -I

• trial-based evidence of effectiveness or ineffectiveness not available• • clinical practice based on opinion, judgment and fashion rather than

evidence• From: JIDR, 43, 360-371, 1999; JIDR, 51, 766-777,2007

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ANTIPSYCHOTIC MEDICATION FOR

CHALLENGING BEHAVIOURS -II

Tyrer et al. The Lancet, 371:57-63, 2008

Design: double-blind placebo-controlled; 26 wks.

Subjects: non-psychotic patients with aggressive challenging behaviour .

Number: 1860 elegible patients, 86 allocated.

Compounds and daily dosages:

5 mg haloperidol (n=28), 2 mg risperidone (n=29)

Response (% MOAS): pl 79, hlp 65%, risp 58

Conclusion: no differences in side effects; greatest decrease with placebo.

Interpretation: antipsychotic drugs should no longer be regarded as an acceptable routine treatment for aggressive challenging behaviour!

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Diagnosis of Schizophrenia

• Characteristic symptoms: Two (or more) of the following, each• present for a significant portion of time during a 1-month period:• 1. delusions• 2. hallucinations• 3. disorganized speech (e.g., frequent derailment or incoher-• ence)• 4. grossly disorganized behavior• 5. negative symptoms, i.e., affective flattening, alogia, or• avolition

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Diagnosis of Schizophrenia

• ammsm

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Towards a rational choice for psychotropics

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Towards a rational choice for psychotropics

• Prior to the 1950s—which is referred to as the pre-neuroleptic age—insulin coma, drug or electrically induced shock treatments, and psychosurgery, including prefrontal lobotomies, were used to treat schizophrenia.

• The impact of these extreme somatic treatments did make a difference, for a time, in symptomatology but were not durable or beneficial and often not ethical.

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Towards a rational choice for psychotropics

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Towards a rational choice for psychotropics

Dosage Forms: O, tablet; S, solution; IM, acute intramuscular; ODT, orally dissolving tablet.

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Relapse

• A client with schizophrenia is vulnerable after a period of stability, however brief or extended, partial or complete, to a return of symptoms. This is referred to as a relapse, and the disease itself has a pattern of relapse and recovery. • As a chronic disorder, schizophrenia is characterized by relapses

alternating with periods of full or partial remission.• -30% to 40% of clients relapse within 1 year after hospital discharge

even if they are receiving maintenance medication.

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CLINICAL EXAMPLE: Relapse

• Daryl, a 26-year-old with a diagnosis of paranoid schizophre-• nia, decided to stop taking his quetiapine (Seroquel) because• he didn’t think he needed it anymore. Within a few days of• stopping the medication, he was unable to leave the house for• fear of someone harming him. Although he liked his job at the• local cannery and knew that he had the chance to earn more• money in the near future, he refused to go to work for fear• that he would be hit by a bus on his way there. He was even-• tually fired because of poor attendance. The loss of a struc-• tured schedule furthered his deterioration and Daryl relapsed,• requiring hospitalization.

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CLINICAL EXAMPLE: Relapse

• In this instance, a decrease in medication increased Daryl’s biologic vulnerability, with marked behavioral, and eventually environmental, consequences. His relapse began with a medication issue and could have been prevented.

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Treatment: Relapse

• There are many reasons for or inadequate response to antipsychotic treatment in schizophrenia patients. Examples are ongoing substance use, psychosocial stressors, inherent refractory illness, and poor medication adherence. Outside of controlled settings, • Serum drug levels can be obtained for most antipsychotic

medications, but there is limited dose-response data for atypical antipsychotic agents (except for clozapine), leaving clinicians little guidance about the interpretation of antipsychotic drug levels.

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CLINICAL EXAMPLE: Relapse

• The result of genetic variation or induction of hepatic CYPs that decrease drug availability, such as the high prevalence of CYP2D6 ultrarapid metabolizers among individuals from North Africa and the Middle East. • The common problem of medication nonadherence among

schizophrenia patients has led to the development of long-acting injectable (LAI) antipsychotic medications, called depot antipsychotics. • They are more widely used in the E.U. than US.• There are currently four available LAI forms in the U.S.: decanoate

esters of fluphenazine and haloperidol, risperidone-impregnated microspheres, and paliperidone palmitate.• Patients receiving LAI antipsychotic medications show consistently

lower relapse rates and suffer fewer adverse effects issue.

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CLINICAL EXAMPLE: Relapse

• LAI risperidone is administered as biweekly intramuscular (IM) injections of 25-50 mg. Based on extensive kinetic modeling of clinical data, paliperidone palmitate therapy in acute schizophrenia is initiated with IM deltoid loading doses of 234 mg at day 1 and 156 mg at day 8 to provide serum paliperidone levels equivalent to 6 mg oral paliperidone during the first week, obviating the need for oral antipsychotic supplementation. Serum paliperidone levels from these two injections peak on day 15 at a level comparable to 12 mg oral paliperidone. Maintenance IM doses are given in deltoid or gluteus muscle every 4 weeks after day 8.

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CLINICAL EXAMPLE: Relapse

• Electroconvulsive therapy is considered a treatment of last resort in refractory schizophrenia and is rarely employed. Despite widespread clinical use of combining several antipsychotic agents, metabolic risk increases with use of multiple antipsychotic agents. In one of few instances where a sound pharmacological rationale exists for combination treatment, the addition of a potent D2 antagonist (e.g., risperidone, haloperidol) to maximally tolerated doses of clozapine (a weak D2 blocker), the results have been decidedly mixed. That multiple antipsychotic agents ("polypharmacy") are commonly used in clinical practice attests to the limitations of current treatment. Lastly, antipsychotic drug therapy is the foundation of schizophrenia treatment, yet adequate management of schizophrenia patients requires a multimodal approach that also includes psychosocial, cognitive, and vocational rehabilitation to promote functional recovery

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CLINICAL EXAMPLE: Relapse

• The result of genetic variation or induction of hepatic CYPs that decrease drug availability, such as the high prevalence of CYP2D6 ultrarapid metabolizers among individuals from North Africa and the Middle East. • The common problem of medication nonadherence among

schizophrenia patients has led to the development of long-acting injectable (LAI) antipsychotic medications, called depot antipsychotics. • They are more widely used in the E.U. than US.• There are currently four available LAI forms in the U.S.: decanoate

esters of fluphenazine and haloperidol, risperidone-impregnated microspheres, and paliperidone palmitate.• Patients receiving LAI antipsychotic medications show consistently

lower relapse rates and suffer fewer adverse effects issue and could have been prevented.

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Examples of improvement of the homeostatic setpoint

• Buspirone attenuates self- injurious and other challenging behaviours• (Verhoeven & Tuinier, JIDR, 1996) • Valproic acid reduces changes in behaviour and mood

(unstable mood disorder)• (Verhoeven & Tuinier, JARID, 2001)• Citalopram is effective in mood and anxiety disorders• (Verhoeven et al., Eur Psychiatry, 2001)• Pipamperone reduces challenging behaviours• (Van Hemert, Acta Psychiat Scand, 1975)•

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Criteria to choose a psychotropic compound

• Scientific and practical data on effectiveness, safety and side-effect profile• Experience of the physician with certain drugs• Comedication and risk for interactions• Data about treatment evaluation in comparable patient groups with

brain abnormalities and comedication (elderly)• Receptor binding that accounts for side effects • Established plasmaconcentration-effect relation

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GENERAL GUIDELINES FOR PRESCRIBING PSYCHOTROPIC• low anticholinergic profile

• (avoid: amitriptyline,, clozapine)

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• known and simple pharmacokinetic profile

• (e.g.: lorazepam, haloperidol, risperidone, venlafaxine, citalopram)

•

• avoid long-term administration of antipsychotics

• for indications other than psychoses

• (induction of tardive challenging behaviours?)

• favorable and known profile of interactions

• (avoid: fluoxetine, paroxetine, phenothiazines)

•

• consider half-life

• (e.g.: benzodiazepines, antidepressants)

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• monitoring of plasma levels

• (e.g.: interactions, half-life time)

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Pharmacological StrategiesAntipsychotics

• Indications: psychotic disorders• -paranoid psychoses• -schizopohrenia• -delirious states• -stereotyped movements

• Compounds: haloperidol (2-6mg→2-6µg/l)• risperidone (active OH-metabolite; • t½: 22hrs)

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Pharmacological StrategiesAntidepressants

• Indications: stress-related disorders• -affective disorder• -anxiety disorder• -obsessive compulsive disorder

• Compounds: citalopram (no pharmacokinetic interactions or withdrawal symptoms)

• nortriptyline (endogenous depression; active E-OH-metabolite)

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Pharmacological StrategiesMood Stabilizers

• Indications: bipolar affective disorder• episodic behavioural dyscontrol• unstable mood disorder• cycloid psychosis

• Compounds: valproic acid• lithium• lamotrigine

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COMPOUNDS OF FIRST CHOICE

• antipsychotics: haloperidol• risperidone (OH-metabolite)• • antidepressants: citalopram• nortriptyline (OH-metabolites)• • mood stabilizers: lithium• valproic acid• • benzodiazepines: lorazepam (t½ 10-16)• temazepam (t½ 8-14)

• others: pipamperone•

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CONCLUSIONS

• Monitor behavioural toxicity and other • adverse drug reactions

• When it swings, prescribe a mood stabilizer

• Avoid recently introduced psychotropics

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PHARMACOKINETIC PROFILE OF SOME NOVEL ANTIDEPRESSANTS

• INHIBITION OF ISOZYME SYSTEM

• Parent compound half-life active metabolite half-life IA2 3A4 IID6

• Fluvoxamine1 17-23 hrs +++ + -

• Fluoxetine1 1-4 days norfluoxetine 7-15 days - + +++

•

• Paroxetine1,2 ± 24 hrs - + ++++

• Sertraline 1 ± 26 hrs desmethylsertraline 62-109 hrs - ± + ±

• Citalopram ± 33 hrs desmethylcitalopram 38-84 hrs - - -

• Venlafaxine2 ± 5hrs desmethylvenlafaxine ± 11 hrs - - ±

• Mirtazapine 20-40 hrs desmethylmirtazapine ?? - - -

• Moclobemide 2 hrs + - +

• Duloxetine ± 12 hrs - - ++

• Hyponatraemia due to SIADH

• Discontinuation syndrome

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CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS

• Indications: depression, panic and phobias, OCD, enuresis, anorexia nervosa, bulimia

• Drug Choice: past response, tolerance to side effects, drug-drug interactions

• Treatment: 1-6 months; recent report suggests changing if no improvement by 4 weeks

• Note: All antidepressants now carry a “black box” warning that they may lead to suicidal thoughts/behavior

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SIDE EFFECTS OF TCA’s

• antimuscarinic effects• postural hypotension• tachycardia, arrhythmias• sedation• weight gain• sexual dysfunction (ejaculatory)

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SYMPTOMS OF MANIA

• increased energy (buying, phoning)• increased sociability• pressured speech, talkativeness• decreased sleep• drunkenness• combative, dangerous behavior

• distractibility• racing thoughts• impulsive actions and decisions• elevated mood• euphoria• grandiosity• irritability/hostility (easily

angered)

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MANIA—too much neurotransmission?MANIA—too much neurotransmission?

Increased production of inositol phosphate (IP-3) which increases intracellular Ca2+ signalling

Increased DAG which:

activates PKC which phosphorylates a number of substrates including myristoylated alanine rich C kinase (MARCK)

MARCK activates nuclear transcription factors and modulates genes that increase neuromodulatory peptide hormones and alters cell signalling which:

changes neurotransmitter synthesisneuronal excitabiltiysynaptic plasticityneuronal cell loss (prefrontal cortex)

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LITHIUM

• a monovalent ion that can enter neurons but is not readily removed.

• major mechanism is the reduction of neuronal PI second messenger resulting in reduced response of neurons to ACh and NE

• may actually enhance 5-HT

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LITHIUM

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CLINICAL PHARMACOLOGY

• primary therapy for mania

• a narrow therapeutic window (0.8-1.2 meq/L; some guides say 0.6-1.4 meq/L)

• absolutely necessary to monitor serum level (trough level approx. 5 days after initial dose)

• solely eliminated by kidney, therefore assess patient’s kidney function

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ADVERSE EFFECTS

• tremor• decreased thyroid function• polydipsia/polyuria• edema• ECG changes (depression of T-wave)• excreted in breast milk

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Other Medications

• Anticonvulsants: carbamazepine and valproic acid for rapid cyclers

• Olanzepine approved for treatment of mania

• St. John’s Wort: questionable efficacy, but high potential for drug-drug interactions

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Categories of evidence for causal relationships and treatment

• (I) Evidence from meta-analysis of RCTs, at least one• large, good quality RCT.• (II) Evidence from small, non-replicated, RCTs, at least one controlled

study without randomization or evidence from at least one other type of quasi-experimentalstudy.• (III) RCTs must have an appropriate control treatment arm; for

primary efficacy this should include a placebo condition.• (IV) Evidence from expert committee reports or opinions• and/or clinical experience of respected authorities.

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Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: meta-analysis

Nicolas A. Crossley, Miguel Constante, Philip McGuire and Paddy Power

The British Journal of Psychiatry (2010)196, 434–439. doi: 10.1192/bjp.bp.109.066217

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Clinical study of treatment in chronic schizophrenia found no advantage for atypicals over typicals when efficacy is compared.

A meta-analysis of treatment in chronic schizophrenia found an advantage for atypicals only when compared with high doses of typicals.Although this observation was not significant, it supports

the notion that when using typical ntipsychotics in individuals with a first episode, lower doses of medication

areindicated compared with individuals with chronic

schizophrenia.

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The other trial, which was thelargest and longest, reported significantly lower relapse rates with risperidone compared with haloperidol (42.1% v. 54.7% respectively), even though no differences were found in remission and medication adherence.

As relapse is an important determinantof long-term outcome, this should be a serious consideration in the choice of antipsychotic

This meta-analysis revealed no significant differences betweentypical and atypical antipsychotics in discontinuation rates or in short-term symptomatic response in individuals with first-episode psychosis.

However, treatment with atypical antipsychotics wasassociated with relatively more weight gain.

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Whereas treatment with typical was associated with a greater incidence of EPS. Choice of antipsychotic drug in thetreatment of first-episode psychosis may thus be more influencedby side-effect profile than efficacy.

In contrast to published efficacy trials, sulpiride was the FGA chosen most often by psychiatrists, whereas haloperidol, the standard industry comparator, was selected infrequently. The point has been made that

haloperidol carries a considerable adverse effect burden, particularly at the relatively high doses.

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Sulpiride,a more selective dopamine D2receptor blockerthanhaloperidol,isalow-potencyFGAthathasbeen licensed in England since the 1960s. Despite itsname, its pharmacologic features have little in commonwithamisulpride,anSGA.Anecdotally,sulpirideissome-times thought to pose a lower risk of EPSs than otherFGAs; this may have been the reason it was chosen rela-tivelyfrequently.IfthepreferenceforsulpirideintheFGAarm explained the results, this drug would have to haveremarkably superior efficacy and relative atypicality tonegate a real advantage of SGAs, particularly when anysuch effect would be diluted among other FGAs

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Overall, the results of these US studies are in line with the data we present from England. All the data suggest that careful prescribing of FGAs, at least in the context of a trial, is

not associated with poorer efficacyor a greater adverse effect burden, both of

which would translate into lower quality of life in the medium term.

In conclusion,there is no disadvantage in terms of quality of life, symptoms, or associated costs of care

across 1year in commencing treatment with FGAs rather than atypical SGAs in people with schizophrenia whose medication is being changed because of

intolerance or inadequate response. (Peter B. Jones Arch Gen Psychiatry. 2006)

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CLINICAL GUIDANCE ON THE USE OF ANTIDEPRESSANT

MEDICATIONS IN CHILDREN AND ADOLESCENTS

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A recent re-analysis by the FDA of adverse events reported in trials of antidepressantsin children and adolescentsi concluded that the risk of treatment-emergent suicidal thinking or behaviour was increased in patients on active drug (up to 4%) compared to those taking placebo (up to 2%).

In New Zealand, Medsafe have issued astatement from ADRAC. These statements outline rational clinical practice.1. Any SSRI use in adolescents with Major Depressive Disorder (MDD) should be undertaken only within the context of comprehensive management of the patient.

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2. The choice of SSRI for adolescents should be made taking into account the recent evaluations of clinical trial data and product information.3. Adolescents who are currently being treated for MDD with an SSRI should nothave their medication ceased abruptly.

Starting with a low dose and building up gradually,o Warning parents and patients about potential activation symptoms, includingthe possible emergence of suicidal thoughts early in treatment,o Careful monitoring in the early weeks for the emergence of behaviouralactivation, with the prescriber being available for contact,o Consultation, wherever possible, with a child and adolescent psychiatrist ordevelopmental paediatricia

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2. Following recovery, the antidepressant should be continued for a period of six to twelve months to

prevent relapse or recurrence.Sudden cessation of SSRIs should be avoided in

order to avoid discontinuationsyndrome

Drug CombinationsCombining antipsychotic drugs confounds evaluation of the efficacy of the drugs

being used.- Use of combinations, however, is widespread, with more emerging

experimental data supporting it.- Tricyclic antidepressants or, more often, SSRIs may be used with antipsychotics

for clear symptoms of depression complicating schizophrenia. Lithium or valproic acid is sometimes added to antipsychotic agents with benefit

to patients who do not respond to the latter drugs alone. Sedative drugs may be added for relief of anxiety or insomnia not controlled by

antipsychotics.

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