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4/25/2011
Disclaimer
Drug‐Induced Psychiatric Conditions
Stacy Miller, PharmD, BCPS
April 22, 2011
NEITHER THE PUBLISHER NOR THE AUTHORS ASSUME ANY LIABILITY FOR ANY INJURY AND OR DAMAGE TO PERSONS OR PROPERTY ARISING FROM THIS WEBSITE AND ITS
ARISING FROM THIS WEBSITE AND ITS CONTENT.
Objectives
• Assess a patient’s risk for developing steroid‐
induced psychosis, fluoroquinolone‐induced central nervous system effects, and interferon‐
induced depression
induced depression
• Either rule out or recognize drug‐induced psychiatric conditions
• When possible, take measures to prevent or treat drug‐induced psychiatric conditions
Steroid‐Induced Psychosis
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4/25/2011
Steroids treat inflammation.
We’re not talking about anabolic steroids.
What is steroid‐induced psychosis?
Euphoria
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Anger,
Agitation
Anxiety, Depression, M d l bilit
Mood lability
Delirium
Alzheimer’s‐
type dementia
type dementia
Cognitive impairment
Hallucinations/Delusions
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3‐10% of patients on corticosteroids
Cerebral Cortex = 11%
35%
3%
13%
12%
Mania
Depression
Mania+Depression
Delirium
Psychosis
28%
Risk factors for steroid‐induced psychosis:
Female gender (?)
Hypoalbumineria
Risk factor for steroid‐induced psychosis:
Dose
Inactive Steroid
>80 mg/day prednisone = 18.6%
41 80 mg/day prednisone = 4 6%
41‐80 mg/day prednisone = 4.6%
≤ 40 mg/day prednisone = 1.3%
Active Steroid
Albumin
Normal albumin concentrations
Hypoalbumineria
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When does steroid‐induced psychosis occur?
Steroid Psychosis
(not delirium)
Option 1: Taper Steroid Dose
Delirium
Symptomss
Steroid
d Dose
Steroid Psychosis
(not delirium)
Treating Steroid Psychosis
Day 1
Day 4
Week 2‐3
Month 2‐4
Day 2
Day 3
Day 4
Day 5
Time
Treating Steroid Psychosis
Treating Steroid Psychosis
Option 2: Divide Steroid into Multiple Daily Doses
Option 3: Switch to Different Steroid
Steroid SSerum Concentrrations
● New chemical structure
● Different specificity or potency
● Alterations in absorption, protein binding, metabolism, excretion, membrane permeability
Once Daily Dosing
Twice Daily Dosing
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Treating Steroid Psychosis
Option 4: Start Medication to Treat Symptoms
Carol is a 52‐year‐old female who had a hysterectomy in your hospital 12 days ago. Following the procedure, she had intractable nausea and vomiting, and was started on 8 mg IV dexamethasone BID. She is now being transferred to your inpatient psychiatric unit with auditory hallucinations and religious delusions. What is the likelihood (given as a % risk) that her current symptoms were caused by the steroid?
1. 18.6%
2. 4.6%
3 1.3%
3.
1 3%
Antidepressant
Mood Stabilizer
M
d S bili
Antipsychotic
Anxiolytic
Not Ideal for Monotherapy. Do WITH Another Option.
33%
1
33%
2
33%
3
Mild:
CNS Effects of Fluoroquinolones
Dizziness
Headache
Drowsiness
Insomnia
Anxiety
Nightmares
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Severe and Rare:
Second most common ADR of fluoroquinolones:
Psychosis
Agitation
Confusion
Depression
CNS (0.2‐11%)
Theory One:
Diary Card Incidence:
Headache 13.2%
Dizziness 9.2%
Somnolence 1.3%
Fluoroquinolones bind here
Spontaneous p
Reporting Incidence:
Headache 2.3%
Dizziness 3%
Somnolence 1.8%
↓ GABA ↓
GABA
Activity
Decreased GABA activity means CNS activation
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Theory Two:
Regardless of theory…
NMDA Receptor
Uninhibited NMDA activity means CNS activation
Mg does not bind or inhibit + FQs
NMDA
Which fluoroquinolones are most likely to cause CNS ADRs?
What about NSAIDs?
Norfloxacin
Moxifloxacin
Ciprofloxacin
Ofloxacin
Levofloxacin
Interaction with FQ’s unlikely.
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Who is at risk?
CNS ADRs in 177 Elderly Patients Levofloxacin 500 mg QDay
Elderly
High Dose
Renal Impairment
Elderly
Managing Patients on Fluoroquinolones
Insomnia
10%
General Population
4%
Headache
5.3%
0.1%
Rose is an 86‐year‐old female with Alzheimers disease presenting with acute delirium. She has been admitted to your inpatient psychiatric unit, and a urinalysis reveals that Rose has a urinary tract infection. You would like to treat with an oral antibiotic, and you know that Rose has a sulfa allergy. Which fluoroquinolone would be most appropriate?
1. Ciprofloxacin
2. Levofloxacin
3. Moxifloxacin
Mild CNS ADRs resolve with continued use.
Avoid by giving with food or at bedtime.
33%
1
33%
2
33%
3
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Interferon‐Induced Depression
Interferon
Image from: http://pathmicro.med.sc.edu/mayer/v‐h3.jpg.
Types of IFN
IFN Indications
•
•
•
•
•
IFN‐α
Hepatitis C
CML
Melanoma
Kaposi’s sarcoma
Multiple myeloma
IFN‐ β
• Multiple sclerosis
IFN‐γ
• Osteopetrosis
• Chronic Granulomatous Disease
CML = Chronic myeloid leukemia
Image from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mmed&part=A2685
Micromedex Healthcare Series: Thompson Reuters Healthcare, Inc.
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Proposed Mechanism of IFN‐Induced Depression
Acetyl CoA
• Hepatitis C: ~ 20‐40% develop MDD Picolinic Acid
– Develops ~3 months after initiation
IFNs
+
IDO
Nicotinic Acid
5‐HT (Serotonin)
Tryptophan
Diet
+
L‐kynurenine
Incidence of MDD with IFN‐α
33% developed MDD
IDO Induction
IDO = Indolamine
Loftis et al. J Affect Disord 2004; 82: 175.
Incidence of MDD with IFN‐α
Incidence of MDD with IFN‐β
MDD Incidence Before IFN
• Cancer: Limited data compared to HCV
14%
MDD Incidence After 12 months of IFN
1%
6%
12%
Depression in 1200 melanoma patients
Interferon Group (n
Interferon Group
(n=608)
608)
Minimum
53%
32%
All
Grade 3
Grade 4
All
Grade 3
Grade 4
360 (59%)
38 (6%)
1 (<1%)
153 (25%)
2 (<1%)
1 (<1%)
Minimum
Mild
Observation Group (n=613)
Observation Group (n
613)
Moderate
Severe
57%
25%
Mild
Moderate
Severe
83% pts in study
85% pts in study
• 40‐50% patients with MS develop MDD
Eggermont et al. Lancet 2008; 372: 117.
Zephir et al. Multiple Sclerosis 2003; 9: 284.
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Incidence of MDD with IFN‐γ
• Limited data and small studies
• Two efficacy studies reported no incidence of MDD:
– Metastatic carcinoid tumor, n=51
M t t ti
i id t
51
– Chronic granulomatous disease, n=76
Stuart et al. Invest New Drugs 2004.
Marciano BE et al. CID 2004.
Treating IFN‐Induced Depression
Risk Factors IFN‐Induced MDD
History of Mental Illness
History of Substance Abuse
Concomitant Ribavirin
History of Suicidal Ideation
Family History of Mental Illness
Interferon Rechallenge
Quarantini et al. Liver Int 2007; 27: 1098.
Treating IFN‐Induced Depression
• Randomized, double‐blind, placebo‐controlled
• Excluded: history of psychiatric illness or active substance abuse
• 100 patients with HCV on IFN‐α + ribavirin
• Patients:
– Hospital Anxiety and Depression Scale (HADS) score ≥ 9
– n=28
• Treatment:
– 20 mg citalopram daily (n=14) or placebo (n=14)
Kraus et al. Gut 2008.
Kraus et al. Gut 2008.
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Evaluating Kraus Study Depression Prophylaxis During Interferon Therapy
• Patients (n=40):
• Weaknesses
– Resected malignant melanoma
– 12 wks of IFN‐α
– Excluded: bipolar disorder, schizophrenia
p
,
p
– Effect of ribavirin?
– Patient population
– Low citalopram dose
Low citalopram dose
• Intervention:
• Strengths
– Randomized, double‐blind, placebo‐controlled
– 10‐40 mg paroxetine (mean 31 mg, n=20) v placebo (n=20)
– Started 2 weeks before IFN therapy
– Use of HADS scale
– Study design
– Appropriately powered
Kraus et al. Gut 2008.
Depression Prophylaxis During Interferon Therapy
• Primary outcome:
Depression Prophylaxis During Interferon Therapy
• Results:
– Decrease in Hamilton Depression Rating Scale (HAM‐D) score
• HAM‐D Scale:
–
–
–
–
Musselman. NEJM 2001.
– Development of MDD: • 11% paroxetine, 45% placebo (p=0.04)
– Change in HAM‐D Score:
0 6: No depression
0‐6: No depression
7‐17: Mild depression
18‐24: Moderate depression
> 25: Severe depression
• Secondary outcome: – Development of MDD during interferon treatment
Musselman. NEJM 2001.
Treatment
Baseline
4 wk
8 wk
12 wk*
Placebo
5 ± 4.4
11.8 ± 7.6
14.5 ± 9.9
15.2 ± 9.9
Paroxetine
5.6 ± 4.7
9.1 ± 5.2
7.8 ± 5.2
8.4 ± 5
*p<0.001
Musselman. NEJM 2001.
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Evaluating Musselman Study
• Weaknesses
Recommendations
• When starting a patient on IFN
– Inadequate length of paroxetine therapy?
– Inadequate starting dose of paroxetine – Did not account for use of concomitant mood‐
Did not account for use of concomitant mood
altering medications • Strengths
– Patient population
– Recognize that the incidence of IFN‐induced MDD is largely unknown
– Identify risk factors for MDD in that patient
Identify risk factors for MDD in that patient
– Determine whether prophylaxis or watchful waiting is more appropriate
– Recall that evidence surrounding both treatment and prophylaxis of IFN‐induced MDD is focused on SSRIs
Musselman. NEJM 2001.
Objectives
• Assess a patient’s risk for developing steroid‐
induced psychosis, fluoroquinolone‐induced central nervous system effects, and interferon‐
induced depression
induced depression
• Either rule out or recognize drug‐induced psychiatric conditions
• When possible, take measures to prevent or treat drug‐induced psychiatric conditions
Questions?
• [email protected]
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