The Psychiatric Management of Tick-Borne Diseases - ILADS

The Psychiatric Management
of Tick-Borne Diseases
ILADS 2007 Scientific Meeting
October 28, 2007
Robert C Bransfield MD, DFAPA
Disclosure Statement
Robert Bransfield, MD, DFAPA, PC
• Most of my income is paid directly from patients
• No insurance, government or other payer contracts
that restrict patient care in return for referrals,
financial considerations or any other benefit
• No patents or other financial interests associated
with Lyme/tick-borne diseases.
• Speakers Bureau: Abbott, Astra Zeneca,
Cephalon, Forest, GSK, Jazz, Lilly, Pfizer, Sanofi
Aventis, Shire, Takeda, UCB, Wyeth
1

Pathopyhsiology
Pathological Cascade
Causes of Disease
Genetic, Developmental, Proximate
Pathophysiology
Dysfunction
Syndrome of Dysfunction
Symptoms
2

Disease Progression
Persistence
of Symptoms
Ineffective
Treatment
Illness Progression &
Treatment Resistance
Understanding the Cause
Over Time
• Predisposing factors
• Precipitating factors
• Perpetuating & disease progression factors
• Pathophysiology
• The next step is disease modifying
treatments
3

Disease Contributors Change with
Time
Symptom
“Intensity”
Predisposing Factors
Precipitating Factors
Perpetuating Factors
1 2 3 4
Preclinical Onset
Course
Short-Term Chronic
Adapted from Spielman AJ et al. Psychiatr Clin North Am. Course of Insomnia; 1987;10:541-553.
Threshold
Schema of Etiologic and Pathogenetic Factors That Have Been Implicated in Cell Death in
Parkinson Disease and Possible Neuroprotective Approaches
Copyright restrictions may apply.
Schapira, A. H. V. et al.
JAMA 2004;291:358-364.
4

Do Psychotropics Have
Antimicrobial Effects or Immune
Effects?
Antibiotics: The First Antidepressants
• In 1952, Zeller and associates found that “MAO was
inhibited by the hydrazine MAOI, iproniazid,” and Selikoff
and co-workers and Bloch and colleagues fortuitously
noticed mood elevation in tuberculosis patients treated
with iproniazid. Crane and Kline independently studied
iproniazid in depressed patients and reported favorable
results. The use of iproniazid was associated with
hepatic toxicity, however, and as a result, other drugs
that differed in a variety of properties and structures but
shared the same common property of MAO inhibition
were studied.
• The other hydrazines--isocarboxazid, nialamide and
phenelzine in this regard and also notes that as far back
as 1948.
Klein DF, Gittelman R, Quikin F, Rifkin A. Diagnosis and Drug Treatment of Psychiatric
Disorders: Adults and Children. Second Edition. Williams & Wilkins, Baltimore. 1980
[a] pp 303-306; [b] p 464; [c] p 269
5

Immunomodulatory effect of SSRIs on
human T lymphocyte function and gene
expression
• Antidepressants have an antiproliferative effect in some
cell lines. Depression may be associated with activation
of some pro-inflammatory cytokines.
• We found that the SSRIs, paroxetine and sertraline
decreased T-cell viability with IC50 around 10 μM.
• These SSRIs inhibit the secretion of the TH1 factortumor
necrosis factor(TNF)α from the cells. On the
molecular level, the SSRIs suppressed signal transducer
and activator of transcription 3 (Stat3) and
cyclooxygenase(Cox)2 protein expression.
• The inhibitory effects were accompanied by alterations in
gene expression as assessed in the gene array. These
findings reveal an immunomodulatory effect of the SSRIs
paroxetine and sertraline in human T cells.
Taler, et al. European Neuropsychopharmacology
Balanced Inflammation
• Inflammation could have a protective role and promote
regeneration of damaged neurons. We do not yet know
how to achieve a "balanced" inflammation. Because
some novel anti-inflammatory treatment might have
detrimental consequences, carefully monitoring disease
progress in patients treated with this category of drugs is
indispensable
• A variety of neurological diseases the initial triggers differ
significantly, while the subsequent pathways involving
inflammatory processes and causing brain damage
share certain pathological mechanisms
Aktas, O. et al. Arch Neurol 2007;64:185-189.
6

Chlamydia
Chlamydiacea and Haloperidole
EB= elementary body
RB = reticulate body
35-40h
Karin D.E. Everett (2000) Vet. Microbiol. 75: 109-126
Murray & Ward (1984) J. Gen. Microbiol.130:193-201
Barbara Fellerhoff
Institute for Immunology LMU Munich
Haloperidole
8h
30h
24h
7

Metabolites of the antipsychotic agent clozapine inhibit
the replication of human immunodeficiency virus type 1
• Clozapine, an atypical antipsychotic, and nine of
its metabolites were studied in vitro for possible
antiviral activity against a model of a human
neurotropic virus, HIV-1.
• In an assay for inhibition of virus-induced
cytopathic effect two metabolites demonstrated
antiviral activity.
• These data suggest that the therapeutic efficacy
of some antipsychotics may be due in part to an
ability to inhibit viral replication. Antiviral agents
may prove to be effective adjuncts in the
treatment of schizophrenia.
Jones-Brando LV, Buthod JL, Holland LE, Yolken RH, Torrey EF.
Schizophr Res. 1997 May 3;25(1):63-70.
Psychotropics
• Antidepressants were developed from TB
drugs that had mood lifting side effects
• Psychotropics effect neurotransmitters &:
– Are sometimes antimicrobial
– Can be immune modulators
– May alter CNS gene expression
– Can be neuroprotective
– Can increase neurogenesis and BDNF
8

There Are No FDA Approved
Treatments for Late Stage Tick-
Borne Disease
FDA Labeling Issues
• 88% of the diagnostic categories in the DSM-TR do not
have a FDA approved treatment [1]
• “The FDA does not regulate the practice of medicine and
physicians may use a drug in ways other than indicated on
the labeling when, in their professional judgment, it is
warranted in a particular case.” [2]
• “The standard of care is often not the same as the FDA
labeling for any particular treatment. Good medical practice
and the best interests of the patient require that physicians
use legally available drugs, biologics and devices according
to their best knowledge and judgment.” [2]
• “The FDA recognizes that off-label use of drugs by
prescribers is often appropriate and may represent the
standard of practice.” [2]
[1] Nasrallah, H. Off-label prescribing: Cutting edge psychopharmacology.
Current Psychiatry; Vol.6,No3, March 2007
[2] FDA
9

Confront Dogma
Think Outside the Box
10

General Considerations
Neuropsychiatric Herxheimer
Reaction
• Treating Lyme/tick-borne disease patients with
antibiotics may cause a Jarisch-Herxheimer
reaction
• This reaction may exacerbate any symptom
caused by the infection
• A sudden appearance of depression, suicide
attempts, agitation & violence may be a part of
this reaction. “You can’t bear to live. It is
beyond the imagination.”
• Slowly starting the antibiotic, close observation
& psychotropics are helpful
11

Substance Abuse and LB/TBI
• Although most LB/TBI patients realize they
have a reduced tolerance to alcohol, a few
abuse alcohol which exacerbates their
symptoms.
• Drug abuse is more common, most
notably pain meds and tranquilizers.
• Well planned treatments minimize these
risks.
Minimize Life Stress
• Chronic illness decreases functioning
which increases stress and contributes to
perpetuating illness.
• Strategies to reduce chronic stress
improve recovery.
12

Antibiotics or Psychotropics?
• When a patient has been treated with just
antibiotics, consider psychotropics.
• When a patient has been treated with just
psychotropics, consider antibiotics.
• When a patient is treatment resistant
consider both.
Dosing Strategies
• Change one treatment at a time
• If something works, continue it
• Some patients are drug sensitive and low
doses are needed
13

Anticipate the Unexpected Adverse
Drug Reaction
• Due to the complexity of the human brain
and individual differences, there will
always be someone with an opposite
response or unusual reaction to any
psychotropic.
• An apparent adverse drug reaction may
instead be a symptom flare or Herxheimer
reaction
• Be prepared to respond to the
unexpected.
Symptomatic Treatment
14

Symptomatic Treatment Reduces
Disease Progression with:
• Insomnia
• Attention deficit hyperactivity disorder
• Anxiety disorders
• Posttraumatic stress disorder
• Depression
• Bipolar disorder
• Schizophrenia
• Alzheimer’s
• Other general medical conditions
Benefit of Symptomatic Treatment
• Chronic stress, dysregulated hyper/hypoarousal
& impaired sleep cause
compromised immune functioning
(increased inflammation, decreased
cellular immune response) & increased
oxidative stress resulting in decreased
neuroprotection and increased
neurodegeneration
• Symptomatic treatments can prevent and
sometimes reverse progression of illness
15

Symptom Priority
• A TBD patent may have over 100 different
symptoms.
• After completing an assessment, prioritize
which symptoms are most sever and
contribute the most towards perpetuating
chronic illness.
• Treat the high priority symptoms first and
work your way down the list.
What Symptoms Perpetuate TBD
Disease?
• Sleep disorders
• Fatigue
• Cognitive impairments
• Depression
•Anxiety
•Pain
• Headaches
• Others
16

Variability in Sleep Patterns in a Normal Adult vs a
Patient With Major Depression
Normal
Adult
Patient With
Major
Depression
Sleep Stage
Sleep Stage
Awake
REM
1
2
3
4
Awake
REM
1234
Sleep
Latency
Sleep
Cycle
Total Sleep Time
1 2 3 4 5 6 7 8
Time (h)
1 2 3 4
Time (h)
5 6 7 8
Adapted with permission from Winokur A, Reynolds CF III. Primary Psychiatry. Nov/Dec 1994:22-27.
Please see important safety information on accompanying slides and full prescribing information.
17

Bidirectional Communication between the Brain and the
Immune System: Implications for Physiological Sleep
and Disorders with Disrupted Sleep
• Cytokines produced by cells of the immune
and nervous systems regulate sleep.
• particularly interleukin-1beta and tumor
necrosis factor-alpha, signal neuroendocrine,
autonomic, limbic and cortical areas of the CNS
to affect neural activity and modify behaviors
(including sleep), hormone release and
autonomic function.
• Sleep disorders are commonly associated with
chronic inflammatory diseases and chronic ageor
stress-related disorders. The best studied are
rheumatoid arthritis, fibromyalgia and chronic
fatigue syndromes.
Lorton D et al. Neuroimmunomodulation. 2006;13(5-6):357-74. Epub 2007 Aug 6.
Sleep restriction increases IL-6 and
pain-related symptoms in healthy
volunteers
• Chronic under-sleeping may contribute to
the high prevalence of pain experiences
observed in the general population
• Chronic sleep restriction leads to mild
elevations in IL-6, an important inflammatory
modulator, and may contribute to the sleep
loss-pain relationship we observed in the
present study
M. Haack, E. Sanchez, J. Broussard, M. Regan, J. Mullington
J Pain; April 2004, Supplement 1 • Volume 5 • Number 3
18

Possible Functions of Slow Wave
Sleep
• Restoration and recovery 1
– SWS rebound following sleep deprivation
– Growth hormone secretion during SWS
– Selective SWS deprivation in animals ⇒ physical
injury and death
– Relationship between ⇓ SWS, aging, and sleep/wake
complaints
• Energy conservation 2
– ⇑ SWS during hibernation
– ⇓ Core body temperature and metabolic rate during
SWS
• Predator avoidance 2
1. Kryger MH et al. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 2 nd ed.
Philadelphia, PA. W.B. Saunders 1994: 301-308.
2. Zepelin H. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 2 nd ed.
Philadelphia, PA: W.B. Saunders 1994: 69-80.
Impaired Sleep Correlates with
Impaired Immune Functioning
• Sleep and the immune system. Int J Immunopharmacol
1995;17:649-54.
• Disordered sleep in fibromyalgia and related myofascial
facial pain conditions. Dent Clin North Am
2001;45:701-13.
• Management of sleep disorders in fibromyalgia.
Rheum Dis Clin North Am. 2002;28:353-65.
• Sleep, neuroimmune and neuroendocrine functions in
fibromyalgia and chronic fatigue syndrome.
Adv Neuroimmunol 1995;5:39-56.
• Fibromyalgia, sleep disorder and chronic fatigue
syndrome. Ciba Found Symp 1993;173:262-79. H. Moldofsky
19

Normalizing the Amplitude of the
Circadian Rhythm
• Activating agent in the morning
• Sleep promoting agent at night
• Combination of both
Normalizing the Amplitude
of Circadian Rhythm
Activating Agents (AM)
• Modafinil
• Stimulants
• Bupropion
• Noradrenergic agents
• SSRIs
• Activating atypicals
• Thyroid
Sleep Promoting (PM)
• Pregabalin, Tigabine
• Trazodone, Quintiapine
• Sodium Oxybate
• Gabapentin
• Non-Benzos: Zolpiderm,
Zaleplon, Zopiclone
• Benzodiazepines
• Doxepin, Amitriptyline, etc.
• Mirtazapine
• Antihistamines
• Sedating atypicals
• Melatonin, Ramelton
20

Potential Uses of Modafinil in
Psychiatric Disorders*
• Modafinil was administered as part of a treatment
regimen in patients (N=237) with a broad spectrum
of treatment-resistant psychiatric, neurological and
general medical disorders accompanied by some
combination of excessive sleepiness, fatigue,
executive dysfunction and apathy.
• In a retrospective chart review with CGI-S, 84.4%
improved and most tolerated the agent well
• Modafinil may offer clinical benefit for treatmentresistant
hypoarousal symptoms in a number of
psychiatric, neurological and general medical
conditions.
*Bransfield RC. The Journal of Applied Research. Vol.4, No. 2, 2004
21

Nociceptive vs Neuropathic Pain States
Nociceptive Neuropathic
• Arises from stimulus outside
of nervous system
• Proportionate to receptor
stimulation
• When acute, serves
protective function
Serra. Acta Neurol Scand. 1999;173(suppl):7
1999;173(suppl):7-11
11.
Examples of Nociceptive and
Neuropathic Pain
vs
Nociceptive Mixed
Caused by
tissue damage
• Arthritis
• Mechanical low
back pain
• Sports/exercise injuries
• Postoperative pain
Caused by
combination
of primary
injury and
secondary
effects
• Low back pain
• Fibromyalgia
• Neck pain
• Cancer pain
• Arises from primary lesion
or dysfunction in nervous
system
• No nociceptive stimulation
required
• Disproportionate to
receptor stimulation
• Other evidence of nerve
damage
Neuropathic
Caused by
lesion or dysfunction
in the nervous system
• Painful DPN
• PHN
• Neuropathic low back pain
• Trigeminal neuralgia
• Central poststroke pain
• Complex regional pain syndrome
• Distal HIV polyneuropathy
22

Sodium Oxybate: CNS
Pharmacology
• Binds to GABA B receptor
– May play important role in pharmacologic
activity at therapeutic dosage levels
– Antagonism of GABAB in animal models
inhibits sodium oxybate–induced sleep and
some neuromodulation effects
• Metabolic effects
– Decreases cerebral glucose utilization
– Cerebral protective effects
Sodium Oxybate:
Open-Label Dose-Escalation Trial—
Effect on Stage 3 and 4 Sleep
Total stage 3 and 4 sleep
(min)
30
25
20
15
10
5
0
Baseline
N=21.
*P=0.012.
Stimulant medications maintained.
Black et al. Sleep. 2001;23(suppl 2):A321.
4.5
(1st dose)
4.5
(wk 0-4)
6.0
(wk 4-6)
Sodium oxybate dose (g)
7.5
(wk 6-8)
*
9.0
(wk 8-10)
23

Increase in NREM Sleep Duration
Sodium Oxybate-Modafinil: 8-Week, Placebo-Controlled
Trial
Median change
from baseline (min)
50
40
30
20
10
0
-10
Baseline (min):
Change from baseline (modafinil)
Placebo
(modafinil
withdrawn)
Modafinil
(unchanged
dosing)
Sodium
oxybate
Modafinil +
sodium
oxybate
327 333 340 324
NREM = non-REM. N=222. SXB-22. P values compared with placebo.
Data on file, Orphan Medical.
Sleep
–
P

Sleep
Administered at Night: Sodium
Oxybate Stabilizes Nocturnal Sleep
GABA
(ventrolateral
Preoptic
area)
–
At night
Norepinephrine
Serotonin
GABA
–
Sodium
oxybate
–
GABAB receptor
Norepinephrine
Histamine
Dopamine
Wake
Serotonin
Acetylcholine
Memantine (Namenda)
• Memantine is FDA approved for moderate to
severe Alzheimer’s disease.
• It is similar to the antiviral, amantadine, and was
used to treat AIDS. Although ineffective for AIDS, it
was effective for AIDS dementia.
• Memantine is considered to be neuroprotective as
a NMDA partial antagonist by selectively block the
excitotoxic effects associated with abnormal
transmission of glutamate, while allowing for the
physiological transmission associated with normal
cell functioning.
• Quinolinic acid is increased in infectious and other
neurodegenerative encephalopathies.
• Quinolinic acid is neurotoxic as an NMDA agonist.
25

Memantine Mechanism of Action
• Low to moderate affinity, uncompetitive
NMDA-receptor antagonist, voltagedependent,
fast blocking/unblocking
kinetics
– Blocks the effects of abnormal glutamate
activity that may lead to neuronal cell
damage/loss and cognitive dysfunction
– Preserves physiological activation of NMDA
receptor required for learning
and memory
Source: Danysz W, et al. Neurotoxicity Res. 2000;2:85-87.
Feedback from Lyme Patients:
Memantine (Namenda)
• “Without it I do less word inventions”
• “Better word retrieval when I speak”
• “Helps word finding problem”
• “It reduces the static, crackle in the head”
• “better verbal comprehension”
• “More focused”
26

Mood Stabilization & Aggression &
Seizure Control
• Anticonvulsant mood stabilizers
– Valproate (Depakote ER)
– Lamotrigine (Lamictal)
– Pregabalin (Lyrica)
– Carbemazepine (Equetro, Tegretol)
– Oxcarbazepine (Trileptal)
• Atypical agents
– Olanzapine (Zyprexa)
– Quintiapine (Seroquel)
– Aripiprazole (Abilify)
– Ziprasidone (Geodon)
• Lithium (Lithobid, etc.)
Valproate (Depakote ER)
• Best treatment for aggression
• Mood stabilizer
• Antidepressant for some
• Anti-migraine
• Reduces neuropathic pain
• Generally Depakote ER has less side
effects
27

Lamotrigine (Lamictal)
• Highly effective antidepressant without
sexual side effects, weight gain or
significant cognitive impairments
• Limited anti-mania effects
• Beneficial to some with depersonalization
and borderline personality
• Anticonvulsant
• Treats neuropathic pain and migraine
• 1:1000 risk of Stevens Johnson Syndrome
Pregabalin (Lyrica)
• Initially approved for the treatment of central
nervous system disorders, including epilepsy,
diabetic neuropathy and post herpetic neuralgia.
• Recently FDA approved for fibromyalgia.
• Studies demonstrate efficacy for generalized
anxiety and sleep disorders.
• Not a mood stabilizer.
28

Carbemazepine (Equetro, Tegretol)
• Mood stabilizer
• Can reduce aggression
• Proven to reduce sound sensitivity in
Lyme patients (Nields)
• Equetro has less side effects
Oxcarbazepine (Trileptal)
• Mood stabilizer
• Metabolite of carbemazipine (Tegretol)
• Sometimes causes hyponatremia
29

Olanzapine (Zyprexa)
• Mood stabilizer, reduces mania, reduces
agitation, antidepressant, reduces
aggression
• Cognitive benefit
• Quite effective for adults with LYD/TBD
• Weight gain and metabolic issues in some
Quintiapine (Seroquel)
• Promotes delta sleep
• More commonly given at bedtime
• Weight gain, but less than olanzapine
(Zyprexa)
30

Aripiprazole (Abilify)
• Minimal weight gain
• Akathesia is common causing a feeling of
restlessness
• Anti-cholinergics often needed for
akathesia
Ziprasidone (Geodon)
• Mood stabilizer and antidepressant
• Can reduce acute suicidal urges in some
• Twice a day or three times a day dosing
needed
• Less weight gain but more EPS than other
atypicals
• Anti-cholinergics often needed
31

Benzodiazepines
• Useful for acute anxiety, but tolerance and
dependence can occur
• May disrupt sleep architecture
Serotonin Norepinephrine Uptake
Inhibitors
• Duoxetine
• Venlafaxine ER, (& Venlafaxine)
• Milnacipran (investigational)
• Tricyclics
32

Duloxetine (Cymbalta)
• SNRI FDA approved for treatment of
depression, generalized anxiety & diabetic
neuropathy
• Effective for chronic pain and somatic pain
symptoms, including fibromyalgia[1]
• Beneficial for anxiety
[1]"A Double-Blind, Multicenter Trial Comparing Duloxetine With Placebo in the Treatment of Fibromyalgia Patients With or Without
Major Depressive Disorder," Lesley M. Arnold, Yili Lu, Leslie J. Crofford, Madelaine Wohlreich, Michael J. Detke, Smriti Iyengar,
and David J. Goldstein, for the Duloxetine Fibromyalgia Trial Group, Arthritis & Rheumatism, September 2004; 50:9; pp. 2974-2984.
Milnacipran
• SNRI under research by Forest Labs for
depression and fibromyalgia
• Similarities to other SNRIs
– Duloxetine (Cymbalta)
– Venlafaxine (Effexor XR)
33

Doxepin
• Low doses are very helpful for irritable gut
(reflux and irritable bowel)
• Also helps sleep
• Antidepressant and anti-anxiety at higher
doses
• Weight gain
SSRIs, SNRIs
• Effective for depression and a spectrum of
anxiety disorders
• Significant individual differences in benefit
and tolerability
34

Acetylcholine Esterase Inhibitors
• Helpful for long term memory impairments
in late stage disease
– Donepezil (Aricept)
– Rivastigmine (Exelon)
– Galantamine (Razadyne, Razadyne ER,
Reminyl)
Sibutramine (Meridia)
• Norepinephrine, Serotonin & Dopamine
Reuptake Inhibitor
• FDA approved for weight loss Schedule IV
• Effective for CFS, Fibro, Tourette’s, PTSD,
Autism, RSD, Cerebral Palsy in research by
Peter Mueller, MD in Princeton, NJ
35

Conclusion
• Psychotropic interventions are a critical
component of a comprehensive treatment
approach.
• Since microbes interact with the immune and
nervous systems, greater interaction is
needed between specialists to more
effectively treat these conditions.
Can We Make a Difference?
36