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Optimal Dosing for Schizophrenia
Raymond
J. Pataracchia, B.Sc., N.D.
Naturopathic Medical Research Clinic
20 Eglinton Avenue East, Suite #441
Toronto, Ontario, Canada, M4P 1A9
www.nmrc.ca
[Published
in the Journal of Orthomolecular Medicine, 2005; 20(2), 93-99.]
Introduction
Neuroleptics
are tranquilizers (major sedatives) that block brain neuron
transmission at the receptor level.1 Neuroleptics can be
useful during acute episodes of schizophrenia but should be prescribed
with the intention of stabilizing the patient, not with the intention
of long-term tranquilization. The human body was not made to function
in a tranquilized state. I do not know of any physician willing to try
this regimen themselves for a prolonged period of time. As this article will discuss, neuroleptic medication can become
problematic, not only due to its side-effects, but also because it can
cause a psychosis on its own with cognitive deficits. This does not
diminish its usefulness in the field to address psychotic symptoms in
times of need. Neuroleptics are a valuable asset in nutritional
adjunct therapy for schizophrenia.
Safe
therapeutic doses of medication that achieve a desirable effect are
considered optimal. This basic principle of ‘optimal dosing’ holds
true for nutritional supplements and prescribed drug medication.
Schizophrenic patients treated with an optimal nutritional adjunct
therapy improve at a consistent rate. In this article I have
referenced several studies and several peer reviewed journal articles
that describe the effectiveness of this treatment. Over 50 years of
clinical experience from practitioners in the field also attest to the
viability of nutritional adjunct therapy. Effectiveness is dependant
on the severity and chronicity of symptoms. As a practitioner, initial
signs of improvement become apparent in subtle ways. It is not
uncommon to receive first-hand reports from parents that their son or
daughter has started to smile, express appropriate emotions, and wants
to help around the house. The ‘negative symptoms’ of schizophrenia
diminish and the patient starts getting along better with family,
friends, and society. These first signs of improvement indicate that
you have achieved optimal nutritional doses. In general, improvement
will continue in a consistent manner with both ‘positive’ and
‘negative’ symptoms alleviation. However, the benefits of
nutritional therapy plateau when the patient maintains previous
‘stabilized’ neuroleptic doses. Despite showing signs of
consistent improvement, the patient reaches a point of inflection and,
if they maintain their previous ‘stabilized’ neuroleptic dose,
improvement does not continue. They remain improved but often times
they are not well enough to enter a vocation or career. The skilled
practitioner, however, recognizes that there is room for improvement.
As this article will describe, continued improvement is observed in
those patients that maintain the lowest effective/optimal dose of
neuroleptic. For many patients, this dose is much lower than their
previous ‘stabilized’ dose. Some patients are able to maintain a
token dose of neuroleptic and some are able to withdraw completely. It
is important to initiate a slow careful titration of neuroleptic
dosing while monitoring symptoms with regular patient follow-ups. If
necessary, inter-practitioner collaboration can be implemented at this
stage.
The Optimal Neuroleptic Dose to Maintain Brain Structure Integrity
Brain
structure loss is one of the biggest and most significant
‘side-effects’ of neuroleptic treatment. Maintaining brain
structure is an important part of the nutritional protocol for
schizophrenic pathology.2 The natural course of this
disease and neuroleptic exposure are both associated with brain
structure compromise.
Increased
lateral and third ventricle size (suggesting atrophy in adjacent brain
structures) may precede the onset of schizophrenia.3,4 A
recent 2002 review by E. Fuller Torrey reports on various studies
suggesting significant ventricular hypertrophy in schizophrenics never
treated with neuroleptics (neuroleptic-naïve) compared to matched
normal controls.5 Torrey reports less conclusively of
various studies suggesting abnormal volumes in the basal ganglia
(caudate, putamen, globus pallidus), thalamus, frontal/parietal
cortex, medial temporal structures, latero-dorsal prefrontal gray
matter, entorhinal cortex, septum pellucidum, and the corpus callosum
of neuroleptic-naïve schizophrenic patients versus normal controls.
Abnormal
brain structure changes have been reported in conjunction with
nueroleptic-treated schizophrenic patients. The risk of sub-cortical
(caudate, putamen, and thalamic) brain structural loss (atrophy) seems
to increase by 6.4% for every 10 g of neuroleptic (chlorpromazine
equivalents) prescribed.6 The review by Torrey mentioned
above does not compare neuroleptic-naïve schizophrenic patients with
neuroleptic-treated schizophrenic patients. A research review is
needed to compare the degree of brain atrophy and hypertrophy in
neuroleptic-naïve versus neuroleptic-treated schizophrenic patients.
I found only two studies comparing these patient cohorts.
Gur
et al report on increased volumes (hypertrophy) of basal ganglia (putamen,
globus pallidus, and caudate) and thalamic structures in a study
comparing 75 neuroleptic-treated schizophrenic patients, 21
neuroleptic-naïve schizophrenic patients, and 128 healthy controls.7
Of the 75 neuroleptic-treated patients, 48 received typical
neuroleptics and 27 received both typical and atypical neuroleptics.
The neuroleptic-treated group reported hypertrophy in the putamen and
globus pallidus versus the neuroleptic-naïve and healthy controls.
The higher the dose of typical neuroleptic the greater the caudate,
putamen, and thalamic hypertrophy. The hypertrophic state reported
here represents structural loss of functional brain tissue with
decreased neuronal pruning, synaptic adaptations, and striatal
activation. This study also reports on atypical neuroleptics and
associated thalamic hypertrophy.
Chakos
et al report on caudate hypertrophy in a study comparing 29
first-episode schizophrenic patients given standardized neuroleptic
regimens for 18 months versus 10 healthy controls.8 This
study reports a 5.7% increase in caudate volume during the 18 months
of neuroleptic treatment. Greater hypertrophy was reported in patients
given larger doses of neuroleptic. Hypertrophy reported here
represents structural loss of functional brain tissue.
Brain
cells can not regenerate and any loss of functional tissue, from
atrophic or hypertrophic changes, represents a substantial
irreversible deficit. This is one area where nutritional support is
very useful.2
Anti-psychotic
medications are tranquilizers or major sedatives designed to block
nerve transmission in the brain. Most neuroleptics block a select
group of neurotransmitter receptors (typically dopamine receptors; but
also glutamate, acetylcholine, serotonin, GABA, and histamine
receptors) in the brain.9 Since nerve receptors are complex
networks spreading all over the brain, these drugs often block
unwanted nerve pathways. In pharmacology, it is said that these drugs
have poor specificity for their target. Many drugs have poor
specificity and this is the main cause of side-effects. When
neuroleptics target unwanted brain pathways many undesireable and
debilitating side-effects can occur. These include unwanted muscle
movements (extrapyramidal symptoms), diabetes,
loss of libido, weight gain, tardive dyskinesia, etc. For
a full list of side-effects refer to the Compendium of Pharmaceuticals
and Specialties (CPS) which will describe the side effects and
indications of specific drugs.1 Some
neuroleptics can have fatal consequences such as agranulocytosis,
associated with clozapine use, and neuroleptic malignant syndrome,
associated with atypical neuroleptics. Nueroleptic withdrawl is also
associated with side-effects.
Neuroleptic
withdrawl is done routinely in psychiatric and general practice,
usually to start a patient on a different neuroleptic when they are
considered refractory to initial treatment.
It is well known that the side effects of neuroleptic withdrawl
are created by chemical and receptor changes initiated by the drug. In
these cases it is common for psychotic symptoms to remerge. When
some patients are withdrawn from neuroleptics, the receptors, starved
for neurotransmitter (especially dopamine) stimulation, compensate by
becoming supersensitive causing a rebound psychosis. In some cases denervation
supersensitivity occurs resulting in irreversible loss of brain
tissue. The concept of denervation supersensitivity has emerged
recently as a potential mechanism for neuroleptic-induced (or
iatrogenic) brain tissue loss and extrapyramidal
side-effects in schizophrenic patients.10-15
Neuroleptic Management
Conventional
psychiatry in the 1950’s adopted the use of neuroleptics. People
with schizophrenia responded to chlorpromazine (the first neuroleptic;
actually an antihistamine) and what followed was the early release
from hospitals of patients considered ‘stabilized’. The relapse
rate was high and people with schizophrenia had to be re-admitted and
released again; hence the ‘revolving door’ era and resultant
economic burden.16,17 Neuroleptic treatment and prognosis
remains encouraging because it is a form of palliation that suppresses
symptoms. Neuroleptic management is considered by most people the only
useful bio-chemical treatment for people with schizophrenia, the
corollary of which implies that there is no hope unless neuroleptic
compliance is maintained. Neuroleptics
work quickly which is a good feature. There are many cases when
tranquillizing a patient becomes useful. The aim however, should not
be long-term management with a neuroleptic. In
neuroleptic management of chronic and first-episode schizophrenia,
maximum symptomatic improvement is thought to occur in the first 6
months and, as the disease progresses the effectiveness seems to
diminish.18
Continued
use of neuroleptics in the management of schizophrenia becomes
problematic not only due to drug side-effects but also because of
their ability to cause psychosis on their own- a psychosis clearly
distinguishable from the natural psychosis of the disease.19-23 Cognitive
deficits are also associated with neuroleptic use.24-27 Dr
Meyer Gross, eminent psychiatrist in England, claimed in the 1950’s
that neuroleptic drugs produced another psychosis in addition to the
natural disease psychosis.19,28 As time progresses the
patient experiences an emergence of drug-psychosis symptoms and apathy
sets in. At this stage many patients become compliant and dependent on
antipsychotic medication.
It is estimated that the
natural recovery rate of schizophrenia without drug administration
approximates 50% versus 10% with those who recover from drug
administration alone.6 Neuroleptics should therefore be
used only when essential, with one neuroleptic at a time, with minimal
doses that can gradually be withdrawn while the nutritional therapy
addresses the biochemical cause of schizophrenic pathology. Multiple
neuroleptic administration is a common practice but it can be
considered experimental at best. The pharmacokinetics and
pharmacodynamics of multiple
neuroleptic dosing have not been well researched and I
fail to find a controlled study to support their use.29-32
The
current practice of administering neuroleptic medication “is
primarily grounded on the subjective clinical experience of
practitioners and not on scientifically derived data. This
uncontrolled, empirical approach dates from initial reports by Delay
et al. (1953)”.33 Neuroleptic
dosing schedules remain ambiguous and more and more clinical evidence
is pointing to the lack of benefit of high-dose neuroleptic treatment
- substantiated by neural transmission studies and relapse data.33
In a meta-analysis by Hegarty et al in 1994 it was noted that
iatrogenic burden placed on schizophrenic patients ‘today’ is more
prominent than it was a 100 years ago.34 Carpenter et al
have claimed dose reduction feasible in patients on maintenance
neuroleptic therapy.35 As a general rule, schizophrenic
symptoms are worsened when neuroleptic doses are too high, too low, or
quickly withdrawn. This is especially true with
neuroleptics that have such a vast array of severe, debilitating, and
life threatening side effects.1
Anti-depressants are often used in schizophrenic patient management if
depression is a major component of the symptomology.36 This
can be useful especially in paranoid schizophrenia. Dr. Abram Hoffer
notes that it is difficult to find a cheerful paranoid schizophrenic.
He has found good results with clomipramine.36
An
Evidence-based Look at Nutritional Adjunct Therapy
In
the year 2000, the Metropolitan King County Council, in the state of
Washington, passed legislation to allow performance monitoring of all
psychiatric care, conventional or otherwise.16 This allowed
them to assess the need to make changes in the health care system.
This evidence-based model would best serve the needs of schizophrenic
patients abroad and is mentioned here as a catalyst and template for
future research endeavours between conventional psychiatrists and
complementary medical practitioners.
It
is important to review the findings of research done on neuroleptic-treated
schizophrenics given nutritional adjuncts involving vitamin B3 with
neuroleptic withdrawl in those cases with clear indication of
continued improvement. Six double-blind placebo controlled trials on
schizophrenic patients have been done using this method.37
For the duration of these trials, all schizophrenic patients were able
to safely maintain prescribed neuroleptic medication. It was found
that some patients required a skilful combination of both neuroleptics
and nutritional treatment while some patients
did better on nutritional
treatment alone.
The B3 therapy is discussed
in detail in various journals and literature sources which I will list
as a review of nutritional orthomolecular psychiatry along with a
review of its effectiveness and the mechanisms of action.19,36-54
The six double blind trials done by Hoffer et al were the first double
blind placebo controlled trials ever done in the history of
psychiatry.54
Today, many patients are
maintained well on low neuroleptic doses. Thousands of cases have been
treated with this vitamin B3 nutritional adjunct method. Nutritional
adjunct therapy has expanded to include supplements in addition to
vitamin B3.2 Nutritional management of schizophrenia is
associated with independence and increased integration into the
community, family unit, and workforce (paying income tax).
In
the clinical management of psychiatric cases it is best to gauge
patient symptoms using outcome measures and unbiased objective
clinical impression. This is a key part of evidence-based medicine.
The patient’s subjective report and the practitioner’s objective
clinical impression (Global Assessment of Functioning (GAF)) are
important especially when used in combination with valid and reliable
outcome measures such as the Positive and Negative Symptom Scale (PANSS),
Experiential World Inventory (EWI), or the Hoffer-Osmond Diagnostic (HOD).
The H.O.D. test is a reliable and valid subjective outcome measure
used to gauge symptoms of behaviour as defined by Karl Menninger
categories of perception, mood, and thinking which together, define
behavior.55,56
The
Key Ingredient, Niacin: How Does it Work?
The
various forms of vitamin B3 include niacin, niacinamide, inositol
hexaniacinate, and NADH. Vitamin B3 can limit the conversion of
norepinephrine to epinephrine (adrenaline). Excess adrenaline or
excess catecholamines such as dopamine (implicated in the dopamine
hypothesis of schizophrenia) are problematic as they can oxidize and
form endogenous toxins. The brain with similar local reactions may
fail to store excess catecholamines, a job normally reserved for
neuromelanin, and hence allow free circulation of neurotoxins.45,49,57
B3 dependent pathways in the body vent the biochemistry of the body
away from the formation of oxidized catecholamines and toxic indoles
which might, under certain circumstances, contribute to synaptic
deletion. Abnormalities in this neuromelanin storage pathway may be
considered a causative factor in schizophrenic (and Parkinson's)
pathology. The ‘adrenochrome hypothesis’ was the first biochemical
theory of schizophrenia described in the history of psychiatry.45
Drs. Abram Hoffer and Humphry Osmond (M.R.C.P., D.P.M) spearheaded
this nutritional approach. Dr. Abram Hoffer, M.D., Ph.D.,
N.D.(honorary), has treated over 5000 patients with this approach and
currently practices in Victoria, B.C., Canada.
The nutritional need/dependency versus deficiency (a less dependant
state) for B3 may indeed exceed the need to address any other
nutritional metabolic compromise in schizophrenia. The optimal dose of
vitamin B3 (excluding the NADH form) for schizophrenia, as determined
over the past 50 years by clinical trial, is about 3000 mg a day but,
some patients require as much as 12000 mg a day depending on response.
Some patients also do well on smaller doses. Vitamin B3 is considered
safe- as described in full, in a recent review on vitamin B3
administration in the Journal of Orthomolecular Medicine, Special
Issue, Volume 18 (3/4), pages 146-160. Time-released forms of vitamin
B3 are not considered safe.
Nutritional
therapy needs to be maintained for at least 5 years and many patients
need longer durations of nutritional supplementation.36 The
duration of nutrient therapy should carry on until the likelihood of
relapse seems unlikely. Chronic patients are not as responsive to
nutritional regimens as are acute cases and not everyone will get
‘well’. Prognostic outcomes of nutritional therapies for
schizophrenia are described in the literature.2,37
In most cases, if patients are taken off prescribed nutrients during a
hospital admission they deteriorate. Many patients are thus demanding
that they maintain their supplement protocols during hospitalizations.36
With
niacin administration there is an interesting side-effect of
longevity. The Mayo Clinic found significant reductions in mortality
in subjects with high baseline cholesterol who used niacin alone.58,59
Niacin
also plays a role in the essential fatty acid metabolism of the brain,
processes of which are disrupted in schizophrenia. Together, vitamin
B3 and C (ascorbic acid) are centrally active in the brain as "niacinamide
acts on the diazepine receptors, while ascorbic acid acts on the
dopamine receptors, as do Haldol and other [neuroleptics or]
tranquilizers".43
Summary
The aim of nutritional
management in schizophrenia is not to offer a cure-all replacement for
standard treatment. Signs of clinical improvement are best determined
with outcome measures before and during nutritional adjunct therapy.
If monitored carefully, neuroleptic withdrawl can be done with minimal
negative side effects when nutritional adjuncts are used in
schizophrenic patients showing consistent improvement. Slow careful
withdrawl is extremely important to avoid rebound psychosis. This
neuroleptic withdrawl concept is an optimal dosing principle
associated with improved patient response.
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