does copper improve or worsen schizophrenia?

2022.4.10: psy/schiz/diet/copper/
does copper improve or worsen schizophrenia?

summary:

. it was found in 1959 that ceruloplasmin, which carries copper,

could improve psychotic symptoms in many schiz'ics.

. however, it was also found that some measure of copper

is elevated in schiz'ia,

or in any condition causing chronic stress or fear.

. ceruloplasmin is used as a measure of copper

because 95% of blood copper is in ceruloplasmin

but ceruloplasmin is an acute phase reactant, 

increased during inflammation, infection, trauma, pregnancy, etc. 

. some who are assuming that copper is a cause of schiz'ia

are theorizing that ceruloplasmin may be 

catalyzing the oxidation of epinephrine 

to some psychosis-inducing indole-like material.

. but if ceruloplasmin can improve psychotic symptoms,

it is likely that the rises in ceruloplasmin 

are a reaction to the stress of schiz'ia,

and not the cause of it.

AMA Arch Neurol Psychiatry. 1957

https://pubmed.ncbi.nlm.nih.gov/13423938/

Comparative study of blood ceruloplasmin in schizophrenia and other disorders

L G ABOOD, F A GIBBS, E GIBBS

https://jamanetwork.com/journals/archneurpsyc/article-abstract/652442

Recently a number of reports have appeared pertaining to a

disturbance in the metabolism of the aromatic amines

in the blood of schizophrenics. 

With such substrates as N,N'-dimethyl-p-phenylenediamine (MPD)1 or adrenaline,2 

it has been possible to demonstrate 

a greater oxidation of these amines in the serum of schizophrenics. 

In both instances the oxidation was attributed to a 

copper-containing protein, ceruloplasmin. 

AMA Arch NeurPsych. 1958

https://jamanetwork.com/journals/archneurpsyc/fullarticle/652660

Ceruloplasmin, Transferrin, and Tryptophan in Schizophrenia

C. E. FROHMAN, et al.

It has been suggested that the blood of schizophrenic patients

contains a toxic factor which may be the cause of 

some of the symptoms of the disease.

The identity of this compound has not been established. 

Particularly interesting, however, are the reports which indicate that

an indole may be a toxic factor.

There are several theories as to how an unusual indole

may arise within the metabolism of the organism. 

One of the most popular involves the oxidation of epinephrine

to some indole-like material.

Heath's study of the oxidation of epinephrine indicates that 

this substance is oxidized more rapidly by 

plasma from schizophrenic persons

than by that from normal controls.

Other workers have attempted to show that

the copper-containing enzyme, ceruloplasmin, 

catalyzes this oxidation.

Acta Psychiatr Scand Suppl . 1959

https://pubmed.ncbi.nlm.nih.gov/14421601/

An approach to biochemical therapy in schizophrenia.

S MARTENS, S VALLBO, B MELANDER

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0447.1959.tb07821.x

. ceruloplasmin represents 95% of the copper present in blood serum.

. it been shown to oxidize, i.a. catechol, adrenaline, and serotonin.

. a rise in ceruloplasmin levels has been demonstrated in 

pregnancy, a number of somatic disesases, and also in acute schiz'ia.

. 1957 may have been the first attempt at injecting ceruloplasmin

but there were concerns about the purity.

Int Rev Neurobiol. 1959

https://pubmed.ncbi.nlm.nih.gov/14421602/

Studies on the role of ceruloplasmin in schizophrenia.

S MARTENS, S VALLBO, B MELANDER

https://www.sciencedirect.com/science/article/abs/pii/S0074774208603190

. Ceruloplasmin given intravenously 

to acute, subacute, and chronic schizophrenics 

bring about a favorable modification in 26 out of 30 cases. 

Biochemical studies on clinical cases indicate that

the clinical improvement can be correlated with 

the increase in serum copper level

but not to the oxidase activity of ceruloplasmin 

in terms of ascorbic acid levels. 

Ceruloplasmin given intravenously to Rhesus monkeys and cats 

prior to, mixed with, or subsequent to LSD 

eliminates the biochemical changes caused by LSD

and this is otherwise indicated by means of 

subsequent intravenous administration of psychotropic drugs. 

Premedication of mice with ceruloplasmin 

decreases the toxic effect of subsequently injected histamine. 

In vitrotests show that ceruloplasmin 

binds the psychotropic drug histamine

to render it nondialyzable. 

The increased concentration of ceruloplasmin in blood 

is reflected by increased serum copper levels

and increased oxidative activity in serum in vitro.

J Neuropsychiatr. 1961

https://pubmed.ncbi.nlm.nih.gov/13767284/

Continued studies on the effect of ceruloplasmin administration in schizophrenic patients.

S MARTENS, S VALLBO, K O KYHLBERG, C O JONSSON

Schizophr Res . 2006 

https://pubmed.ncbi.nlm.nih.gov/16842975/

Plasma copper, iron, ceruloplasmin and ferroxidase activity in schizophrenia

Teri L Wolf 1, Joan Kotun, James H Meador-Woodruff

As ceruloplasmin and copper abnormalities

have been implicated in schizophrenia, 

we investigated the role of a second copper-containing

non-ceruloplasmin protein, the iron oxidase ferroxidase II

in a prospective study of ten inpatients with schizophrenia

and a comparison group. 

Ferroxidase II is a protein known to 

reciprocally regulate with ceruloplasmin in Wilson's disease, 

an illness characterized by psychotic symptoms, 

decreased ceruloplasmin, 

and increased copper deposition in tissues. 

Ferroxidase II plays a key role in the maintenance of 

near-normal iron metabolism in Wilson's disease, 

but its role in schizophrenia has never been studied. 

In this study, we assayed ceruloplasmin by two enzymatic assays, 

a standard clinical laboratory p-phenylenediamine oxidation assay

and a second assay based on the rate of the oxidation and incorporation of iron (Fe3+) into transferrin; 

we assayed ferroxidase II activity using this second iron oxidation assay. 

We found that ceruloplasmin levels as measured by

both enzymatic methods, but not ferroxidase II, 

were elevated in schizophrenia. 

It has been proposed that copper, 

as a component of several enzymes linked to dopamine synthesis, 

may play a role in schizophrenia by 

exacerbating or perpetuating dopaminergic dysregulation. 

Our study suggests that

the ceruloplasmin elevation in schizophrenia is specific, 

and not simply an elevation of 

plasma copper-containing oxidative enzymes. 

Increases in ceruloplasmin may result in increased levels of copper, 

which ultimately proves deleterious in schizophrenia.

Fortschr Neurol Psychiatr . 2010 [Article in German]

https://pubmed.ncbi.nlm.nih.gov/20812166/

[The role of ceruloplasmin in the differential diagnosis of neuropsychiatric disorders]

B J Connemann et al.

The blue copper protein ceruloplasmin has been of interest to psychiatrists for decades

following Heilmeyer's observation of

elevated serum copper levels in schizophrenic patients. 

Immunoturbidimetry, however, does not yield 

elevated serum ceruloplasmin concentrations in schizophrenia

while ceruloplasmin-related oxidase activity

appears to be elevated in patients with schizophrenia 

and reduced in patients with Alzheimer's disease. 

Low serum concentrations of

immuno-turbidimetrically measured ceruloplasmin, 

and of oxidase activity, 

are typical of Wilson's disease, Menkes' disease, and aceruloplasminemia.

Behavioral and Brain Functions 2008

https://behavioralandbrainfunctions.biomedcentral.com/articles/10.1186/1744-9081-4-52

High ceruloplasmin levels are associated with

obsessive compulsive disorder: a case control study.

Osman Virit, et al.

Several studies indicate that

elevated serum ceruloplasmin levels

may play a role in schizophrenia

by exacerbating or perpetuating dopaminergic dysregulation. 

Nowadays OCD is increasingly speculated to be

a different disorder than other anxiety disorders, 

and rather is considered to be more similar to

psychotic disorders. 

The objective of this study was to explore whether there is an

association of ceruloplasmin with OCD as in schizophrenia.

The mean ceruloplasmin level U/L in 

544.46 ± 26.53, pure OCD patients, 

424.43 ± 31.50 co-morbid OCD patients

222.35 ± 8.88 control group persons 

Background

Ceruloplasmin is a protein of the α2-globulin fraction of human blood serum. 

It contains 95% of serum copper. 

In the central nervous system of humans and other mammals, 

ceruloplasmin is expressed in neurons and astroglial cells, 

e.g., of the cerebral microvascular network. 

Ceruloplasmin carries copper from liver to numerous tissues. 

The symptoms of Wilson's disease, 

that is characterized by low levels of ceruloplasmin 

with subsequent copper deposition in various tissues including brain, 

often mimic those of schizophrenia. 

Ceruloplasmin is also an iron oxidase; 

for this capacity, it has been labeled ferroxidase I. 

In addition, ceruloplasmin is an acute phase reactant, 

whose concentration increases in inflammation, infection, trauma, etc. 

For these properties it is known as an antioxidant. 

Ceruloplasmin has other functions, 

including the oxidation of serotonin, epinephrine, and norepinephrine. 

There are numerous studies reporting an association between ceruloplasmin and schizophrenia, 

but the nature of the relationship remains unclear [2–9]. 

One possible explanation has been ceruloplasmin and copper relation

since abnormalities in copper levels or metabolism 

may lead to dopaminergic dysregulation. 

In addition, ceruloplasmin has been associated with

some clinical features of schizophrenia [2, 4, 5, 8]. 

Some symptomatology of OCD resembles schizophrenia. 

Also dopaminergic dysregulation in the certain areas of brain 

may play a role in OCD etiopathogenesis as in schizophrenia [10, 11]. 

Nowadays, OCD is increasingly speculated to be a 

different disorder than other anxiety disorders. 

OCD is rather thought to be similar to psychotic disorders [12, 13]. 

The objective of this study is to explore, 

whether there is a role of ceruloplasmin in OCD as in schizophrenia. 

Therefore, we investigated the possible association between serum ceruloplasmin levels and OCD. 

the definition of schizophrenia

https://amerdreamduh.blogspot.com/2022/04/the-definition-of-schizophrenia.html