The neurochemistry of mania: A hypothesis of etiology and a rationale for treatment

Prog. Neum-Psychophormocol. 6 Bid. Psychiot. Prinled in Cleat Britain. All rights reserved

027ll-5946&O SO.90 + SO @ 1990 Pogamon Press plc

1990. Vol. 14. pp. 42X-429

THE NEUROCHEMISTRY OF MANIA: A HYPOTHESIS OF ETIOLOGY AND A RATIONALE FOR TREATMENT

DANIEL BURR LEIVA* Cupertino, California

(Final fon,

1. 2. 3. 4. 5. 6.

May 1969)

Abstract Introduction Reversal of Mania by Enhancement of Brain Cholinergic (Acetylcholine) Activity Clinical use of Cholinergic Effect in the Treatment of Mania The Cholinergic Insufficiency Hypothesis for the Causation of Mania. Presynaptic Receptors: Their Presumptive Role in the Modulation and Balance of Brain Neurotransmitters Conclusions References

Leiva, Daniel Burr. The Neurochemistry of Mania: A Hypothesis of Etiology and a Rationale for Treatment . Prog. Neuro-Psychopharmacol. & Biol.Psychiat.1990.14: 423-429 1.

The author delineates the emergence of an important concept in the Neurochemistry of mental illness, that of a Cholinergic Factor in Mania. This concept which evolved steadily over a period of 22 years from 1950-l 972, the author believes has given us our first significant insight into the etiology and treatment of the Manic state.

2.

In addition, the author examines the Adrenergic-Cholinergic hypothesis of Mania and Depression and the Brain Cholinergic-Adrenergic Balance hypothesis for Mania and Schizophrenia.

3.

Also described in this article are some successful preliminary attempts by others, to treat Mania with Phosphatidyl Choline and the author will present, for the first time, data relating to success with the use of Phosphatidyl Choline in bringing about permanent remission of mania in 10 treatment subjects since 1993.

4.

In conclusion the author proposes a Cholinergic Insufficiency Hypothesis as a primary factor in the causation of Mania and comments on a presumptive role in the modulation and balance of Adrenergic Dominance by Presynaptic Receptors positioned on the Nerve Terminals of Adrenergic Neurons.

‘Former USFWS Fellow in Psychiatric Research, The Langley PorterNeuropsychiatric Institute,San FIWI&CO.California

423

D. B. teiva

424

i
The anti-manic activity of Brain Acetylchotine has remained largely unappreciated. in spite of mounting expe~mental and clinical evidence for its unique anti-manic properties. in this mon~~ph, author will examine this oversight and in addition, will offer a neumchemi~i

h~thesis

the

for the etioi-

ogy of mania and introduce a hypothesis for the anti-manic function of Presynapttc Receptors positioned on Adrenergic Neurons. Because it is therapeutically vital that the anti-manic function of the Brain Choiinergic Factor be fully appreciated, we present what we believe to be convincing experimental and clinical evidence for the anti-manic activity of Brain Acetyichoiine.

2. Reversal of dent

of Brain C~

The a~i-manic activity of Brain Ac~~hoi~ne ades. This failure to ~gh~liy

I

has been in intention

*

. *

for at least the past two dec-

ascribe major anti-manic activity to Brain A~~i~hoiine

continues in the

face of accumulating experimental and clinical evidence for the anti-manic properties of this Cholinergic Neurotransmitter. A retrospective search of the literature indicates that as early as 1950 Rountree et al., made the signal observation that a Choiinergic drug (diisopropylfiurophosphonate)

caused an inhibiting effect

on the symptoms of Mania, and it seems fair to say that the concept of the anti-manic activity of the Cholinergic Neurotransmi~er, Acetylcholkie, derives from this observation made thi~y-eight years ago.

in 1957 the Muscarinic inhibition of psychotic manifestations of Schizophrenia and the Nicotinic Inhibition of Mania was noted by Pfeiffer and Jenny, and in 1970 Fibiger et al., reported a Choiinergic modulating effect on Adrenergic arousal in the developing rat.

By 1972 it was quite clear that there was a Cholinetgic Factor in Mania and a Choiinergic-Adrenergic hypothesis of Mania and Depression was proposed by Janowsky and Davis (1972). in 1974, elaboration on this hypothesis by Davis and Janowsky int~u~

the concept of a brain

Neurochemistry

Cholinergic-Ad~nergic

425

of mania

batance as necessary for the prevention of both Mania and Schizophrenia.

Further confirmation of the anti-manic effect of Brain Acetylcholine came swiftly from several research centers including the observation of Janowsky et al., (1973) Carroll et al., (1973) and Davis et al., (1978) all of whom reported a consistent but brief remission of Mania produced by the administration of Physostigmine, a potent cholinesterase inhibitor which caused a Cholinergic effect when given to Manic patients. In addition, Fritze and Beckman (1988) have more recently used the Cholinergic Agonist RS, 88 to get this Cholinergic effect. Inexplicably, however, clinical confirmation of the use of the Cholinergic Effect in the control of Mania did not appear until 1980 when Cohen and Miller published their report on the successfui treatment of Mania by admini~r~ion

and loading of a Choline rich

nutrient, purified Lecithin. This experiment was repeated in 1982 by Cohen et al., who reported remission of Mania in 5 of 8 test subjects following the administration of purified Lecithin (Phosphatidyl Choline) in a linear double blind, placebo controlled, study performed at the Laboratories for Psychiatric Research at McLean Hospital and the Dept. of Psychiatry at Harvard Medical School.

3. $&&&EB

. . of Cholrnemtc Ff&&t~ the Trem

Independently, we have been su~e~fully

of M&9

treating Mania by precursor loading with Phosphatidyl

Choline since f 978. Using an Open Label method since 1983 we have do~mented complete remission in 10 Manic-Depressive patients, some with Psychosis, using Precursor Therapy alone. These patients all represent variations of the DSM Ill diagnosis of Manic Depressive Disorder. All of our

30

20 !I * 10

n txs~~t

2

3

4

5

6

7

6

910

Ftg 1. Years of recurrent mania before treatment wfth Ph~h~l

Choline

426

D. B. Leiva

patients had suffered recurrent bouts of Manic Depressive Disorder, none had been free of the symptoms of this disease when untreated, and one patient had suffered recurrent mania for 27 years(Fig 1).

To date, the mean length of complete remission without Lithium in our treatment subjects has been approximately 1.32 years with a range of 3.5 months to 7.23 years of complete remission when treated with Precursor Loading technology alone (Fig 2). The mean time of 1.32 years in remission represents the mean of the aggregate time in remission of

C&f

1

2 3 4 5 6 7 8 9 10

Fig 2. Years of complete remission without Lithium and after successful treatment with Phosphatidyi Choline

patients treated in the past who are still in remission, as well as those brought into remission more recently. We are conffdent that those treated more recently will remain in remission as long as those treated earlier, if they remain on a maintenance Precursor Program which we recommend.

if Lithium or Neuroieptic medication was used in treatment by previous physicians, and if patients arrived at our office still medicated, both of these drugs could be discontinued usually within 4 to 6 weeks after starting Precursor Loading therapy. In some instances Neuroieptic medications were used temporarily for initial control of severe agitation.

Operationally our therapeutic technique provides that Phosphatidyl Choline and Pantothenic Acid be introduced first to establish the anti-manic effect of Choline, then L-Tryptophan and Pyrtdoxai 5’ phos-

Neurochemistry

of mania

427

phate is added to potentiate this effect. Not any of our patients has had a recurrence of his fvlanicDepressive Disorder if he remained on a maintenance Precursor Phosphatidyl Choline, Pantothenic Acid, L-Tryptophan and Pyridoxal 5’ phosphate regimen.

We have been impressed with the safety, efficacy and the virtual absence of side effects with the proper use of Precursor Therapy. Each of the 10 treatment subjects tolerated the Precursors extremely well. There were no instances of nausea or diarrhea as had been reported in 1990 by research workers whose subjects received Lecithin and not highly purified Phophadidyl Choline in capsule form.

4. The Cd

.

.

In Neuroscience there is a biological imperative which demands that in the mammalian species there must exist an exquisite balance between operational peripheral Parasympathetic and Sympathetic Nervous Systems in order that the animal’s somatic vegetative systems be able to function normally. Given this biological paradigm it can be predicted through inferential reasoning that there must then be a Central counterpart of this, in precisely balanced Brain Adrenergic-Cholinergic Neurotransmitters, for optimal functioning of the Brain’s myriad psychosystems.

An Insufficiency of the Cholinergic Brain Neurotransmitter, Acetylcholine. therefore would cause an Imbalance which would result in an Adrenergic Dominance. In this concept, Norepinephrine would be dominant in Mania. Furthermore, it seems likely that a specific insufficiency of Acetylcholine Nicotinic Activity(Rountree et al., 1950) and (Pfeiffer and Jenny 1957) is necessary for the causation of the Manic state. Using this paradigm it can be hypothesized that in some types of Schizophrenia, Dopamine Dominance due to a Cholinergic Insufficiency would cause an imbalance resulting in these types of Schizophrenia.

In this case it seems likely that specifically diminished Muscarinic Cholinergic

Activity (Pfeiffer and Jenny 1957) would ‘be the molecular lesion causing these types of Schizophrenia

5. wars.

. Therr * Presugtgtive Rolein

The central role of Brain Acetylcholine in the control of Mania has not been generally appreciated, and for this reason the question of how Acetylcholine and Serotonin exert an Anti-manic effect on Adrenergic Dominance has not been addressed.

The answer to this problem may lie in the modulating activity of Presynaptic Receptors both Cholin-

428

D. B. Leiva

ergic and Setotonergic which are positioned on the Nerve Terminals of Adrenergic Neurons found in many central brain regions (De Belieroche and Bradford 1978, Chesseiet 1984, and Bradford 1988) and which can modulate Neurotransmitter release and re-uptake. in addition there are known to be Auto-receptors on Nerve Terminals in Cortical and Hypothalamic Structures by which Norepinephrine can modulate its own release and re-uptake (Chesseiet 1984).

These facts suggest direct neurochemicai mechanisms by which Choiinergic and Serotonergic Agents as well as Adrenergic Agents themselves might act as modulators of No~pineph~ne release and reuptake. This mo~lation can bring about an Ad~ne~ic-Choiine~ic Symptomatolo~.

balance which e~inguishes Manic

Serotonin is thought to have a role in the m~ulation

of Manic hyperactivity (Prange

et al.,1 974) presumably by way of the Presynaptic Receptor mechanism. When some types of Schizophrenia are treated by creating a Choiinergic-Adrenergic balance, it seems likely that both Serotonin and Acetylchoiine act in consort thru Presynaptic Receptors to cause a beneficial modulation and balance of Dopaminergic Activity. This modulation can bring about an Adrenergic-Choiinergic balance which extinguishes some types of Schizophrenic Symptomatoiogy.

8. (=onckrsions in this monograph we have descrfbed the succesfui treatment of the Manic State by enhancement of the Choiinergic Effect of Brain Acetylcholine. in addition we have proposed a Cholinergic insufficiency Hypothesis for the causation of Mania and we have suggested that a specific insufficiency of Brain Choiinergic Nicotinic Activity is required for this effect, and likewise that a specific insufficiency of Cholinergic Muscarinic Activity is required for the causation of some types of Schizophrenia. While the Nicotinic-~sca~nic that if more recent ~~borative

hypotheses are attractive, and are almost surely correct, we suggest research data had been available, con~rmation of these complex

Hypotheses would have been more certain. The basic concept of a Choiinergic insufficiency Causation for Mania, on the other hand, appears so well documented and unassailable, that widespread interest in this Hypothesis seems assured. Finally, we have presented for the first time, a Hypothesis for the Anti-Manic function of Presynaptic Receptors both Cholinergic and Serotonergic, as well as for Auto-receptors found in many central brain regions, all positioned on the Nerve Terminals of,Adrenergic Neurons, and all of which can modulate release and re-uptake of Norepinephrine. This modulation can in effect, function to extinguish Manic Symptomatology.

Neurochemistry

of mania

429

BRADFORD, H.F. (1988) The Cholinerglc Neurotransmltter System In: Chemical Neurobiology, W.H. Freeman and Cc. Ch. 4 Pp. 172-173. CARROLL, B.J., FRAZER, A. and SCHLESS, A.(l973) Lancet I: 427-428

Cholinergic Reversal of Manic Symptoms.

CHESSELET, M.F. (1984) Presynaptic Regulation of Neurotransmitter Release in the Brain: Neuroscience, 12: 347975. COHEN, B.M.,and MILLER, A.L, LIPINSKI, J.F. and POPE, H.G. (1980) Lecithin in Mania: A Preliminary report. Am. J. Psychiatry m 242-243. COHEN, B.M. and LIPINSKI, J.F., and ALTESMAN, R.F. (1982) Lecithin in the treatment of Mania: Doubleblind, placebo-controlled triats. Am.J. Psychiatry m: 1182-l 164 DAVIS, J.M. and JANOWSKY, D. (1974) Proceedings: Cholinergic and Adrenergic Balance in Mania and Schizophrenia. Psychopharmacol.Bull1p; 49-50. DAVIS, D.L. BERGER, P.A., HOLLISTER, LE. and DeFraites, E. (1978) Physostigmlne in Mania. Arch. Gen. Psychiatry 3fi: 119-I 22. DE BELLEROCHE, J. and BRADFORD, H.F. (1978) Biochemical Evidence for the Presence of Pre-Synaptic Receptors on Dopamlnergic Nerve Terminals. Brain Research, 142: 53-68 FIBIGER, H.D.,LYTLE, LD. and CAMPBELL, B.A. (1970) Cholinergic modulation of Adrenergic Arousal in the developing rat. J. Corn. Physiol. Psychol. Iz: 384-89. FRITZE, J. and BECKMAN, H. (1968) The Cholinergic Agonist R.S. 86: A Pharmacopsychological Neuropsychobiology: 19 (1): 3539 JANOWSKY, D.S. and DAVIS, JM (1972) A Cholinergic-Adrenergic Lancet 2: 542-547.

Study.

Hypothesis of Manla and Depression.

JANOWSKY, D.S., EL YOUSEF, M. K’HALED and DAVIS, JOHN M. (1973) Parasympathetic Suppression of Manic Symptoms by Physostigmine. Arch. Gen Psychiatry 28; 542-547. PFEIFFER, C.C. and JENNEY, E.H. (1957) The inhibition of conditioned response and the counteraction of Schizophrenia by muscarfnic stimulation of the brain. Ann. NY Acad. Sci. 8& 753-64 PRANGE, A.J. JR, WILSON, l.c., LYNN, C.W., ALLTOP, L.B.and STIKELEATHER, R.A. (1974) L-Tryptophan in Mania. Arch. Gen. Psychiatry 3p: 60. ROUNTREE, D.W., NEVIN S. and WILSON, A. (1950) The effects of diisopropylfluro phosphonate in Schizophrenia and Manic-Depression. J. Neurol. Neurosurg. Psychiatry j& 47-59

Inquiries and reprint requests should be addressed to: Daniel Burr Leiva MD 20395 Paclflca Dr. Suite #I 96 Cupertfno, CA 95014