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A unified theory of mental illness
Medico/ Hypotheses (1989) 29, 173-175 0 Longman Group UK Ltd 1989
A Unified
Theory
of Mental
Illness
B. ANDERSON
2707 Castle Gardens #277 Arlington, Texas, 76073, USA
Abstract - I propose that in certain mental illnesses the mechanics for making, releasing, and responding to neurotransmitters are all normal; what is faulty is a portion of the mechanism whereby the brain recognizes abnormal behavior and feeds back on to the neuronal pathways producing the behavior to alter function of that neuronal system and re-establish normal behavior. All the above uses the physical structure of the brain. The existence of the feedback mechanism, and its pertubation, is deduced from data about the mechanism of antidepressants.
Introduction
To date, research into the mechanisms of mental illnesses has focused on neurotransmitter abnormalities. Information that pharmacologic therapies interact with neuronal receptors has lead to the simple suggestion that there is a primary abnormality of neurotransmitter production. Ignored have been the mechanisms by which cells sense changed input and output, and alter their responsivity to active neurotransmitters thereby maintaining normal function. Since the body has homeostatic control of numerous variables it would not be surprising if mood were one of the variables so controlled. Beginning with a discussion of the pharmacologic therapies for depression a basis for assuming it is the regulatory mechanism rather than the regulated mechanisms that are disturbed in mental illness will be derived. Discussion
Depression
is a mood
state characterized
by
persistent and severe dysphoria not appropriate to external conditions, and associated with physical symptoms: sleep disturbance, weight loss, decreased libido, and psychomotor retardation (1). Almost every therapy clinically useful in the therapy of depression has been shown to either downregulate Beta-adrenergic receptors or the norepinephrine responsive adenylate cyclase (subsequently this combination of effects will be referred to as downregulation of the norepinephrine affected cell (NorEAC)) (2). Since this effect of useful medications is so generalized it is reasonable to assume that it is the therapeutic mechanism. Some people are more likely to become depressed. This fact suggests that there is a subset of humans who are deficient in their ability to endogenously downregulate their NorEAC; if they could downregulate the Nor EAC they would not become depressed. The mechanism for the increased NorEAC output that these people cannot respond to must be one 173
174 of three: a) an increase in the number of Betaadrenergic receptors or Beta-adrenergic receptor input so excessive that it cannot be compensated for by catabolic mechanisms, b) such deficient catabolism that a decrease in production of receptors or a decrease in NorE output cannot compensate, and c) that there is a defect in the setting of NorE tone to be maintained. The first possibility seems unlikely since studies have shown no difference in the number of Beta-adrenergic receptors between controls and depressed patients (if the excessive NorEAC output were secondary to excessive input we would still expect some receptor downregulation even if it were inadequate to compensate completely) (3). The second option is equally untenable since we know that pharmaceuticals lead to downregulation quite adequately. The cell’s catabolic machinery works appropriately when commanded to. This leaves only the third option. It makes the defect of depression somewhat analogous to a fever. When a patient has an elevated temperature it is not, in general, because the metabolic pathways are cycling out of control, or that the heat disipatory mechanisms are faulty, but instead results from a change in the feedback system that balances the two. A higher than usual setpoint has been established. Moods may be maladaptive. A depressed individual is less capable of caring for himself or his offspring. It seems reasonable given the survival significance of altered mood states that the organism would have acquired the capacity to detect undesirable mood states and change them. Let us theorize the general events that occur after the loss of a loved one. The death would serve as a stimulus for the increased activity of the NorEAC. This, via a series of intermediate steps, would lead to depressed behavior. The normal individual would “sense” the mood and feedback to downregulate the NorEAC. In the depressive individual there is a break in the feedback loop, and the depression persists. The defect in the feedback loop in depression would probably not be at the end where the mood is sensed. If the sensing mechanism were defective we would anticipate mood alterations at the other end of the spectrum from depression to also go uncorrected (perhaps a defect of this type could account for manic-depressive disorder). If the defect of feedback were at the effector end we would not expect medications to have any
MEDICAL
HYPOTHESES
way of working since the final pathway would have been interrupted. This leaves only the communication pathway between the sensor and effector mechanisms. Concluded from the above is that a system exists for the detection of certain moods, and this detection initiates activity to alter the mood. In depression the portion of the chain that conducts information from sensor to effector has been interrupted. A parallel can be seen with schizophrenia where the suggestion has been made that it is a dopamine disease (4), and it has been reported that there is an increased number of dopamine -2 receptors in drug naive subjects with the disease (5). It should be obvious that the explanation for schizophrenia is not merely increased production or decreased catabolism of dopamine-2 receptors. The plasticity of the dopamine system is well documented. If either the catabolic or anabolic pathways were defective it is likely the individual could recover normal dopamine affected cell tone by augment of the other end of the production/breakdown pathway. What is defective in schizophrenia is the capacity to “sense” the abnormal behavior, and feedback on the dopamine system to downregulate it and restore normal behavior. Since dopamine-2 receptor antagonism does not restore the person to normal it would seem that more than just the dopamine system is involved in this disorder. The fedback regulation system of the sort proposed or mood regulation would of necessity be generalized to all the systems involved in mood production, and a defect here could be seen to account for the wealth of non dopamine2 receptor pathology in schizophrenia. Although no direct evidence is available for other mood disorders various defects in the general regulatory system outlined above could easily be postulated to account for all other mood disorders. The practical outcome is that depression is likely not as simple as an inactive enzyme. It likely results from a subtle distortion of neuronal communication, and this will be difficult to recognize without better knowledge of how complex neural networks produce behavior. Contraiwise, a discovery of a gene linked to a mental disorder might provide a unique opportunity to study the basis for neuronal organization. Fortunately our total ignorance of the mechanism of mental disease has not prevented US from discovering useful therapies for most of them.
A UNIFIED
THEORY
OF MENTAL
ILLNESS
The hypothesis in summary is that mood states are important to human function therefore the brain has the ability to regulate these states. The neuronal system which senses the abnormal behavior would then feedback via different neuronal systems to affect yet other neuronal systems whose excessive (excitatory or inhibitory) activity had lead to the undesirable state. This system if impeded at any level would produce a disorder of mood. References 1. Major depressive episode. p 210 in Diagnostic and Statistical Manual of Mental Disorders. 3rd edition Washington DC. APA, 1980.
175 2. Sulser F, Janowsky J, Okada F, Manier D H. Mobley P L. Regulation of recognition and action function of the norepinephrine (ne) receptor coupled adenylate cyclase system in the brain: Implications for the therapy of depression. Neuropharm 22: 425, 1983. 3. Mann J J. Brown R P, Halper J P. et al. Reduced sensitivity of lymphocyte Beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. NEJM 313: 715, 1985. 4. Deutsch S I, Davis K L. Schizophrenia: A review of diagnostic and biological issues II. Biological issues. Hosp Comm Psych 34: 423, 1983. 5. Wong D F. Wagner Jr H N, Tune Le. et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug naive schizophrenics. Science 234: 1558. 1986.
A Unified
Theory
of Mental
Illness
B. ANDERSON
2707 Castle Gardens #277 Arlington, Texas, 76073, USA
Abstract - I propose that in certain mental illnesses the mechanics for making, releasing, and responding to neurotransmitters are all normal; what is faulty is a portion of the mechanism whereby the brain recognizes abnormal behavior and feeds back on to the neuronal pathways producing the behavior to alter function of that neuronal system and re-establish normal behavior. All the above uses the physical structure of the brain. The existence of the feedback mechanism, and its pertubation, is deduced from data about the mechanism of antidepressants.
Introduction
To date, research into the mechanisms of mental illnesses has focused on neurotransmitter abnormalities. Information that pharmacologic therapies interact with neuronal receptors has lead to the simple suggestion that there is a primary abnormality of neurotransmitter production. Ignored have been the mechanisms by which cells sense changed input and output, and alter their responsivity to active neurotransmitters thereby maintaining normal function. Since the body has homeostatic control of numerous variables it would not be surprising if mood were one of the variables so controlled. Beginning with a discussion of the pharmacologic therapies for depression a basis for assuming it is the regulatory mechanism rather than the regulated mechanisms that are disturbed in mental illness will be derived. Discussion
Depression
is a mood
state characterized
by
persistent and severe dysphoria not appropriate to external conditions, and associated with physical symptoms: sleep disturbance, weight loss, decreased libido, and psychomotor retardation (1). Almost every therapy clinically useful in the therapy of depression has been shown to either downregulate Beta-adrenergic receptors or the norepinephrine responsive adenylate cyclase (subsequently this combination of effects will be referred to as downregulation of the norepinephrine affected cell (NorEAC)) (2). Since this effect of useful medications is so generalized it is reasonable to assume that it is the therapeutic mechanism. Some people are more likely to become depressed. This fact suggests that there is a subset of humans who are deficient in their ability to endogenously downregulate their NorEAC; if they could downregulate the Nor EAC they would not become depressed. The mechanism for the increased NorEAC output that these people cannot respond to must be one 173
174 of three: a) an increase in the number of Betaadrenergic receptors or Beta-adrenergic receptor input so excessive that it cannot be compensated for by catabolic mechanisms, b) such deficient catabolism that a decrease in production of receptors or a decrease in NorE output cannot compensate, and c) that there is a defect in the setting of NorE tone to be maintained. The first possibility seems unlikely since studies have shown no difference in the number of Beta-adrenergic receptors between controls and depressed patients (if the excessive NorEAC output were secondary to excessive input we would still expect some receptor downregulation even if it were inadequate to compensate completely) (3). The second option is equally untenable since we know that pharmaceuticals lead to downregulation quite adequately. The cell’s catabolic machinery works appropriately when commanded to. This leaves only the third option. It makes the defect of depression somewhat analogous to a fever. When a patient has an elevated temperature it is not, in general, because the metabolic pathways are cycling out of control, or that the heat disipatory mechanisms are faulty, but instead results from a change in the feedback system that balances the two. A higher than usual setpoint has been established. Moods may be maladaptive. A depressed individual is less capable of caring for himself or his offspring. It seems reasonable given the survival significance of altered mood states that the organism would have acquired the capacity to detect undesirable mood states and change them. Let us theorize the general events that occur after the loss of a loved one. The death would serve as a stimulus for the increased activity of the NorEAC. This, via a series of intermediate steps, would lead to depressed behavior. The normal individual would “sense” the mood and feedback to downregulate the NorEAC. In the depressive individual there is a break in the feedback loop, and the depression persists. The defect in the feedback loop in depression would probably not be at the end where the mood is sensed. If the sensing mechanism were defective we would anticipate mood alterations at the other end of the spectrum from depression to also go uncorrected (perhaps a defect of this type could account for manic-depressive disorder). If the defect of feedback were at the effector end we would not expect medications to have any
MEDICAL
HYPOTHESES
way of working since the final pathway would have been interrupted. This leaves only the communication pathway between the sensor and effector mechanisms. Concluded from the above is that a system exists for the detection of certain moods, and this detection initiates activity to alter the mood. In depression the portion of the chain that conducts information from sensor to effector has been interrupted. A parallel can be seen with schizophrenia where the suggestion has been made that it is a dopamine disease (4), and it has been reported that there is an increased number of dopamine -2 receptors in drug naive subjects with the disease (5). It should be obvious that the explanation for schizophrenia is not merely increased production or decreased catabolism of dopamine-2 receptors. The plasticity of the dopamine system is well documented. If either the catabolic or anabolic pathways were defective it is likely the individual could recover normal dopamine affected cell tone by augment of the other end of the production/breakdown pathway. What is defective in schizophrenia is the capacity to “sense” the abnormal behavior, and feedback on the dopamine system to downregulate it and restore normal behavior. Since dopamine-2 receptor antagonism does not restore the person to normal it would seem that more than just the dopamine system is involved in this disorder. The fedback regulation system of the sort proposed or mood regulation would of necessity be generalized to all the systems involved in mood production, and a defect here could be seen to account for the wealth of non dopamine2 receptor pathology in schizophrenia. Although no direct evidence is available for other mood disorders various defects in the general regulatory system outlined above could easily be postulated to account for all other mood disorders. The practical outcome is that depression is likely not as simple as an inactive enzyme. It likely results from a subtle distortion of neuronal communication, and this will be difficult to recognize without better knowledge of how complex neural networks produce behavior. Contraiwise, a discovery of a gene linked to a mental disorder might provide a unique opportunity to study the basis for neuronal organization. Fortunately our total ignorance of the mechanism of mental disease has not prevented US from discovering useful therapies for most of them.
A UNIFIED
THEORY
OF MENTAL
ILLNESS
The hypothesis in summary is that mood states are important to human function therefore the brain has the ability to regulate these states. The neuronal system which senses the abnormal behavior would then feedback via different neuronal systems to affect yet other neuronal systems whose excessive (excitatory or inhibitory) activity had lead to the undesirable state. This system if impeded at any level would produce a disorder of mood. References 1. Major depressive episode. p 210 in Diagnostic and Statistical Manual of Mental Disorders. 3rd edition Washington DC. APA, 1980.
175 2. Sulser F, Janowsky J, Okada F, Manier D H. Mobley P L. Regulation of recognition and action function of the norepinephrine (ne) receptor coupled adenylate cyclase system in the brain: Implications for the therapy of depression. Neuropharm 22: 425, 1983. 3. Mann J J. Brown R P, Halper J P. et al. Reduced sensitivity of lymphocyte Beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. NEJM 313: 715, 1985. 4. Deutsch S I, Davis K L. Schizophrenia: A review of diagnostic and biological issues II. Biological issues. Hosp Comm Psych 34: 423, 1983. 5. Wong D F. Wagner Jr H N, Tune Le. et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug naive schizophrenics. Science 234: 1558. 1986.