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MAD Theory: A Comprehensive Exposition

Shinagawa Psychosomatic Clinic – Free Memoranda (Study Sessions #21–#29): Decomposed and Synthesized

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Introduction: The Theory’s Position and Purpose

The MAD theory is a hypothetical model that attempts to explain the mechanisms of depression from a single biological foundation: the response characteristics of individual neurons. It originates from the author’s critical awareness that many existing theories of depression, while possessing a certain descriptive accuracy, tend at some point to dissolve into unverifiable social theories, theories of the human condition, or theories specific to the Japanese character.

The assessment that such theories were “merely fashionable at the time, and memorable only insofar as their naming was catchy” is a harsh one, but the MAD theory responds to this by aiming to establish a biological core that remains constant across historical periods.

At the same time, this theory is positioned as an account of the mechanism underlying the Primacy of Mania hypothesis (PM hypothesis). The central task of this theory is to provide a neuronal-level foundation for the proposition that depression always follows a preceding state of excitation — a manic state, or its equivalent in the form of neuronal hyperactivity.

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Part One: The Basic Physiology of Neurons — The Foundation of the Theory

1-1. The Basic Structure and Function of Neurons

The brain is composed of neurons. Information enters via dendrites, is processed within the cell body (priority determination, signal integration, inhibition, and selection), and neurotransmitters are released through the axon into the synaptic cleft of the next neuron. On the surface of the receiving cell are receptors that capture the transmitter substances.

Known neurotransmitters include serotonin, dopamine, noradrenaline, acetylcholine, and GABA.

Neurons are supported by glial cells (supporting cells), which are responsible for nutritional supply, repair, and myelin sheath formation. Some theories posit that abnormalities in this component constitute the etiology.

1-2. Action Potential and Refractory Period

The resting membrane potential of a neuron is approximately −70 mV. When a stimulus is applied and the threshold (approximately −55 mV) is exceeded, an action potential is generated, reaching a peak of +40 mV. This is followed by hyperpolarization (in which the membrane potential temporarily falls below the resting level), and the cell enters a refractory period.

During the refractory period, the cell does not respond to new stimuli. This is a protective mechanism against excessive reactivity. “Until processing is complete, the next signal is made to wait.”

1-3. The Hierarchical Structure of the Brain and Jacksonianism

The brain has a hierarchical structure, in which more recently evolved (phylogenetically higher-order) layers inhibit those below them.

When the function of a given layer ceases, three changes occur simultaneously: first, direct symptoms resulting from the loss of function of that region; second, the disinhibition and emergence of lower-order functions that had previously been suppressed by that region; and third, the organism’s overall response to both of these changes. This three-layered superimposition complicates clinical observation. This is referred to as Jacksonianism.

The exaggeration of patellar tendon reflexes following hemiplegia caused by cerebrovascular disease — in which the reflex “jumps briskly” — is a classic example of disinhibition: the upper motor neuron’s inhibitory control over the lower motor neuron has been lost.

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Part Two: The Core of MAD Theory — Three Types of Neurons

2-1. The Basic Idea of the Theory

The central operation of the MAD theory is as follows:

“When a single neuron is isolated and subjected to repeated identical stimuli at fixed intervals, neurons are classified into three types according to the response characteristics they exhibit.”

This simple thought experiment becomes the explanatory principle that integrates everything: depression, premorbid character, bipolar disorder, comorbidities, and treatment theory.

It should be noted that experimentally, electrical measurement using glass electrodes is feasible for large neurons (such as the squid giant axon), but methodological difficulties arise with smaller neurons. Furthermore, when the interval between repeated stimuli is extremely short, the refractory period prevents any response from being obtained, and therefore an appropriate interval must be set.

2-2. The M-cell (Manie-cell: Manic cell)

Definition: A type that progressively amplifies its response to repeated stimulation.

Response profile: As stimulation continues, output (response magnitude) increases further and further. A pattern of sensitization and potentiation.

Comparative model: The kindling phenomenon in epilepsy, and the priming phenomenon in schizophrenia (in which responses become faster and larger with repetition), correspond to this type.

Limits and cessation: However, the response cannot increase indefinitely. Energy is finite, replenishment is required for continuation, and waste products and fatigue substances accumulate. The cell is eventually driven into cessation (functional arrest).

Adaptive significance: The capacity to respond to ever-newer changes is learning-adaptive. There is a risk that an excessively large response will damage the system, but if the process is halted at a certain point, the cell functions safely. (When a cat’s tail is repeatedly touched, it gradually becomes more painful, and the cat escapes — a protective mechanism for moving away from the stimulus.)

Temperament and character correlates: Enthusiastic engagement, elation, vitality.

Clinical correlate: The cell population that produces manic and hypomanic states.

2-3. The A-cell (Anankastic-cell: Obsessive-compulsive cell)

Definition: A type that consistently returns the same response to repeated stimulation.

Response profile: Same input → same output. Stable, constant response. Neither sensitization nor attenuation.

Characteristics: Repeating, iterating, not becoming bored, perseverance.

Limits and cessation: This cell’s activity too will eventually come to an end. Fuel depletion, accumulation of waste products → replenishment and clearance become necessary → when output and replenishment can no longer proceed in parallel, the cell ceases. “It is better to rest before reaching the limit, in order to recover.”

Adaptive significance: Functions as a stable processing system by continuing to produce reliable output.

Temperament and character correlates: Meticulousness, compulsivity, adherence to rules, repetition and persistence.

Clinical correlate: The cell population that forms the basis of obsessive-compulsive tendencies.

2-4. The D-cell (Depressive-cell: Depressive cell)

Definition: A type that responds once or twice to repeated stimulation and then rapidly attenuates, becoming unresponsive.

Response profile: An initial response is present, and output then falls to nearly zero very quickly. A pattern of rapid exhaustion and habituation.

Characteristics: Compared with the other two types, “a very quiet cell that gives up quickly.”

Special consideration: The D-cell is not in a state of dysfunction — cessation is its natural mode of being. Even when neurons of the M-cell or A-cell type continue to fire, the muscles that act on those signals become exhausted more quickly than the neurons themselves. The D-cell serves a protective function: by terminating the neural response before the muscle reaches its limit, it protects the muscle. (If the nerve stops responding before the Achilles tendon ruptures or a muscle tear occurs, the muscle is spared.)

Distribution: The author considers that the great majority of neurons in the human brain are of the D-type. This is an important premise. D-cells are always present in abundance in everyone — they are, so to speak, the “default” cellular characteristic.

Temperament and character correlates: Persistence of negative mood, asthenic disposition.

Clinical correlate: The cell population that constitutes the substratum of depressive states. When M- and A-cells are active, D-cells do not come to the foreground, but when M and A cease functioning, D-cells “remain” and form the depressive state.

2-5. The Relationships Among the Three Types and Intermediate Forms

Continuous intermediate forms exist among the three types. In practice, pure single-type M, A, or D cells are rare; mixed types predominate.

As one example, an intermediate type can be conceived that shows an M-like increase in response to the same repeated stimulus in the initial phase (ascending phase), then an A-like stable output for a period (steady-state phase), and finally D-like cessation (exhaustion phase) — as a temporal sequence.

Furthermore, since a single neuron may possess multiple axon collaterals, different characteristics may be displayed across different collaterals. Under hormonal influence, for instance, a cell may temporarily exhibit a response that differs from its intrinsic characteristics.

Although the theory treats these as “pure tripartite types” for the sake of simplification, such complexity is in fact presupposed.

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Part Three: The MAD Profile and Premorbid Character

3-1. Neuronal Description of Premorbid Character

The biological substrate of a given individual’s premorbid character is partly determined by which of the three cell types — M, A, and D — are distributed in which brain regions, and in what quantities.

Schematically: if the vertical axis represents the number (or quantity) of cells of each type, and the horizontal axis represents the M→A→D spectrum, then each individual’s predominance among the types constitutes the biological profile of their character.

For convenience, if each type is expressed in three levels — “many, moderate, few” — then 3 × 3 × 3 = 27 combinations are possible; at 5 levels, 125 combinations; treated as a continuous quantity, effectively infinite variation arises.

Important constraint: D-cells are “many” in the majority of people (since the great majority of neurons in the brain are of the D-type). Consequently, individual differences in practice tend to be generated by the relative abundance of M- and A-cells.

3-2. Kasahara’s Four Character Axes and Their Correspondence to MAD

Yomishi Kasahara identified four axes of premorbid character in depression: Enthusiastic engagement (netchu-sei), meticulousness, persistence of negative affect, and consideration for others (taita-hairyo).

The MAD theory corresponds neatly to the first three of these axes:

Kasahara’s Axis	MAD Correspondence	Character Component
Enthusiastic engagement / vitality	Abundance of M-cells	Elation, activity, sensitization tendency
Meticulousness / compulsivity	Abundance of A-cells	Repetitiveness, persistence, constancy
Persistence of negative affect / asthenia	Abundance of D-cells (always many)	Exhaustion tendency, depressive baseline
Consideration for others	No MAD correspondence	Social component (see below)

This correspondence constitutes one of the important supporting bases of the theory.

3-3. The Position of Consideration for Others — As a Social Component

Consideration for others is not included in MAD. This is an important conceptual clarification.

Reasoning: Consideration for others is “a complex function that results from the combination of various lower-order functions,” and belongs not to the response characteristics of individual neurons but to higher-order social and interpersonal functioning. MAD is a matter of lower-order biological substrate, while consideration for others is distinguished as a complex function that is constituted upon that substrate.

Furthermore, the author argues that consideration for others is a component that undergoes transformation across historical periods. Whereas “altruistic consideration for others” was once predominant, the contemporary era has seen a shift toward “self-protective, self-interested regard for others,” and further toward a thinning of other-regard itself.

If consideration for others were to be regarded as an intrinsic part of depression, then only depression arising within a specific cultural context — that of Germany and Japan during the era of striving to become first-rate nations, and primarily the narrowly defined melancholic type — would be “true depression,” with all others classified as “incomplete” or “immature” forms. That would be an error.

The MAD components constitute the invariant core that persists across historical periods, and it is more accurate to understand that “the dominant spirit of each era (Zeitgeist) modifies these core symptoms.”

3-4. Correspondences Between Representative Premorbid Character Types and MAD Profiles

The major premorbid character types are organized as follows:

1. Adhesive temperament (Shimoda) — MAD profile: M-many, A-many, D-many (consideration for others: many) Diligent at work, thorough, meticulous, strong sense of responsibility, perfectionist. Both M and A are active, and D is also abundant (as is true for everyone). Since both M and A components can reach hyperactivity, the pathway to exhaustion becomes complex. This type has a tendency to lead to manic-depressive illness.

2. Cyclothymic temperament (Kraepelin) — MAD profile: M-many, A-few, D-many Sociable, competitive, humorous, energetic. The M component is markedly predominant, while A is scarce. When M goes down, the state becomes D-predominant. This type tends to lead to manic-depressive illness (especially resembling Bipolar I).

3. Typus melancholicus (Tellenbach) — MAD profile: M-few, A-many, D-many (abbreviated: mAD) Serious, meticulous, punctual and rule-respecting, unable to decline requests, exacting toward oneself. The M component is constitutively sparse, and the A component becomes the center of the character. Upon exhaustion, the A component ceases to function, producing the depressive state of M-few, A-few, D-many. This type has the highest tendency to lead to unipolar depression.

4. Obsessive-compulsive character — MAD profile: M-few, A-many, D-moderate-to-many Difficulty with transitions; responses tend to be stereotyped. Rather than novel thinking, difficulties are overcome through repeated effort. The A component is overwhelmingly dominant.

5. Asthenic character — MAD profile: M-few, A-few, D-many Neither enthusiasm nor meticulousness is strong. However, in the contemporary asthenic character, a grandiose ego and narcissistic component are frequently retained internally, with surface timidity and inner narcissism coexisting. This approximates dysthymia-prone depression.

6. Premorbid character of Bipolar II — MAD profile: M-moderate, A-moderate, D-many Both M and A components are moderate — neither particularly enthusiastic nor particularly meticulous. The asthenic tendency is strong. This corresponds to the premorbid character of BP-II, which involves cycles of hypomania and depression.

Each of the above types has five or more degrees of continuous intermediate forms, and many unnamed types exist.

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Part Four: The Mechanism of Depressive States — The MAD Explanation of the Primacy of Mania Hypothesis

4-1. The Central Proposition

Depression cannot exist in isolation.

M and A hyperactivity (heightened activity) → exhaustion → functional arrest → the characteristics of D-cells come to the foreground = depressive state.

This is the mechanistic explanation of the PM hypothesis via MAD theory. Depression is understood not as “something actively occurring,” but as a phenomenon of subtraction and residue — “when M and A have disappeared, D remains and becomes manifest.”

4-2. The Common Depressive State

Regardless of which premorbid character type serves as the starting point, the fully developed depressive state ultimately reached takes a common form:

M-few, A-few, D-many

This is the state clinically observed as “depression.”

The D-cell is a population that ceases after one or two responses, and cessation is its natural mode. Therefore, rather than saying “D-cells cause depression,” the more accurate formulation is: “When M and A have been active and then go down, D remains, and depression is the inevitable consequence.”

4-3. Detailed Descriptions of the Onset Process in Each Character Type

Onset process in adhesive temperament (M-many, A-many, D-many)

Starting point: M-many, A-many, D-many (+ consideration for others: many)

① Overexertion at work or in private life; or sustained excitement from excessively joyful events (the mechanism is identical for both). ② M-cells progressively return larger responses (manic hyperactivity phase), eventually reach the limit of endurance, and cease. ③ The state changes to M-few, A-many, D-many. → At this point, meticulousness (A) and depressive tendency (D) come to the foreground. The presentation temporarily resembles that of the typus melancholicus. → The person attempts to manage the situation by drawing upon the A component. ④ If the A component also continues exerting itself without interruption, it too ceases to function. ⑤ The state becomes M-few, A-few, D-many, leaving only depression (D). This constitutes the depressive episode.

Recovery: Time is required until M and A recover their function (approximately three months). Only when recovery reaches M-many, A-many, D-many is there a complete return to the original adhesive temperament.

Onset process in typus melancholicus (M-few, A-many, D-many)

Starting point: M-few, A-many, D-many (mAD)

① Working conscientiously with a strong sense of responsibility, until completely exhausted. ② The A component goes down and ceases to function. ③ The state becomes M-few, A-few, D-many. This is the depressive state.

(From step ③ onward, the same state as that reached midway through the adhesive temperament’s course is reached. That is, a common depressive state is formed from different starting points.)

Recovery: Recovery to M-few, A-many, D-many (mAD) constitutes a return to the premorbid typus melancholicus. The endpoint of recovery is lower than in the adhesive temperament (since recovery of the M component is not required).

4-4. Differences in the “Quality of Effort” at Onset Across Types

Both the adhesive temperament and the typus melancholicus lead to depression, but the locus of exhaustion differs.

Adhesive temperament: M-many → M-few (depletion of enthusiasm and vitality is central) Typus melancholicus: A-many → A-few (depletion of the sustained meticulousness and sense of responsibility is central)

The terminal state is M-few, A-few, D-many in both cases, but the qualitative experience of “becoming exhausted” differs subtly.

4-5. Bipolar Disorder as Described by MAD Theory

Bipolar I: The M component is “M-many.” When M-cells are active, a clear manic state is present; when M-cells go into cessation, a depressive state follows.

Bipolar II: The M component is “M-moderate” (smaller than in Type I). A ranges from many to moderate; D is many. The activity of M-cells does not exceed hypomania, and when it ceases, depression follows.

By this model, pure mania is difficult to conceive. Since the great majority of human brain neurons possess D-characteristics, any given individual should have a composition of at least M-many, A-few, D-moderate-to-many, and the manic state is invariably modified by the influence of A and D components.

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Part Five: Comorbidities and Related Conditions as Described by MAD Theory

5-1. The Relationship to Anxiety Disorders

Whereas manic-depressive illness (bipolar disorder) involves the hyperactivity and cessation of MAD cells as a non-localized, diffuse cerebral process, anxiety disorders can be understood as localized lesions.

When M-cell hyperactivity and cessation occur in a form that involves specific brain regions related to anxiety disorders, panic disorder is formed in place of a manic state (M-cell hyperactivity in a specific region → subsequent functional arrest → localized depressive change). The clinical course of panic disorder, in which episodes repeatedly appear and subside, corresponds to the activity cycle of M-cells.

When localized lesions primarily involving A-cells are present, a clinical picture approximating generalized anxiety disorder (GAD) is formed.

5-2. The Relationship to Schizophrenia

Schizophrenia is conceived as a localized lesion. The “priming phenomenon” of relapse (in which relapses become easier to trigger with each recurrence) is attributable to the involvement of the M- and A-cell systems.

Because schizophrenia itself functions as a chronic, persistent stressor, the eventual result is a non-localized cessation of M-cells, which manifests as post-psychotic depression (the depressive state following the acute psychotic phase).

The acute phase of schizophrenia (agitation, hallucinations, delusions) is the hyperactivity phase of M- and A-cells; the negative symptoms (blunted affect, avolition, poverty of thought) can be understood as the result of their permanent functional arrest. This is the same principle as the intellectual deterioration following epileptic seizures (permanent functional arrest of M-cells).

5-3. Continuity with Epilepsy

An epileptic seizure is the most typical state of M-cell hyperactivity (kindling), and in terms of neuronal excitation, epilepsy, schizophrenia, and the manic state can all be aligned along a common axis of principle.

Neuronal function is lost as a consequence of excitation. When the loss persists without recovery (permanent functional arrest), the result is intellectual deterioration in epilepsy and negative symptoms in schizophrenia; when recovery occurs over time, the result is the depressive phase of manic-depressive illness — a continuous understanding becomes possible.

5-4. The Position of Apathy in Parkinson’s Disease

Apathy as observed in Parkinson’s disease is distinguished from depression. Apathy is a reduction in the motivation for behavior, cognition, and affect: loss of interest and loss of pleasure are present, but dysphoria does not occur, as is conventionally held.

This was previously understood as a depressive state linked to the dopaminergic system, but advances in diagnostic nosology have progressively established the distinction.

In terms of the relationship to MAD theory, this may require separate understanding as a problem specific to the dopaminergic system (which may partially overlap with M-cells) rather than a problem of D-cells per se. The author does not provide a definitive position on this point.

5-5. The Relationship to Bereavement and PTSD

Depression arising from bereavement or PTSD is characterized by its rapid onset, which differs from the usual mechanism of hyperactivity → exhaustion → cessation in which M and A “become fatigued and go down.”

It is closer to a state of suspended animation induced by sudden shock, rather than activity cessation through fatigue. Strictly speaking, there may therefore be aspects that more closely resemble a “dissociative reaction” than depression. However, it shares with ordinary depression the common endpoint of a state in which the M-A component has ceased functioning (M-few, A-few, D-many).

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Part Six: The Contemporary Increase in Depression and Social Theory

6-1. The MAD Explanation for the Increase in Depression

In the past, when physical labor was predominant, overexertion would first manifest as muscle tears, Achilles tendon ruptures, or accumulation of muscular fatigue — the body (motor apparatus) would produce the signal of its limits first and force rest. The flesh functioned as a stopper before the neurons could burn out.

However, contemporary labor is centered on informational output from the brain to documents and computers, and the fatigue of the motor apparatus does not function as a stopper. Even in the presence of eye fatigue and stiff shoulders, there is no forced interruption from damage to muscles, joints, or tendons. As a result, neurons continue to exhaust themselves progressively, leading to functional arrest of MA-cells and an increase in depression.

6-2. Why Children Are Less Prone to Depression

In children, the M component does not cease functioning, or at least rarely does so. The reasons are as follows:

Sleep duration is long (M and A recover within a single night’s sleep), neuronal recovery is rapid, and the volume of stressful tasks is smaller than in adults. Children are therefore persistently active and less susceptible to depression.

It is only upon reaching a certain level of maturity that individuals are exposed to excessive stress and their neuronal recovery slows, eventually leading to depression.

In the contemporary era, cessation of MA-cell activity has begun to be seen around the age of 20, giving rise to the early onset of depression.

6-3. The MAD Explanation for the Diversification and Attenuation of Depression

In the contemporary era, although the biological substrate (the imbalance of MAD components) is the same, the “spirit of the age” (Zeitgeist) that modifies it has changed. Premorbid characters of the adhesive and melancholic types have increasingly been presenting without the component of consideration for others, with symptoms becoming “colored by an immature, narcissistic character tendency.”

This corresponds to the contemporary transformations of depression: earlier onset, attenuation of severity, neurotic coloring, transition toward adjustment disorders, and treatment resistance.

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Part Seven: Treatment Theory — Practice Derived from MAD Theory

7-1. The Basic Principle of Treatment

Taking time and waiting for MA-cells to recover.

This is the essence of treatment. The author candidly states that “thinking in this way does not decisively change treatment in itself,” but the direction implied by the theory is clear.

The three pillars of treatment: protecting MA-cells and waiting for their recovery; preventing suicide; and educating patients regarding the mechanisms, in order to prevent relapse.

7-2. Pharmacotherapy as Understood Through MAD Theory

SSRIs (selective serotonin reuptake inhibitors): Through long-term downregulation, they reduce serotonin receptors, thereby suppressing the hyperactivity of a portion of M- and A-cells. They also suppress anxiety by inhibiting the hyperactivity of M- and A-cells in localized regions related to anxiety disorders.

Regarding the relationship to the serotonin hypothesis (the conventional theory explaining depression as a reduction in serotonin): it is interpreted as follows — “since serotonin decreases as a result of the functional arrest of M and A cells, what is being discussed is supplementing that decrease.” The change in serotonin is positioned not as the cause of depression but as its result (the biochemical consequence of M/A functional arrest).

Mood stabilizers (originally anticonvulsants): Prevent M and A from overexerting themselves until they burn out. By setting an upper limit on effort, they protect MA-cells. From the perspective of MAD theory, the logic that “preventing excessive excitation prevents the occurrence of depression” becomes self-evident.

Regarding other proposed mechanisms such as the HPA axis, BDNF, and mitochondrial hypotheses, the author takes the pragmatic position: “I do not deny any of them; if they prove useful as needed, they may be adopted.”

7-3. Lifestyle Adjustment and Behavioral Approaches

Working through the night for consecutive days or engaging in intensive bursts of work “because things are going well” is harmful. The ideal lifestyle is as follows:

Working steadily every day, resting steadily every day, and allowing the fatigue of each day to be recovered through that day’s sleep. Rather than thinking “let me tackle this whole mountain of work at once,” distributing it as “let me divide the mountain into three portions and address it over three months.” Rather than “one person pushing through alone for a month,” adopting an approach of distributing the load among subordinates for parallel processing across multiple brains.

The key to prevention is transformation from a constitution that can push hard, into a constitution that distributes exertion.

7-4. The Direction of Psychotherapy According to MAD Theory

The center of treatment is primarily psychoeducation. Patients come to understand the MAD mechanism and then, on the basis of that understanding, detect and prevent “overexertion” themselves, and put into practice the distribution of peaks of effort.

As a guiding approach to coping with conflicts, the following are proposed: “postponing,” “considering whether one can wait,” “wondering whether one can live at 60%,” and “quiet on rainy days, warm on snowy days.”

While adopting the position that “deeper psychological engagement is largely unnecessary,” the author also states that it is beneficial to address psychotherapeutically the individual’s inner circumstances, family circumstances, and life circumstances as they relate to the question “why does this person push themselves so hard.”

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Part Eight: The Scope and Limits of the Theory — The Author’s Own Assessment

8-1. What the Theory Can Explain

Using this MAD model, the author states that the following matters can be “explained with precision”:

“Depression follows after overexertion.” “It will be sufficient to rest for a while.” “Only suicide must be prevented.” “Major life decisions should be deferred.” “Overexertion even after joyful events can lead to depression.” “Children are less susceptible to depression.” “The reasons for the increase in depression.”

A further benefit is an intuitive understanding of why mood stabilizers are effective in preventing depression.

8-2. Defense of Ignoring Localization

The author recognizes that “focusing on cell characteristics distributed throughout the whole, while ignoring the location of neural circuits” may not be broadly accepted.

However, the symptoms of depression are a diffuse, systemic phenomenon that “encompasses everything from affect to the autonomic nervous system, and in recent years is said to leave residual cognitive symptoms” — they cannot be fully explained by the assumption of a localized lesion. “There is something that involves the entire organism and seems to shut down the very force for living at its root. This is not a problem of parts, but a more total problem” — it is from this intuition that the MAD model departs.

8-3. The Limits of the Theory

The limits the author himself acknowledges are as follows:

Connection to the empirical research system expressed in the common language of DSM or ICD is difficult in the formal structure of this theory. The operation of functionally classifying neurons as “M, A, or D” is difficult to verify directly using current experimental neuroscientific methods. Furthermore, the experimental basis for “classifying cells distributed throughout the brain by their response characteristics” remains at the level of theoretical inference.

The author is aware of this, and it is reflected in the formulation: “I have presented this as one model, one that is as simple and as broadly explanatory as possible.”

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Comprehensive Assessment and Position

The MAD theory is a comprehensive model that attempts to explain multiple domains in a unified manner, using as its axis the simple concept of neuronal response characteristics — the sensitizing type (M), the steady-state type (A), and the exhaustion type (D).

Its explanatory range extends to: the correspondence with Kasahara’s four premorbid character axes; the neuronal foundation of traditional premorbid character typologies such as the adhesive temperament, typus melancholicus, cyclothymic temperament, and asthenic character; the differentiation between Bipolar I and II; the common final pathway of the depressive state (M-few, A-few, D-many); an intuitive understanding of the mechanism of action of mood stabilizers and SSRIs; an explanation of the contemporary diversification of depression; and a continuous understanding that encompasses schizophrenia, epilepsy, and anxiety disorders.

The core of the MAD theory as a mechanism for the PM hypothesis (Primacy of Mania hypothesis) is contained in the following single statement:

“Depression cannot exist in isolation; however subtle, a manic phase representing a period of M-cell hyperactivity immediately precedes it. The functional arrest of M- (and A-) cells is the mechanism underlying the primacy of mania, and the characteristics of the D-cells that remain as a result manifest as the depressive state.”

This constitutes a neuronal-level concretization of the PM hypothesis advanced by Ghaemi and others, and simultaneously aims to provide an intuitive, cell-physiological foundation for the proposition that “depression is not a primary illness, but a phenomenon that follows in the wake of excitation.”

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The above is a comprehensive exposition achieved by decomposing and synthesizing the content of the document corpus (Sessions #21–#29). Overlapping sections have been consolidated, and the arguments of each document have been integrated as completely as possible.