Hyperintentional Self-Observation in Major Depressive Disorder. Combined Biological and Behavioral Treatment


by Bernhard Mitterauer, MD

Prof. em. (University of Salzburg)

Volitronics-Institute for Basic Research

Wals, Austria

John Pellam John Pellam John Pellam John Pellam John Pellam John Pellam John Pellam John Pellam John Pellam John Pellam The BWW Society The Bibliotheque World Wide Society The Institute for Positive Global Solutions Pellam Journal of Science Journal of Global Issues and Solutions



A new combined treatment of major depressive disorder is proposed. It is based on a hypothetical model of hyperintentional self-observation generated in tripartite synapses and their network. Hyperintentional self-observation makes the patient incapable of realizing his/her intentions in the environment in real time and the modes of normal behavior (sleeping, eating, working, etc.) are disturbed. This depressive suffering causes a loss of existential self-understanding, experienced as depressive mood. The biological treatment with antidepressants which balance synaptic information processing through reuptake inhibition of neurotransmitter substances can be improved by action therapeutic strategies. Although the testing of the underlying pathophysiology of the model is limited, the elucidation of the impaired self-understanding of hyperintentional self-observation is possible during the behavioral treatment process.




Depression is a worldwide psycho-bio-social disorder. Generally, the concept of self-observation plays a central role in all sciences. In the past, we started out with a psychological theory of self-observation mainly based on biocybernetic models of the observer [1, 2, 3, 4]. Recently, quantum physics request a brain theory of self-observation as conditio sine qua non for every natural and interdisciplinary science [5]. Here, I propose a brain theory of self-observation controlled by subjective intentional programs generated in tripartite synapses and their networks (syncytia) [6, 7].


In the present paper major depression is defined as hyperintentional self-observation. Based on the diagnostic criteria of depression [8], the hypothetical model is outlined. After the description and interpretation of the etiopathology of hyperintentional self-observation, the brain-biological treatment is discussed. Moreover, the combination of current antidepressant drugs with the behavioral treatment strategy, termed action therapy, may exert significant mood stabilizing effects.


Despite rapid technical progress the testing of the pathophysiological model remains limited. However, one can explore the impaired action pattern of the patient and stepwise give back the lost self-understanding on the behavioral level.



Diagnostic criteria of hyperintentional self-observation in major depressive disorder


In addition to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [8], the conception of a basic depressive disorder can be diagnosed as follows [modified after 9]:

1)     Psychobiological hyperintentionality responsible for non-feasible self-observations.

2)     Inability to realize one or more biological modes of behavior such as sleeping, eating, working, etc., in the sense of “I cannot do what I could do”.

3)     Compulsion to behave in one or more modes of behavior, “I have to do”.

4)     Ability to describe this disordered behavior by self-observation, but no subjective explanation for it.

5)     Loss of self-understanding.


Hypothetical model


Basically, patients with a major depression suffer from subjective hyperintentionality. This means that the self-observing brain is able to observe actual events in the environment, but this information does not activate actions that are intended to be realized. It is hypothesized that disorders in the astrocytic syncytium may represent a major component of the pathophysiology of depression, termed syncytiopathy [10]. If the expression of connexin proteins in the syncytium is downregulated, a compensatory upregulation of astrocytic receptors may occur, leading to an overexpression of these receptors. Overexpressed astrocytic receptors could embody subjective intentions of the self-observing patient. Since the overexpression of various astrocytic receptor types may fundamentally cause a depressive mood, these patterns of astrocytic receptors must be balanced into a physiological level of neuronal-glial interactions.


The increase of neurotransmitter substances by antidepressants as a primary treatment can balance the synaptic information processing, but it has no significant effect on the hyperintentionality, since only the number of astrocytic receptors is satisfied and not the self-observing patient. Here we deal with a kind of keeping calm without real effects on the patients’ intentions to actually experience feasible actions in the environment in the sense of a regained self-understanding. Therefore, a parallel behavioral treatment is necessary to stepwise activate the action potential in order for events not only to be observed, but also generated and experienced by the patient himself. During this therapeutic process the patient experiences and understands the difference between realizable and unrealizable intentions or between intention and destiny.


Hyperintentional self-observation in tripartite synapses and in the syncytium causing depression


As already discussed, astrocytes interconnected by gap junctions build an astrocytic syncytium. Gap junctions are composed of connexin proteins that are activated by substances of the neuronal system as the primary pathway based on Ca2+ wave propagation between astrocytes. In the astrocytic syncytium the expression of connexins and of various receptor types are regulated by a complex transcription network [11]. If the expression of connexins is downregulated, caused by genetic, epigenetic, stress factors, etc. [12], a compensatory upregulation of astrocytic receptors may occur, leading to an overproduction of these receptors.  Such an excess of astrocytic receptors causes an imbalance of synaptic information transmission, because of a relative lack of neurotransmitters for the occupancy of astrocytic receptors and, as a result, neurotransmission is protracted [13]. In addition, the downregulation of connexins may negatively influence intracellular signalling within the syncytium, since not enough connexin proteins can be produced for a complete coupling of all possible interactions between astrocytes. Supposing that this glial network structure embodies incomplete intentional programs, receptor overexpression can be interpreted as embodiment of hyperintentionality. Most importantly, these synaptic locations cannot process sensory information in real time, since synaptic information processing is protracted, which may be responsible for a depressed mood with typical symptoms on the behavioral level [14].


Tripartite synapses and the glial syncytium


A tripartite synapse consists not only of the presynapse and the postsynapse as neuronal components, but also of the astrocyte as the glial component. Glial cells are capable of expressing the same extending variety of receptors as neurons [15]. This synaptic structure processes information between the neuronal and the glial network (syncytium): the astrocytic syncytium is composed of gap junctions and gap junction plaques. Gap junction plaques may function in both memory [16] and intentional programs [17]. Synaptic information processing occurs within time scales of milliseconds to seconds, seconds to minutes, minutes to hours or longer [18, 19]. I hypothesize that intentional programs are embodied in the glial syncytium and that they select appropriate receptor patterns on the astrocyte according to repeated neuronal sensory activation. An astrocyte exerts dynamic structuring and functions via its numerous perisynaptic processes [20]. By contacting and retracting of their endfeet an appropriate receptor pattern is selected that modulates the astrocytic receptor sheath for its activation by neurotransmitter substances [21]. Each astrocyte contacts by its processes n- synapses generating tripartite synapses. This structure of glial-neuronal interaction is called astrocytic domain organization [22].


Most importantly, gap junctions operate between perisynaptic astrocytic processes originating from a single astrocyte [23] in the sense of reflexive gap junctions [24], constituting an autonomous network within a single astrocyte. The gap junction network selects repeated activation of glial receptors by neurotransmitter occupancy and feeds forward this selected pattern to perisynaptic astrocytic processes modifying their movement dynamics. Integrated information processing within the astrocytic body feeds back to perisynaptic astrocytic processes in a pulsating manner [25, 26]. This model of glial-neuronal interaction in the tripartite synapse describes an elementary mechanism of self-observation [7].


The quantum mechanical action cycle theory allows the interpretation of synaptic glial-neuronal interaction as a model of self-observation. It is possible to describe the information from the neuronal synapse as description of the observation in the environment (via perception systems), the information structuring by the motile astrocytic processes as explanations, and the interactions between the astrocytes via gap junctions as description of the explanation of the observed in the sense of an intentional programming within the glial network. Since each domain is organized within a finite structure, it is possible to characterize their domain organization as standpoints of self-observation [27].


Biological treatment


With regard to the glial cell system the effects of antidepressant drugs can be experimentally shown [28, 29]. Basically, antidepressants inhibit the reuptake of neurotransmitter substances via transporter inhibition. Augmentation of transmitter substances by antidepressants balance postsynaptic receptor activation, but may not directly work on astrocytic receptors.


Although the balancing effect of antidepressants enables processing of sensory information in real time, the overexpressed receptor pattern on astrocytes may not be balanced in the network operations. This means that clinical remission of depression is basically generated by neurotransmitter saturation of the overexpressed astrocytic receptor pattern within tripartite synapses and is not primarily exerted through actual sensory information from the environment, but by transmitter reuptake inhibition.


Concerning the effects of antidepressants on glia some findings are significant for the model proposed. Experimental investigations identified a pronounced up- or downregulation of glial proteins such as NDRG2 [30]. Increased expression of Connexin 43 (a major component of astrocytic gap junctions) in the prefrontal cortex following chronic treatment with fluoxetine is reported [31]. In a chronic stress-model of depression in rats a stress-induced reduction of hippocampal GFAP expression was reversed by treatment with the tricyclic antidepressant clomipramine [32]. The most consistent finding on astrocytic activation was observed after electroconvulsive stimulation (ECS) [33].


Moreover, it has been demonstrated that astrocytes in the intact mouse prefrontal cortex exhibit functional 5-HT receptors and are targets for antidepressant drugs. These findings provide evidence that astrocytic function can be directly modulated by SSRIs. However, the relevance of these astrocytic therapeutic effects of SSRI is unclear [34].


Most relevantly, the discovery that ketamine (N-methyl-D-asparate glutamate receptor antagonist NMDA) rapidly increases the number and functions of synaptic connections has focused the attention on synaptogenesis suggesting that disruption of synaptogenesis and loss of connections underlies the pathophysiology of depression [35]. Ketamine can produce rapid und robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression [36]. Although current experimental findings and interpretations focus on the neuronal system, I have hypothesized that in therapy-resistant depression a significant excess of NMDA receptors on astrocytes is causing a severe lack of glutamate which cannot be balanced by reuptake inhibitory drugs, and the blockade of the excess of NMDA receptors in astrocytes may rapidly balance synaptic information processing. Since ketamine could act on various neuronal and glial cell types, my hypothesis should also refer to pertinent experimental findings with supporting arguments [37].


Behavioral treatment


The most common psychotherapeutic approach in depression is cognitive therapy. The behavioral treatment proposed here mainly concerns the clinical treatment of patients suffering from a severe major depression. As already discussed, the biological treatment with antidepressant drugs leads to a restitution of depressive behavior but hyperintentionality persists. The behavioral treatment strategy proposed enables the patient to stepwise observe events in the environment generated in real time by himself. This is an experience of event-related acting again. Hence, actions do not occur as self-reflections within the brain, but are comprehending intentions in the environment: “to grasp what I do”. I speak of action therapy of depression [9]. What are the action strategies with the aim to reconstitute a balance between intentions and corresponding actions in the environment?


  1. Self-explanation. What is the actual action potential? What can the patient do? What is the patient able to do regarding to his/her action potency? For the perfectionist psyche of a depressive person it is essential to act in an appropriate location in order to conduct an intended behavior. If we can find a suitable place or situation the patient can be encouraged to make anything spontaneously. Despite his or her perfectionistic personality to act perfectly in an important and valuable manner, the patient must learn to accept anything realizable at the beginning of the treatment. Since persons with depression prefer a typical sensory quality, we should focus on contacts in this sensory quality. For instance, to communicate via vision and touching or in auditorily centered contacts. Each action subjectively appropriate to the patient must be confirmed in the sense of a positive feedback.
  2. Self-experience. In this stage of treatment the patient is able to self-observe that he/she is acting in an appropriate and subjectively intended environmental situation. This seemingly minimal self-experience to act mostly exerts an enormous effect. The experience of acting is accompanied with a mild improvement of depressed mood. Now, the patient is beginning to intend communication.
  3. Communicative self-experience. Now, first intended communicative actions must be expressed. Where do you want to do something and with which person? Which sensory contacts do you prefer? Listening, conversations, watching TV, body contacts such as massage, sports, dancing, etc. What kind of communication with respect to locations and characteristics of the partner is important? Where should the communication take place? If several communication actions can be realized, the patient experiences a kind of self-liberation. In parallel, the perfectionistic personality should be convinced that the actual communicative self-experience leads to further contacts according to the intended behavior. In the typical case that the patient wants to do several or even many actions at the same time, the action potential must be structured. Otherwise, these hyperintentions cause depressive mood again.
  4. Creative self-programming. Not only the self-experience is very action-potent, but also the learning effect of being able to act according to intentions in an appropriate environment and communicative situations reconstitute the self-understanding. Now the patient is able to self-structure the intended action potential in everyday life with the growing experience to realize what is realizable.

Importantly, these four basic steps of an action therapy of depression must be applied dependent on the course of mood elevation.


Biological testing of the model


Basically, the counting of the number of receptors on astrocytes should be possible. For instance, optogenetic techniques enable an increasingly exact method to show cells in the brain in vivo. Hence, optogenetic techniques could compare normal astrocytic receptor expression or activation with overexpressed astrocytic receptor patterns. Fully aware of the fact that actual intentions and mood states cannot be elucidated in animal experiments, testing of human hyperintentionality in the brain is principally limited. The biological argument for this principal impossibility is the fact that the many perisynaptic astrocytic processes of a single astrocyte contact about 2.000.000 synapses and the network between astrocytes comprises a superastronomic amount of synapses [22].


However, the investigation of the expression of connexins in tissue of post-mortem brains with depression may be possible [38]. If downregulation of astrocytic connexins can be identified, the astrocytic syncytium is incomplete leading to impaired intentional programming. Moreover, the brain region investigated is important. Antidepressants lead to functional inactivation of connexin 43 in the hippocampus and exert an increased activity of the cortex [39]. It is hypothesized that connexin 43 gap junctions and connexin channels exert different effects on stress and antidepressant drug response [39]. What the genetic mechanisms responsible for a downregulation of astrocytic connexin concerns, one should be cautious to look for specific “depression genes” [11]. Importantly, the variability in the human genome has far too exceeding expectations. New approaches are necessary to understand the contribution of structural variants to depressive disease [40]. Most interesting is the experimental indication that ketamine blocks NMDA receptors causing a rapid antidepressant effect. If this effect also works on astrocytic NMDA receptors, this balancing of synaptic information processing may exert a normalization of connexin expression in the astrocytic syncytium. It should be mentioned that at specific brain locations both glial gap junctions and tripartite synapses can be overexpressed, e.g. in the hippocampus, where emotions are generated.


Together, exciting technical progress [41] can enable experimental findings in tripartite synapses and their network leading to a better biological explanation and testing of the model of depression proposed. However, limitations of experimental research require an improvement of our understanding of patients suffering from depression on the behavioral level and by treatment experiences [42].




The psyche of a patient suffering from depression is existentially determined by nonfeasible hyperintentional programs in the sense of an unfulfilled destiny of a permanent existence of his/her great individuality. Since the patient feels the loss of permanent existence and is incapable of acting in real time, the combined biological and behavioral therapy proposed can cope with major depressive disorder. The rationale is based on an improvement of depression with antidepressants and action therapy. The latter enables a stepwise normalization of the subjective hyperintentionality that is caused by persistent mental self-observation, but without the experience of acting according to actual events in the environment.


Although we have developed an appropriate questionnaire for the diagnosis of depression that works out well, its validation on a representative sample is still necessary. Admittedly, the therapeutic method outlined mainly concerns the clinical treatment of severe major depression, but it exerts significant mood stabilizing effects in general practice as well. Basically, such a combined treatment can explain the subjective reality in which the suffering from depression is generated. Empathic communication is paving the way towards regaining an intended existence in the environment.






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I am very grateful to Birgitta Kofler-Westergren for preparing the final version of the paper.

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