Auditory verbal hallucinations in schizophrenia and post-traumatic stress disorder: common phenomenology, common cause, common interventions? (2015)

I’ve been thinking along similar lines…

Auditory verbal hallucinations in schizophrenia and post-traumatic stress disorder: common phenomenology, common cause, common interventions?

Auditory verbal hallucinations (AVH: ‘hearing voices’) are found in both schizophrenia and post-traumatic stress disorder (PTSD). In this paper we first demonstrate that AVH in these two diagnoses share a qualitatively similar phenomenology. We then show that the presence of AVH in schizophrenia is often associated with earlier exposure to traumatic/emotionally overwhelming events, as it is by definition in PTSD. We next argue that the content of AVH relates to earlier traumatic events in a similar way in both PTSD and schizophrenia, most commonly having direct or indirect thematic links to emotionally overwhelming events, rather than being direct re-experiencing. We then propose, following cognitive models of PTSD, that the reconstructive nature of memory may be able to account for the nature of these associations between trauma and AVH content, as may threat-hypervigilance and the individual’s personal goals. We conclude that a notable subset of people diagnosed with schizophrenia with AVH are having phenomenologically and aetiologically identical experiences to PTSD patients who hear voices. As such we propose that the iron curtain between AVH in PTSD (often termed ‘dissociative AVH’) and AVH in schizophrenia (so-called ‘psychotic AVH’) needs to be torn down, as these are often the same experience. One implication of this is that these trauma-related AVH require a common trans-diagnostic treatment strategy. Whilst antipsychotics are already increasingly being used to treat AVH in PTSD, we argue for the centrality of trauma-based interventions for trauma-based AVH in both PTSD and in people diagnosed with schizophrenia.

Another recent article highlights how “interventions specifically targeting aspects of self-experience, including self-affection, self-reflection, self-schema and self-concept, may be sufficient to reduce distress and disruption in the context of hearing voices” [1].

See also:

Are some Auditory Verbal Hallucinations trauma/fear memories that are amendable via therapy & pharmacologically enhanced reconsolidation/extinction?

Clinical perspectives on the relationship between psychosis and dissociation: utility of structural dissociation and implications for practice (2015)

Trauma-related dissociation and altered states of consciousness: a call for clinical, treatment, and neuroscience research (2015)

Hallucinations: New interventions supporting people with distressing voices and/or visions

Hallucinations as a trauma-based memory: Implications for psychological interventions.

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Auditory hallucinations: A review of the ERC “VOICE” project (2015)

While often considered to be solely a symptom of schizophrenia, “recent studies have identified that about 4%-5% of the general population experience “hearing voices” when excluding previous mental health problems, medication, drug use, and other potentially confounding factors in this group of individuals”. A recent study [1] found:

“…7.3% of the sample reported a life-time prevalence of AVH. Those with AVH were more likely to be single and unemployed, reported higher levels of depression and anxiety, and experienced a higher number of severe life events compared with those without AVH. Only 16% of those who experienced AVH in the general population sought professional help for these experiences. Compared to those who did not seek professional help, participants that had were more likely to experience AVH with a negative content, experience them on a daily basis, undergo negative reactions when experiencing AVH, and resist AVH. In conclusion, the prevalence of AVH was found to be relatively high. The results also revealed higher levels of reduced mental health for individuals who sought professional help, followed by those who did not, compared with those who had never experienced AVH”

Prevalence rates of AVHs are estimated at 11.3-62.8% in patients with bipolar disorder and 5.4-40.6% in patients with major depression [2] Hearing voices due to trauma is also common and “it has been suggested on the basis of the negative emotional content of AVHs that they may represent misinterpreted recall of strong emotional and traumatic memories that would act like intrusions, and that are mislabeled as coming from the outer world.” Other models include “a failure to adequately monitor and label verbal thoughts as coming from the inside rather than from the outside of the patient’s head, often called an “inner speech” model”

A recent article goes into more detail:

Auditory hallucinations: A review of the ERC “VOICE” project (2015)

In this invited review I provide a selective overview of recent research on brain mechanisms and cognitive processes involved in auditory hallucinations. The review is focused on research carried out in the “VOICE” ERC Advanced Grant Project, funded by the European Research Council, but I also review and discuss the literature in general. Auditory hallucinations are suggested to be perceptual phenomena, with a neuronal origin in the speech perception areas in the temporal lobe. The phenomenology of auditory hallucinations is conceptualized along three domains, or dimensions; a perceptual dimension, experienced as someone speaking to the patient; a cognitive dimension, experienced as an inability to inhibit, or ignore the voices, and an emotional dimension, experienced as the “voices” having primarily a negative, or sinister, emotional tone. I will review cognitive, imaging, and neurochemistry data related to these dimensions, primarily the first two. The reviewed data are summarized in a model that sees auditory hallucinations as initiated from temporal lobe neuronal hyper-activation that draws attentional focus inward, and which is not inhibited due to frontal lobe hypo-activation. It is further suggested that this is maintained through abnormal glutamate and possibly gamma-amino-butyric-acid transmitter mediation, which could point towards new pathways for pharmacological treatment. A final section discusses new methods of acquiring quantitative data on the phenomenology and subjective experience of auditory hallucination that goes beyond standard interview questionnaires, by suggesting an iPhone/iPod app.

“AVHs are the most characteristic symptom of schizophrenia and psychosis, and they “define” the disorder from a clinical and phenomenological point of view. Clinically, what drains the patient both cognitively, emotionally, and physically is the ongoing “dialogue” and typically negative comments and commands from the “voice”, which recruits almost all available cognitive resources, and with the resulting typical signs of reality disorientation, and inward attentional focus. From a phenomenological point of view, AVHs are characterized by a limited set of core features; the experience is auditory in nature, with a distinct perceptual quality of “hearing a voice”…  The “voice” is typically localized outside of the head, although recent research has shown that hearing the “voice” as coming from the inside is more common than previously believed. The “voices” also typically have negative emotional valence, which is in addition experienced as controlling the patient, revealing a lack of executive cognitive power by the patient.”

Some interventions are mentioned:

“Failure of attention and executive control in AVH patients may also be the starting point for novel cognitive training attempts. Cognitive behavior therapy for schizophrenia and auditory hallucinations has long been directed towards giving the patient the skills necessary to voluntarily inhibit and shift attention away from the “voice”. Recent approaches to cognitive therapy have been more focused on specific training procedures, rather than inducing a therapeutic change of strategy. Thus, a distinction can be made between treatments which in the case of schizophrenia will mean abolishing symptoms, therapies inducing new strategies on how to cope with stressful situations, and training which is specifically aimed at handling a single event, or symptom. We have developed an iPod/iPhone app based on the dichotic listening paradigm, described above, as a tool to learn how to inhibit and ignore the “voice”, also to be used in social situations, like riding on a bus, or being in other social situations, which can be used “there-and-then” whenever the patient feels the urge to have help in withstanding the “voice”. Preliminary results from 15 patients show some promising effects that warrant further research on the use of app-technology for training and learning new mental skills in patients with schizophrenia.”

The neurochemistry of AVHs is ‘reviewed’:

“…We do not know what triggers an AVH at the cellular level, causing the subjective experience of perceiving a “voice” in the absence of an external stimulus

Glutamate is suggested to have an effect on positive symptoms associated with schizophrenia through balancing sub-cortical dopamine release. The classic pathway for the involvement of glutamate in schizophrenia and in the regulation of positive symptoms is that reduced cortical glutamate levels, and/or dysfunctional N-methyl-D-aspartate (NMDA) receptors, hypo-activate GABA interneurons, which leaves striatal dopamine release uninhibited, resulting in dopamine excess in the schizophrenia brain. The finding of reduced glutamate levels in schizophrenia patients would fit with a number of other studies which show that when healthy individuals are given ketamin and phencyclidin (PCP), which are drugs that act as NMDA receptor antagonists, they show signs and symptoms of a psychosis. The possible relationship between glutamate reduction and dopamine was described by Carlsson et al such that prefrontal glutamate release will result in activation of GABA interneurons to balance too high levels of glutamate, which will also have an inhibitory effect on striatal dopamine release. When glutamate levels fall below critical levels or when GABA receptors are dysfunctional, GABA interneurons will consequently be hypo-activated and dopamine release will be correspondingly uninhibited. This will result in excess dopamine, and in particular dopamine D2-receptor activity, producing positive psychotic symptoms. It should be pointed out, however, that a more recent article concluded after reviewing the schizophrenia literature, with both decreases and increases of dopamine, particularly in frontal regions”

Trauma-related dissociation and altered states of consciousness: a call for clinical, treatment, and neuroscience research (2015)

Trauma-related dissociation and altered states of consciousness: a call for clinical, treatment, and neuroscience research

The primary aim of this commentary is to describe trauma-related dissociation and altered states of consciousness in the context of a four-dimensional model that has recently been proposed (Frewen & Lanius, 2015). This model categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and are associated with trauma-related altered states of consciousness (TRASC) along four dimensions: (1) time; (2) thought; (3) body; and (4) emotion. Clinical applications and future research directions relevant to each dimension are discussed. Conceptualizing TRASC across the dimensions of time, thought, body, and emotion has transdiagnostic implications for trauma-related disorders described in both the Diagnostic Statistical Manual and the International Classifications of Diseases. The four-dimensional model provides a framework, guided by existing models of dissociation, for future research examining the phenomenological, neurobiological, and physiological underpinnings of trauma-related dissociation.

doi:10.3402/ejpt.v6.27905
A summary of the 4-D model that categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and are associated with trauma-related altered states of consciousness (TRASC) along four dimensions: (1) time; (2) thought; (3) body; and (4) emotion. The bottom pink part of the boxes indicates non-dissociative processes and normal waking consciousness, whereas the orange part of the boxes denote dissociative processes and TRASC. The first arrow (infrequency) indicates that the experience of TRASC is hypothesized to be less common than presentations of normal waking consciousness given that states of normal waking consciousness, by definition, are the most common phenomenological state of human beings. It should be noted that the four dimensions of consciousness are not mutually exclusive, but may refer to the same phenomena viewed from different perspectives (e.g., depersonalisation can manifest itself both in the dimension body and emotion). From Frewen and Lanius (2015).

“Psychological trauma may not only affect the perspective of an individual’s narrative but also the plot and the structure of the narrative. Although often able to maintain first-person perspective, trauma survivors may exhibit distinctly negative self-referential thinking, including “I am a bad person” or “I do not deserve to live”

Traumatized individuals may, however, occasionally exhibit alterations in the perspective of their narrative. These alterations can lead survivors to experience voices in the second-person perspective, for example, telling them, “you are bad” or “you deserve to die,” an experience thought to reflect a dissociative process associated with TRASC. When this occurs, the person is no longer the only storyteller of his/her lived experience but rather another or other narrative voice(s) also speak inside his/her head. These voices may present distinctly different goals, motivations, and affects, in the extreme case creating the experience of possessing multiple selves. Research in the area of voice hearing has suggested that this phenomenon is elevated significantly in individuals suffering from trauma-related disorders, including in individuals diagnosed with PTSD, dissociative disorders, and borderline personality disorders as compared to patients with other psychiatric disorders; voice hearing is also related to the experience of dissociative symptomatology and a history of early life adversity”

“From a clinical perspective on trauma-related voice hearing, it is crucial to create a shared narrative by identifying the strengths of each voice or self state in the present and by encouraging awareness and communication among different voices or self states, thereby facilitating collaboration between or among distinctly compartmentalized and contradictory goals, motivations, and affects associated with each voice or self state. The latter is also critical in fostering of self-compassion, which is sorely lacking in many survivors of chronic trauma due to ongoing conflict among different voices or self states.”

“…while remembering an event, mental time travel is “partial” in that the present self voluntarily directs attention to the past self, thus maintaining awareness of the present self in the present time. In this case, the “I” is proposed to exist in the present self, which outweighs the representation of the past self in past time. In contrast, during a reliving experience, mental time travel occurs “fully,” generally not by choice, and is usually triggered by internal and/or external stimuli that bear some resemblance to a past self-state. In this case, the “I” is thought to inhabit the past self, which is thought to outweigh the presence of the present self, thus lacking a mental time traveler and the ability to voluntarily position oneself in the past or in the future.”

“…it may be critical to strengthen the self among survivors of trauma, in order to facilitate the emergence of a mental time traveler that is able to remember rather than to relive the past. Processes relevant to this development across all four dimensions of consciousness include the encouragement of safe relationships, including the therapeutic relationship, enhancing mindful awareness of the present through mindfulness exercises, emotion regulation, distress tolerance skills, and building capacity for positive affect tolerance. Based on the theoretical assumptions reviewed here, strengthening the sense of self through the use of present-centered therapies in combination with exposure-based treatments may be crucial to successfully overcoming severe dissociative flashbacks.”

“…among individuals who suffer from the aftermath of trauma, the mind/body connection is often severed, leading to the subjective experience of feeling partially or fully detached from one’s body, or alternatively, as if one’s body does not belong to oneself.”

“It is critical for clinicians to understand the subjective experience from which the traumatized individual experiences his/her body and its relation to the surrounding world. Body-scan meditations, intended to facilitate awareness and the monitoring bodily sensations, form a central part of the mindfulness-based stress reduction program developed by Kabat-Zinn (1990) and provide an important means of assessing states of full or partial depersonalization, while at the same time enhancing the capacity for interoceptive awareness and diminishing detachment from bodily states. It is critical to note, however, that body scans must be carried out in a trauma-sensitive way in order to prevent the traumatized individual from becoming overwhelmed during this exercise”

“In the aftermath of trauma, however, it is well documented that emotion dysregulation can range from states of emotional undermodulation during which the individual experiences painful states of fear, anger, guilt, and shame to states of emotional overmodulation, during which the individual experiences emotional detachment such as states of depersonalization, derealization, emotional numbing, and affective shut-down.”

“Clinical efforts to assist individuals in overcoming emotional numbing and affective shutdown may center around assisting the traumatized individual to shift out of his/her shut-down state in order to be able to feel a full range of emotions, particularly pleasure and joy”

Future directions for research are covered:

“Future research is needed to identify more precisely the neurobiology underlying voice hearing and negative self-referential processing in trauma-related disorders as compared to that underlying voice hearing in psychotic-spectrum and other psychiatric disorders. This will be important to facilitate more accurate diagnosis, thereby guiding the most appropriate treatment interventions. Here, it will also be critical to examine how emotional triggers, for example, positive or negative self-related statements, may affect differently the presentation and underlying neurobiology of voice hearing in trauma-related disorders as compared to psychotic and other psychiatric disorders. Moreover, it will be important to examine the integrity of neural networks, such as the default mode network, which has been associated with an integrated sense of self across time , pre- and post-treatment interventions that target specifically the creation of a shared narrative between or among voices that may be associated with different self states.

From a clinical perspective, treatment outcome studies that focus specifically on interventions designed to affect voice hearing in trauma-related disorders should also be urgent foci of investigation”

See also:

Auditory Hallucinations in Chronic Trauma Disorders: Phenomenology and Psychological Mechanisms

Clinical perspectives on the relationship between psychosis and dissociation: utility of structural dissociation and implications for practice (2015)

Are some Auditory Verbal Hallucinations trauma/fear memories that are amendable via therapy & pharmacologically enhanced reconsolidation/extinction?

A pilot study exploring compassion in narratives of individuals with psychosis: implications for an attachment-based understanding of recovery

‘Hearing voices’, ‘pseudohallucinations’ and ‘lucid dreams’

Journaling as Therapy (2015)

Auditory Hallucinations May Vary Across Cultures

An interesting interview highlighting the impact of culture and different social environments on the experience of ‘voice hearing’:

Auditory Hallucinations May Vary Across Cultures

For people with schizophrenia, hearing voices can be terrifying. But that’s not necessarily true everywhere in the world. Stanford University anthropologist Tanya Luhrmann tells NPR’s Arun Rath about her research, which suggests that people with psychotic disorders hear voices differently, depending on their social and cultural environments.

“The Americans I spoke to, they felt assaulted by horrible voices that told them that they were worthless and they should die. Those voices were full of violence. In Ghana, the Africans heard an audible God who told them not to ignore those evil voices. And in Chennai, people heard annoying relatives who told them to do chores and cleanup.”

“…Americans think of their minds as a private fortress. And they have this model that when you hear an audible voice, it means that your mind is broken. And I think people find that terribly upsetting. I think they’re different social invitations in Chennai and Accra. I think that there’s a much more of a invitation to think about things supernatural, to think about the religious world, to interpret these experiences as the voice of a spirit. Particularly in Chennai, there’s this invitation to a much more social world to interpret that auditory experience as if it’s another person. Somehow, this kind of – this sense of private violation is so much more salient to the Americans than it was to people in these two other worlds.”

‘Hearing voices’, ‘pseudohallucinations’ and ‘lucid dreams’

Expanding on the post: Clinical perspectives on the relationship between psychosis and dissociation: utility of structural dissociation and implications for practice (2015)

‘Pseudohallucinations versus hallucinations: wherein lies the difference?’ [1]:

“Pseudohallucination has been variously defined in the literature as an experience similar to hallucinations but falling short in some formal characteristics. The concept has achieved greater relevance in psychiatry with the introduction of the Hearing Voices Network in Australia by Richmond Fellowship in 2005. In this program, voices are understood as part of the individual’s life experience with an emphasis on acceptance and respect. However, there does appear to be a blurring of phenomenological differentiation in hallucinosis that has significant relevance to the psychiatric profession.

The term pseudohallucinations was first used by the German psychiatrist Hagen to refer to a perceptual phenomenon that could be mistaken for a hallucination. Kadinsky built on this definition as he had experienced both hallucinations and pseudohallucinations himself. He defined pseudohallucinations as subjective stimulation of sensory areas giving rise to concrete perceptions that lacked the objectivity or the realness of the hallucinatory experience.

Jaspers, who built on Kadinsky’s work, emphasized the concept of the inner subjective space, where vivid, subjective sensory images occurred spontaneously but lacked the realness of hallucinations. Blueler viewed pseudohallucinations as perceptions with full sensory clarity, internal localization and intact reality testing.

The theme in these early writings is that pseudohallucinations could be differentiated from hallucinations in that the experience occurred in the subjective inner space and lacked the sensory realness of hallucinations.

Van der Zwaard and Polak did a comprehensive review on pseudohallucinations and found that internal localization of voices and subjective insight did not discriminate pseudohallucinations from hallucinations. They broke down the concept of pseudohallucinations into categories. Nonpsychotic hallucinations represented isolated experiences of external voices such as hearing a loved one’s voice after death. Partial hallucinations were those having reduced sensory vividness with the presence of insight. Lastly, transient hallucinations represented lack of insight as in brief reactive psychoses.”

Comparing schizophrenia with PTSD, the authors found several differences:

  • Delusions differed significantly between the groups, with schizophrenia subjects scoring significantly higher than PTSD subjects. By any measure of effect size this difference was large.
  • PTSD subjects reported more negative content than schizophrenia subjects, including verbal abuse or personal threats to self. The effect size for this difference was moderate to high.
  • The groups differed significantly in terms of their experience of abuse.

“PTSD clients appeared to experience the voices in isolation rather than as part of a complex delusional system. The voices were also more likely to be critical and negative towards the individual, consistent with the experience of abuse.”

On the contrary:

“PTSD subjects were just as likely as schizophrenic subjects to perceive voices as loud, occurring outside the head and having no control over them. There was no difference between groups in the duration and frequency of hallucinations with both groups reporting the phenomena occurring daily or hourly and lasting over time.”

To conclude:

“It is important to note that neither this study nor the literature support the traditional view of pseudohallucinations necessarily occurring in the internal subjective space or retaining insight. The experience of hearing voices could not be easily differentiated in terms of loudness, position, control, frequency or duration of voices.”

Some guidelines are provided:

“Experienced clinicians are highly sensitive to the extreme suggestibility of the dissociated individual and may appropriately minimize discussion of the experience of hallucination to avoid exacerbating the situation. Informal feedback however from individuals taking part in this study, were that their clinicians tended to avoid discussion of their experiences, and they perceived themselves as not being believed with regards to these distressing experiences. The term pseudohallucination was seen as negative and critical of their experience.

Some of the experiences of pseudohallucinations are far more persistent than transitory, as shown in the above individuals with PTSD with dissociation. The diagnosis of brief psychotic disorder does not appropriately describe the phenomenology. The term trauma-intrusive hallucinations has been recognized as occurring along a continuum with hallucinations and could be added to a dimensional system, as a symptom of PTSD associated with dissociation. It would be significantly less pejorative than pseudohallucination, which associates with being “unreal” or “not severe”

subtyping of pseudohallucinations

“…the standard of care when the disorder is more complicated, such as with complex PTSD, trauma-related borderline personality disorder, and complex dissociative disorders, is phase-oriented treatment. The treatment phases are (a) safety, stabilization, symptom reduction, and skills training; (b) treatment of traumatic memories; and (c) personality (re)integration and (re)habilitation. Their application often takes the form of a spiral, in which different phases can be alternated according to the client’s needs. Phase-oriented treatment models have developed based on consistent clinical observations that the majority of patients with complex trauma-related disorders need to develop specific skills prior to meeting the challenges of integrating traumatic memories and their personality. Empirical support is developing for this clinical standard of care.” [2]


Lucid dreams responding to a novel intervention have also reported [3].

“Lucid Dreams are a form of dream life, during which the dreamer may be aware that he/she is dreaming, can stop/re-start the dreams, depending on the pleasantness or unpleasant nature of the dream, and experiences the dream as if he/she were fully awake. Depending on their content, they may be pleasant, un-pleasant or terrifying, at least in the context of patients, who also exhibit characteristics of Reward Deficiency Syndrome (RDS) and Posttraumatic Stress Disorder (PTSD). We present eight clinical cases, with known substance abuse, childhood abuse and diagnosed PTSD/RDS. The administration of a putative dopamine agonist, KB200Z™, was associated with the elimination of unpleasant and/or terrifying, lucid dreams in 87.5% of the cases presented, whereas one very heavy cocaine abuser showed a minimal response. These results required the continuous use of this nutraceutical. The lucid dreams themselves were distinguishable from typical, PTSD nightmares insofar as their content did not appear to reflect a symbolic rendition of an originally-experienced, historical trauma. Each of the cases was diagnosed with a form of RDS, i.e., ADHD, ADD, and/or Tourette’s syndrome. They all also suffered from some form of Post-Traumatic-Stress-Disorder (PTSD) and other psychiatric diagnoses as well. The reduction or elimination of terrifying Lucid Dreams seemed to be dependent on KB220Z, whereby voluntary stopping of the agent results in reinstatement of the terrifying non-pleasant nature of the dreams. Following more required research on a much larger population we anticipate confirmation of these seemingly interesting observations. If these results in a small number of patients are indeed confirmed we may have found a frontline solution to a very perplexing and complicated symptom known as lucid dreams.”

Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia – an opportunity to target NO?

Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia: A 1H MRS study

This is a (1)H MR spectroscopy (MRS) study of glutamate (Glu), measured as Glx, levels in temporal and frontal lobe regions in patients with schizophrenia compared with a healthy control group with the objective of revealing aspects of the underlying neurochemistry of auditory hallucinations. We further compared and correlated Glu(Glx) levels for the patients-only against frequency and severity of auditory hallucinations and the sum of Positive symptoms, and also for frequency and severity of emotional withdrawal, and sum of Negative symptoms. The sample included 23 patients with an ICD-10 and DSM-IV diagnosis of schizophrenia, and 26 healthy control subjects without any known psychiatric or neurological disorders. Symptom scores were obtained from the Positive and Negative Syndrome Scale (PANSS). (1)H MRS data were acquired on a 3T MR scanner from two temporal and two frontal voxels, using standard sequences and analysis parameters. The results showed that schizophrenia patients as a group had reduced Glu(Glx) levels in the voxels of interest compared to the healthy control subjects, while increased levels were found for patients with frequent and severe auditory hallucinations, relative to patients with less frequent and severe hallucination. We further found significant positive correlations between frequency and severity of auditory hallucinations, and for sum Positive symptoms, and Glu(Glx) levels in all regions, not seen when the analysis was done for negative symptoms. It is concluded that the results show for the first time that glutamate may be a mediating factor in auditory hallucinations in schizophrenia.

“It is therefore not unreasonable to suggest that Glu levels actually may be increased in patients with frequent and severe auditory hallucinations, despite that schizophrenia patients in general have been found to show decreased Glu levels. It would similarly not be unreasonable to suggest that such a relationship between Glu and auditory hallucinations might extend to other positive symptoms, considering that the hallucination symptom is highly correlated with other positive symptoms, but not with negative symptoms.

…[results] point towards an alternative hypothesis; that glutamatergic hyper-activity is not kept in balance by corresponding increased GABA release to inhibit excessive Glu release in frontal and temporal areas, because of a specific glutamate-GABA deficit that is underlying auditory hallucinations. Thus, auditory hallucinations may be the result not only of striatal dopamine excess at D2-receptors, as the classic model predicts, but also of glutamate over-activation in cortical regions. Such a hypothesis has the advantage of being parsimonious and closer to the neuroanatomical substrates of auditory hallucinations”


Are auditory hallucinations distinct aspects of schizophrenia that require a different treatment approach?

From: Drug development in schizophrenia: are glutamatergic targets still worth aiming at?

“…efforts to enhance interneuron firing via GABAergic agents have largely been unsuccessful. [a second] approach follows from the observation of increased glutamate release following ketamine administration. Excessive glutamate concentrations may be disruptive to network synchrony and, at high concentrations, can be neurotoxic. Preliminary evidence has suggested that elevation of glutamate in hippocampus may precede gray matter loss early in the illness. Both lamotrigine and mGluR2/3 agonists reduce excessive glutamate release and each has shown promise in attenuating behavioral effects of ketamine in humans. Each produced promising results in early trials that were not replicated in subsequent multicenter trials, although a meta-analysis suggested that lamotrigine may be effective when added to clozapine. Given the evidence that excessive glutamate transmission may be present only in early stage illness, this approach also should be studied in first episode or prodromal patients.”

Targeting NO as a therapeutic intervention?

“A future direction for drug development involves targeting intracellular pathways downstream of NMDA receptors. Following NMDA-gated channel opening, calcium influx activates the calmodulin, nitric oxide synthase, and adenylate cyclase pathway, which results in generation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and phosphorylation of cAMP response element-binding protein which regulates synaptic plasticity and neurogenesis. The nitric oxide synthase pathway has been strongly linked to schizophrenia in genetic association studies and offers multiple potential targets. A recent preliminary study of the nitric oxide donor, nitroprusside, reported a marked improvement of positive and negative symptoms in acutely ill patients following a single intravenous administration. Phosphodiesterase (PDE) inhibitors may also enhance the production of cAMP and cGMP and are in development for cognitive enhancement. Results with PDE5 inhibitors in schizophrenia, which increase cGMP and improve memory in animals, have been mixed; these results are difficult to interpret in light of uncertainty about PDE5 levels in human brain. Inhibitors of PDE4 and PDE10 are currently in development for schizophrenia and several classes of PDE inhibitors have shown promise for cognitive enhancement”

Other interventions targeting NO?

Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects

agmatine NO
l-Arginine is converted to NO in the postsynaptic neuron. The NO that is produced diffuses back to the presynaptic neuron, where it enhances the release of glutamate via guanylate cyclase (GC) and cGMP. Glutamate that is released from the presynaptic terminal activates NMDA receptors, and Ca2+ enters and, via calmodulin (CaM), activates the NOS again

“Recent evidence suggests a link between NO and dopamine in psychiatric disorders like schizophrenia. Genetic studies examining a large population of schizophrenic patients revealed that polymorphisms in the neuronal NOS gene may confer increased susceptibility to schizophrenia. NO is increased in plasma of schizophrenic patients and NOS inhibitors like L-NAME or L-NNA could block several symptoms in animal models of schizophrenia like apomorphine induced climbing, PPI and amphetamine, ketamine or phencyclidine induced hyperlocomotion etc., comparable to that of conventional antipsychotics like haloperidol and clozapine. Moreover, potent antipsychotics are reported to decrease NO synthesis in brain. Subsequent studies have shown an inverse relation between NO levels and release of prolactin. In fact NOS inhibitors increase the prolactin secretion in rodents.”

glu no da
Effects of nitric oxide (NO) on dopamine (DA) transmission. (1) Glutamate (Glu) activates N-methyl-d-aspartate receptors (NMDAr) in NO neurons, opening calcium channels and leading to Ca2+ influx. (2) Increased intracellular Ca2+ activates neuronal nitric oxide synthase (nNOS), generating NO from l-arginine (L-arg). (3) Nitric oxide diffuses to the extracellular space, inhibiting the dopamine transporter (DAT), which reduces DA reuptake and increases extracellular DA. (4) Dopamine activates postsynaptic D2 receptors. (5) Nitric oxide also directly facilitates D2 activation or postsynaptic transduction mechanisms, increasing DA transmission. (6) Nitric oxide also increases Glu release, which exacerbates its effect on NO production. Apomorphine acts at postsynaptic D2 receptors, and amphetamine stimulates presynaptic DA release and decreases DA reuptake. 7-NI blocks NO synthesis, reducing the facilitatory effect of NO on DA transmission. Solid line: activation; dashed line: inhibition. [source]

“Nitric oxide (NO) can positively modulate dopaminergic neurotransmission, since it appears to block dopamine reuptake and to facilitate postsynaptic activation, and drugs that inhibit NO may have potential antipsychotic effects. 7-Nitroindazole (7-NI) and NG-nitro-l-arginine (L-NOARG) are specific and nonspecific NO synthase inhibitors, respectively, and attenuate the disruption of prepulse inhibition induced by methylphenidate and phencyclidine, proposed models of antipsychotic action. Furthermore, in reserpine-treated mice, L-NOARG and 7-NI attenuated the increase in locomotor activity induced by D1 and D2 agonists. Locomotor hyperactivity induced by dopamine agonists is another animal model for the study of antipsychotic-like action. Clinical studies found changes in NO synthase (NOS)-containing interneurons in frontal and limbic cortices in schizophrenia patients”

See:

Agmatine: α2-adrenergic receptor activation, imidazoline receptor activation, NMDA receptor blockage and NOS inhibition or NO-NMDA cascade inhibition.

See examine.com for a full overview

“Agmatine is an endogenous polyamine intermediary derived from the biosynthesis of the proteinogenic amino acid l-arginine through the enzyme arginine decarboxylase (ADC) and inactivated by agmatinase. Highly expressed in brain, especially in the hippocampus and cortex, synthesis of agmatine occurs primarily in glial astrocytes but also in microglia. Agmatine is also dietary derived, readily crossing the blood brain barrier where endogenous levels in the hippocampus can increase several folds. Synthesised or exogenously derived, astrocyte agmatine is packaged and stored in synaptic vesicles where reports suggest that it may be co-localised with glutamine for release by depolarisation into the extracellular space and uptake by neurons where glutamine is converted to glutamate.

The neuronal glutamate released is cleared from the extracellular space along with agmatine through uptake by astrocytes and microglia, where glutamate is converted back to glutamine completing the highly regulated glial and neuronal cell compartmentation of glutamate metabolism through this critical glutamine–glutamate cycling that maintains glutamatergic homeostasis. Tightly regulated itself (agmatine homeostasis), agmatine plays a key role along with d-serine in these plasticity-related processes of glutamatergic homeostasis that keeps the brain far from excitation. In delightful reciprocity, glutamatergic homeostasis contributes to the regulation of agmatine synthesis and homeostasis.

Early findings of imidazolidine binding notwithstanding, it is now recognised that agmatine’s role in brain is as an inhibitory modulator of excitatory glutamatergic neurogliotransmitter events, the putative consequence of antagonist activity of NMDA receptors and their Ca2+ ion channels, (followed by) the essential inhibition of NOS, thus inhibiting the induction of the free radical proinflammatory mediator NO and oxidative stress . Agmatine is unique to date among endogenous biogenic amines, as selectively exhibiting antagonist activity at non-glycine β sites of NMDA receptors. Astrocyte derived d-serine is a co-agonist modulator of glutamate neurotransmission as an endogenous ligand for the glycine site of NMDA receptors [see more]. These agmatine induced inhibitory effects lead to the downstream inhibitory modulation of glutamate/Ca2+ and NO expression in glial/neuronal cells of the hippocampus, as well as the essential lowering of extracellular glutamate, the combined effects of which downregulates excitatory brain activity. This, thus, is the putative molecular basis of agmatine’s central neuroprotective and anti-inflammatory action that keeps the complex biological system of brain far from excitation, neuronoglial cyotoxicity, enhanced apoptotic signalling and cell death that characterise the gamut of neuropathic brain disorders that range from Multiple Sclerosis (MS), Amyotropic Lateral Sclerosis (ALS), Huntington’s and Parkinson’s disease to Alzheimer’s and clinical depression, among others.

In addition to its inhibition of both intracellular and extracellular glutamate and Ca2+-induced cytotoxicity, there exists an ever ripening body of data to suggest that agmatine’s more critical protection against cytotoxicity is related to its inhibition of NOS, with consequent downregulation in production of proinflammatory mediators, such as NO and oxidative stress, downregulating genes associated with microglial activation, recognised as a primary cause of neurological pathogenicity in the brain, oxidative cytotoxicity induces destabilisation of astrocyte lysosomes with leakage into the cytosol, decreased mitochondrial ability/capacity and damage with the release of mitochondrial cytochrome c. More ominous, oxidative toxicity may advantageously lead to protein misfolding and neurodegeneration. It is, thus, that agmatine’s impressive neuroprotective repertoire includes the essential safeguarding of neurons by stabilising astrocytes and mitochondria, achieved through stabilisation of lysosomes, peroxisosomes and ubiquitin–proteosome function in astrocyte mitochondria. While providing such abundant layers of neuroprotection, agmatine’s central inhibitory modulation of excitatory glutamatergic transmission participates in the brain plasticity-related modulation of synaptic plasticity and the Long term Potentiation (LTP) linked processes of learning and memory-cognition.” [1]

Nitric oxide synthase inhibitors have been demonstrated to normalize PCP-induced impairments, not only in PPI, but also in higher cognitive functions such as latent inhibition. Similarly, agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition [2], blocks conditioned avoidance responses; attenuates apomorphine induced climbing and diminishes amphetamine and ketamine-induced hyperlocomotor activity [3]

“…agmatine has an important role in regulating metabolic pathways of l-arginine. It inhibits all isoforms of enzyme, NOS which synthesize NO from l-arginine. …NOS inhibition by agmatine may be the basis for ability to antagonize ketamine induced hyperlocomotor activity as well as dopamine mediated behaviors relevant to schizophrenia. Alternately besides NMDA receptors, contribution of other receptor system like imidazoline, α2-adrenergic in agmatine induced behavior can not be completely ruled out.”

“…agmatine demonstrates an interesting profile when tested in the PCP model of schizophrenia, partially blocking a deficit in pre-attentive sensory information processing. However, this study suggests that agmatine does not alter the PPI response per se in mice. Further studies of the potential role of agmatine in psychiatric disease may answer important questions regarding pathophysiology and the role of arginine metabolism in brain function. Thus, the agmatine system may be of future interest both as a novel treatment target and as a part of the pathophysiological mechanisms underlying several brain disorders.”

L-Lysine:

6g/day of L-lysine added to risperidone has shown superiority over placebo [4] Large doses can deplete intra-cellular L-arginine stores, leading to a reduction in NO [more here].

Methylene Blue:

Methylene blue, which blocks NO-dependent soluble guanylate cyclase-mediated intracellular signalling, has been shown to exert therapeutic effects as an adjuvant to established antipsychotics in the treatment for schizophrenia. [5]

Myricitrin – a nitric oxide (NO) and protein kinase C (PKC) inhibitor [6]

Sigma-1 agonism may exert NMDA/nNOS-mediated neuroprotection [7] [full text]


See also

Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia.

Sodium nitroprusside – a rapid acting antipsychotic

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

Transcranial direct current stimulation as a treatment for auditory hallucinations. (2015)

Transcranial direct current stimulation as a treatment for auditory hallucinations.

Auditory hallucinations (AH) are a symptom of several psychiatric disorders, such as schizophrenia. In a significant minority of patients, AH are resistant to antipsychotic medication. Alternative treatment options for this medication resistant group are scarce and most of them focus on coping with the hallucinations. Finding an alternative treatment that can diminish AH is of great importance. Transcranial direct current stimulation (tDCS) is a safe and non-invasive technique that is able to directly influence cortical excitability through the application of very low electric currents. A 1–2 mA direct current is applied between two surface electrodes, one serving as the anode and the other as the cathode. Cortical excitability is increased in the vicinity of the anode and reduced near the cathode. The technique, which has only a few transient side effects and is cheap and portable, is increasingly explored as a treatment for neurological and psychiatric symptoms. It has shown efficacy on symptoms of depression, bipolar disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, epilepsy, and stroke. However, the application of tDCS as a treatment for AH is relatively new. This article provides an overview of the current knowledge in this field and guidelines for future research.

See also:

DIY tDCS

Affordable tDCS units