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Psychedelic Medicine 2025: Key Insights and Challenges

Posted in Clinical topics, Neuroscience with tags , , , , , on November 10, 2025 by nvmmanager

An Inflection Point in Psychedelic Medicine

The field of psychedelic-assisted therapy stands at a critical, paradoxical juncture in 2025. The period has been defined by a profound split between regulatory adversity and accelerating clinical and scientific progress. On one hand, the therapeutic pipeline faced a seismic shock in August 2024 with the U.S. Food and Drug Administration (FDA) rejection of the New Drug Application (NDA) for MDMA-assisted therapy for post-traumatic stress disorder (PTSD). This decision, driven by fundamental concerns over trial design, functional unblinding, and data integrity, has exposed a methodological crisis for the entire field, questioning the suitability of the “gold-standard” placebo-controlled trial for powerfully psychoactive substances.

On the other hand, clinical momentum for other compounds has never been stronger. In June 2025, COMPASS Pathways announced the first-ever successful Phase 3 trial results for a classic psychedelic, with its COMP360 (psilocybin) program for treatment-resistant depression (TRD). This was preceded by the FDA granting Breakthrough Therapy Designation to MindMed’s MM120 (LSD) for generalized anxiety disorder (GAD) based on a novel “drug-only” protocol.

Simultaneously, a multi-scale neuroscientific framework has emerged, providing a powerful and unified biological rationale for the rapid and sustained therapeutic effects observed in clinics. The “Psychoplastogen” and “Reopening Critical Periods” hypotheses have moved the field from descriptive psychology to quantitative neurobiology. This report analyzes the 2024-2025 clinical landscape, deconstructs the unified mechanistic models, and provides a forward outlook on a field that has moved past its initial “renaissance” and into a more rigorous, challenging, and mechanistically-driven “second wave.”

Part I: The Clinical and Regulatory Landscape (2024-2025)

The past 18 months have been among the most consequential in the history of psychedelic medicine, characterized by a landmark regulatory failure that has reshaped trial design expectations, juxtaposed with a series of major clinical and regulatory successes for psilocybin and LSD programs.

1.1 MDMA-Assisted Therapy for PTSD: A Pivotal Regulatory Setback

The most significant event of the 2024-2025 period was the FDA’s rejection of the NDA for MDMA-assisted therapy for PTSD, a treatment developed and sponsored by Lykos Therapeutics (formerly MAPS Public Benefit Corporation).

Pivotal Phase 3 Efficacy (MAPP1 & MAPP2): The application was supported by two ostensibly successful Phase 3, randomized, double-blind, placebo-controlled trials (MAPP1 and MAPP2). The data, particularly from the confirmatory MAPP2 trial (n=104) published in Nature Medicine , demonstrated profound efficacy for participants with severe, chronic PTSD (average symptom duration > 16 years).

Key efficacy data from the MAPP2 trial showed that 71.2% of participants in the MDMA-assisted therapy group no longer met the diagnostic criteria for PTSD, compared to 47.6% in the placebo-plus-therapy group. Furthermore, 46.2% of participants in the MDMA arm achieved complete remission, more than double the 21.4% in the placebo group. The trials reported no serious adverse effects related to the drug. This data represented a potential breakthrough for a patient population with immense unmet need.

The August 2024 FDA Rejection: Despite this efficacy, the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) voted 10-1 that the treatment’s benefits did not outweigh its risks. The FDA subsequently issued a Complete Response Letter (CRL) on August 9, 2024, rejecting the application.

The CRL, made public in September 2025 , and the PDAC’s preceding deliberations detailed fundamental flaws in the trial, demanding at least one additional large-scale study. The key deficiencies included :

  1. Functional Unblinding and Expectancy Bias: This was the central methodological failure. Due to MDMA’s powerful psychoactive effects, participants and therapists were “functionally unblinded,” meaning they could easily guess whether they had received the active drug or the placebo. This invalidates the integrity of the placebo control, as the positive results could be driven by expectancy bias. The FDA noted this was compounded by selection bias, as approximately 40% of trial participants had prior illicit MDMA use, further compromising the blind.
  2. Inadequate Safety and Abuse Potential Data: The CRL cited a “failure to report positive or abuse potential adverse events”. By not systematically collecting data on favorable subjective effects like euphoria, the sponsor failed to provide the FDA with the necessary information to assess the drug’s true abuse liability. Cardiovascular risks were also a prominent concern.
  3. Data Integrity and Therapist Bias: With the therapists also unblinded, the advisory panel raised concerns about potential “misconduct and bias”. The positive expectations of the therapists, who were responsible for the crucial psychotherapy component , may have biased data collection and therapeutic outcomes.
  4. Lack of Durability Data: The trials failed to establish efficacy beyond 18 weeks, which the FDA deemed insufficient for the chronic nature of PTSD. The follow-up study was considered inadequate due to poor design and low enrollment.

This rejection has triggered an industry-wide “recalibration” , signaling that the standard double-blind, placebo-controlled trial design is likely incompatible with subjectively powerful psychoactive substances. The entire field must now innovate new trial designs to overcome the “unblinding” hurdle, a challenge that has immediate implications for all other psychedelic compounds in development.

1.2 Psilocybin for Depressive Disorders: The Emerging Front-Runner

In stark contrast to the MDMA setback, the psilocybin pipeline for depression achieved critical, positive milestones in 2024-2025.

COMPASS Pathways (COMP360) for TRD: On June 23, 2025, COMPASS Pathways announced that its first pivotal Phase 3 trial (COMP005) for synthetic psilocybin (COMP360) in Treatment-Resistant Depression (TRD) successfully met its primary endpoint. This represents the first Phase 3 efficacy data for any classic psychedelic.

The trial (n=258) demonstrated a highly statistically significant and clinically meaningful reduction in depression severity at Week 6.

  • Primary Endpoint: A single 25 mg dose of COMP360 showed a mean treatment difference of -3.6 points on the Montgomery-Åsberg Depression Rating Scale (MADRS) compared to placebo.
  • Statistical Significance: The result was highly significant, with a p-value of <0.001.
  • Safety: The Independent Data Safety Monitoring Board (DSMB) confirmed no new safety signals and found “no clinically meaningful imbalance in suicidal ideation” between the arms.

Usona Institute (uAspire) for MDD: A parallel Phase 3 program (uAspire, NCT06308653) is being conducted by the nonprofit Usona Institute for Major Depressive Disorder (MDD). This randomized, double-blind, multicenter study is actively recruiting as of late 2025. Both Usona and COMPASS hold FDA Breakthrough Therapy designations for their psilocybin programs.

Novel Analogs: The CYB003 Breakthrough: Signaling a move toward “next-generation” compounds, Cybin Inc. received FDA Breakthrough Therapy Designation in March 2024 for CYB003. This is a deuterated psilocybin analog designed for a potentially improved pharmacokinetic profile. The designation was based on Phase 2 data demonstrating unprecedented durability. After two 16 mg doses, 75% of participants achieved remission at 4 months. Follow-up data confirmed this durability, with 71% of the 16 mg group remaining in remission at 12 months.

The success of COMP360, however, creates a direct conflict with the FDA’s MDMA CRL. The COMP005 trial, like the MAPP trials, used a low-dose (1 mg) placebo, which is just as susceptible to functional unblinding. This sets the stage for a major regulatory confrontation, as the FDA must now decide whether to apply the same harsh methodological standard to a second, statistically powerful dataset.

1.3 Emerging Clinical Targets: GAD and Expanded Depression Treatment

Beyond PTSD and TRD, 2024-2025 saw significant developments in GAD and an expansion of the only approved psychedelic-like drug.

LSD (MM120) for Generalized Anxiety Disorder (GAD): In March 2024, MindMed’s MM120 (lysergide d-tartrate, or LSD) received FDA Breakthrough Therapy Designation for GAD. This was based on a highly successful Phase 2b trial (n=198), the results of which were published in September 2025.

  • Key Data: A single 100 µg dose of MM120 produced rapid and durable anxiety relief.
  • Efficacy: At 12 weeks, 65% of participants showed a clinical response, versus 30.8% for placebo.
  • Remission: A 47.5% clinical remission rate was observed at 12 weeks, versus 20% for placebo.

This trial represents a potential paradigm shift. The MM120 dose was administered without any accompanying psychotherapy. Its success provides the first robust evidence that the pharmacological agent alone may be sufficient for a durable therapeutic effect. This “drug-only” protocol offers a far more scalable and less costly model that also neatly sidesteps the “drug-plus-therapy” confounding issue that was central to the MDMA rejection.

Ketamine and Esketamine (Spravato): Expanded Approval: The field’s only FDA-approved drug, esketamine (Spravato), also saw a major label expansion. In January 2025, the FDA approved Spravato (esketamine) nasal spray as a standalone monotherapy for adults with TRD. Previously, it was only approved as an adjunct to an oral antidepressant. This decision solidifies the role of glutamatergic modulators (NMDA receptor antagonists) as a rapid-acting standard of care and sets a new commercial and clinical benchmark for the incoming psilocybin-based therapies.

Table 1: Summary of Key Late-Stage Clinical Trial Data (2024-2025)

Compound (Sponsor)IndicationTrial / PhaseKey Efficacy EndpointResult (Drug vs. Placebo)Key Regulatory Status (as of Oct 2025)
Midomafetamine (MDMA) (Lykos)PTSDMAPP2 (Phase 3)PTSD Remission (CAPS-5)46.2% vs. 21.4%NDA Rejected (Aug 2024). New Phase 3 trial requested.
Psilocybin (COMP360) (COMPASS)TRDCOMP005 (Phase 3)Change in MADRS @ 6 wks-3.6 point difference (p<0.001)Phase 3 Ongoing (COMP006 enrolling).
Psilocybin (Usona)MDDuAspire (Phase 3)Change in MADRS (NCT06308653)Data Not Yet AvailablePhase 3 Recruiting.
Deuterated Psilocybin (CYB003) (Cybin)MDD (Adjunct)Phase 2Remission (MADRS) @ 12 mos71% (16mg dose)Breakthrough Designation (Mar 2024). Phase 3 planned.
LSD (MM120) (MindMed)GADPhase 2bRemission (HAM-A) @ 12 wks47.5% vs. 20%Breakthrough Designation (Mar 2024).
Esketamine (Spravato) (J&J)TRD(Post-Market)(N/A)(N/A)Expanded Approval for Monotherapy (Jan 2025).

Part II: Mechanisms of Action: A Multi-Scale Neuroscientific Framework

The powerful clinical effects detailed in Part I are driven by a unique neurobiology that is now understood across multiple scales, from initial receptor binding to the restructuring of large-scale brain networks.

2.1 Pharmacological and Receptor-Level Mechanisms

The therapeutic cascade is initiated by distinct molecular actions that separate the major classes of psychedelic-like drugs.

Classic Psychedelics (Psilocybin, LSD): The defining action of all classic psychedelics is their function as agonists at the serotonin 5-HT2A receptor. Psilocybin itself is a prodrug, which is converted to its active metabolite, psilocin, to exert its effects. These 5-HT2A receptors are heavily expressed on layer 5 pyramidal neurons in the prefrontal cortex (PFC). Agonism at these receptors modulates pyramidal cell excitability , initiating a cascade that results in a surge of glutamate signaling.

A pivotal recent insight is the “intracellular receptor” hypothesis. Psychedelics like psilocin are lipophilic, allowing them to pass through the cell membrane. This enables them to activate a second pool of 5-HT2A receptors located inside the neuron. The brain’s endogenous serotonin, which is not lipophilic, cannot access this intracellular pool. This intracellular activation is specifically linked to the induction of neuronal growth and neuroplasticity , explaining why psychedelics produce robust plasticity while SSRIs (which only increase external serotonin) do not.

Entactogens (MDMA): MDMA is not a classic 5-HT2A agonist. Its primary mechanism is as a monoamine releasing agent. It enters the neuron via monoamine transporters (especially the serotonin transporter, SERT) and inhibits the vesicular transporter (VMAT). This action, combined with reversing the direction of the external transporters, causes a massive, acute flood of serotonin, norepinephrine, and dopamine into the synapse. This serotonergic flood, particularly via 5-HT1A receptors, then triggers the indirect release of oxytocin. This oxytocin release is the neurobiological basis for MDMA’s signature “entactogenic” or “empathogenic” effect: heightened trust, reduced fear, and enhanced emotional connection.

Dissociatives (Ketamine/Esketamine): This class works on a completely different primary system: the glutamatergic pathway. Ketamine and its S-enantiomer esketamine are non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor. This antagonism is believed to drive rapid synaptogenesis through downstream activation of AMPA receptors, a distinct path to the same plasticity-based outcome.

Table 2: Comparative Neurobiological Mechanisms

Compound ClassExamplesPrimary Molecular TargetKey Downstream Effect(s)Proposed Mechanistic Class
Classic PsychedelicPsilocybin, LSD, DMT5-HT2A Receptor AgonistGlutamate surge ; BDNF increase ; DMN disintegrationPsychedelic; Psychoplastogen
EntactogenMDMA (Midomafetamine)Monoamine Transporter ReversalMassive Serotonin/Norepinephrine release ; Indirect Oxytocin releaseEntactogen; Empathogen
DissociativeKetamine, Esketamine (Spravato)NMDA Receptor AntagonistGlutamate modulation; AMPA receptor activation; Rapid synaptogenesisDissociative; Psychoplastogen

2.2 Cellular and Network-Level Neuroplasticity

The long-term therapeutic benefits of these drugs are not believed to come from the acute drug effects, but from the persistent changes in brain structure and function that these drugs initiate.

The “Psychoplastogen” Effect: Rapid and Persistent Synaptogenesis Psychedelics and ketamine are now classified as “psychoplastogens”: small molecules that rapidly induce structural and functional neural plasticity. This is the cellular-level mechanism for long-term change.

  • Key Evidence: Preclinical in vivo imaging studies in mice have shown that a single dose of psilocybin induces a significant (~10%) increase in the density and size of dendritic spines—the physical sites of synaptic connection—in the frontal cortex.
  • Timing and Persistence: This synaptogenesis occurs rapidly (within 24 hours) and, crucially, is persistent, with these new connections remaining stable for at least one month.
  • Molecular Pathway: This structural growth is driven by the activation of specific molecular pathways, primarily the Brain-Derived Neurotrophic Factor (BDNF) signaling cascade. Psychedelic (and MDMA ) administration increases BDNF levels , which binds to its TrkB receptor, activating downstream pathways like mTOR to initiate the physical construction of new synapses.

The “Entropic Brain” Hypothesis: Acute Network Reconfiguration This is the network-level mechanism correlating with the acute subjective experience. In disorders like depression, key brain networks become rigid and over-connected. The Default Mode Network (DMN)—a network involved in self-referential thought and rumination—is often hyperactive.

  • Key Evidence: Human fMRI studies consistently show that psychedelics acutely “break” this rigidity. They cause a robust decrease in functional connectivity within the DMN (the network “disintegrates”) and a simultaneous increase in functional connectivity between the DMN and other brain networks (the brain becomes more globally integrated). This acute “entropic” state is thought to be the neural correlate of “ego-dissolution” and provides the “reset” that allows maladaptive thought patterns to be broken.

A Unifying Hypothesis: Reopening “Critical Periods” The most recent and powerful unifying theory posits that psychedelics function as “master keys” to reopen transient windows of “youthful” brain plasticity, known as “critical periods”.

  • Mechanism: In adulthood, these periods are “closed,” with neuronal circuits cemented in place by the extracellular matrix (ECM). Research shows that psychedelics tweak the activity of genes related to the ECM, effectively loosening this molecular scaffold.
  • Unifying the Models: This “Critical Period” model elegantly unifies the other two mechanisms. The acute “loosening” of the ECM is the “Entropic Brain” state (network-level disruption). This return to a “youthful” plastic state is what allows for the “Psychoplastogen” effect (rapid, new synaptogenesis). The drug loosens the circuits to open a window of plasticity, and new learning occurs to form new, stable circuits.
  • MDMA and PTSD: This model also perfectly explains MDMA’s specific utility for PTSD. Research found MDMA specifically reopens the social reward learning critical period. This allows patients, within the safety of a therapeutic context, to re-learn social trust and safety, processing traumatic memories without being overwhelmed.

Table 3: Multi-Scale Models of Psychedelic Action

Mechanistic HypothesisNeurological ScaleCore TenetKey Evidence
“Entropic Brain” / DMN DisruptionNetwork-Level (Acute)Psychedelics acutely “disintegrate” rigid brain networks, especially the Default Mode Network (DMN), and increase global connectivity.fMRI shows decreased intra-DMN connectivity and increased inter-network connectivity. Correlates with “ego-dissolution”.
“Psychoplastogen” EffectCellular-Level (Persistent)A single dose induces rapid (24h) and persistent (1+ mo) structural neuroplasticity (synaptogenesis & dendritic spine growth).In vivo microscopy in mice shows ~10% increase in dendritic spine density in PFC. Mediated by BDNF/TrkB/mTOR pathways.
“Reopening Critical Periods”Unifying Model (Developmental)Psychedelics act as “master keys” to reopen windows of “youthful” plasticity by loosening the extracellular matrix (ECM).Psychedelics (MDMA, LSD, Psilocybin) all reopen the social learning critical period in mice. Mediated by ECM gene expression changes.

2.3 Bridging the Mechanistic Gap: The Role of Subjective Experience

The central, unresolved question is how the neurobiological changes (plasticity) relate to the psychological changes (the “trip”). Current evidence strongly suggests the subjective experience is not a side effect, but is, in fact, the central mediator of therapeutic change.

Clinical data robustly correlates the quality of the acute session with long-term reductions in depression.

  • “Mystical Experience”: High scores on the Mystical Experience Questionnaire (MEQ) or the “Oceanic Boundlessness” (OBN) subscale are strong predictors of positive therapeutic outcomes. This correlation remains significant even after controlling for the simple intensity of the drug effect, indicating that the type of experience, not just its strength, is key.
  • “Emotional Breakthrough” and “Insight”: Conversely, high “Dread of Ego Dissolution” (i.e., anxiety) predicts poorer outcomes. The therapeutic experience is one that facilitates “emotional breakthrough” and provides “vivid insights into self-identity” , which serve as “narrative inflection points” for behavioral change.

This evidence reconciles the psychological and biological models. The “Critical Period” and “Psychoplastogen” effects (neurobiology) open a window of heightened plasticity and learning. The profound “Mystical Experience” or “Psychological Insight” (psychology) is the content of the lesson that is learned during that open window. The subsequent synaptogenesis is the brain physically encoding that new, healthier perspective into its structure. This is why the therapeutic framework—”set and setting” and post-session integration therapy —is critical: it guides the learning process while the brain is in this unique, plastic state.

Part III: Synthesis and Forward Outlook

The developments of 2024-2025 demonstrate that while the initial “psychedelic renaissance” hype has met a harsh regulatory reality, the underlying science is stronger than ever. The clinical momentum for psilocybin and LSD is undeniable, and the mechanistic understanding has matured from descriptive phenomenology to a concrete, multi-scale biological model. The future of the field rests on navigating three key challenges exposed by these recent developments.

Analysis: Key Challenges and Future Directions

  1. The “Unblinding” Conundrum: The field’s most urgent challenge is solving the placebo problem. The MDMA CRL has made it clear that the FDA will not approve a drug based on a trial design that is so clearly compromised by functional unblinding. Future trials must incorporate novel designs, such as high-dose vs. low-dose comparisons or the use of “active” placebos (e.g., niacin, midazolam) that mimic some side effects, to maintain a credible blind. The fate of the COMPASS Pathways’ psilocybin application, which used a similar low-dose placebo, will be the critical test case.
  2. The “Scalability” Crisis: The “drug-plus-therapy” model, as implemented in the MDMA trials, is not a viable public health solution at scale. Requiring 8-hour sessions with two dedicated therapists and an estimated cost of $12,000 per patient makes it inaccessible to the majority. This is why the success of MindMed’s “drug-only” MM120 trial for GAD is so disruptive. It suggests a scalable path forward where the drug’s power may be sufficient on its own, radically simplifying the treatment model.
  3. The “Psychoplastogen vs. Psychedelic” Debate: The most profound scientific question is whether the “trip” is truly necessary. The discovery of the intracellular 5-HT2A target and the “psychoplastogen” hypothesis have fueled a search for “non-hallucinogenic” analogs that promote plasticity without a subjective experience. If these compounds succeed, they neatly bypass both the unblinding and scalability problems. If they fail, it will provide definitive proof that the subjective, mystical experience is the indispensable ingredient for therapeutic change.

Concluding Expert Recommendations

The 2024-2025 period marks the end of the field’s optimistic “first wave” and the beginning of a more mature, and more difficult, “second wave.” The MDMA rejection was a necessary (and painful) regulatory correction that forces the field to solve its fundamental methodological flaws. The path forward requires a multi-pronged strategy:

  • For Clinicians and Sponsors: Trial designs must immediately pivot away from naive placebos and toward active-comparator or dose-ranging studies to address the unblinding crisis.
  • For Researchers: Focus must intensify on the “Critical Period” model as the unifying framework, specifically identifying the biomarkers (e.g., ECM-related proteins) that define the “open” and “closed” plastic states.
  • For Health Systems: The commercial success of esketamine monotherapy provides a clear reimbursement and clinical pathway (e.g., REMS programs ) for in-clinic psychoactive substances, creating a blueprint for psilocybin and LSD if they achieve approval.

Ultimately, the future of psychedelic medicine rests on resolving the central tension between mechanism and experience: whether durable healing is a product of pure neurobiology, or whether it requires a guided journey through the mind.

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The Unique Processing in Autistic Brains Explained

Posted in Clinical topics, Neuroscience with tags , , , on September 2, 2025 by nvm.m

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The Autistic Architecture

Autism Spectrum Disorder (ASD) is a complex condition with diverse symptoms, affecting how individuals interact with the world and process information. 

Heuristics of Autism

Normally, the brain is constantly making predictions about the world and adjusting those predictions based on new information it receives. This process is called “Bayesian inference.” In simple terms, the brain uses its “prior beliefs” (what it already expects) and new “sensory data” (what it sees, hears, touches, etc.) to figure out what’s happening.

A key concept in understanding autism from this perspective is “divisive normalization.” It is like a surge protector that balances incoming information. In a typical brain, this helps to prevent overstimulation and focuses attention. In autism, this “volume knob” might be turned down or function differently, leading to:

  • Hyper- or Hypo-reactivity to sensory input: Some autistic individuals might be overwhelmed by bright lights or loud sounds (hyper-reactivity), while others might not notice things most people would (hypo-reactivity).
  • Atypical integration of multisensory information: It’s like trying to listen to two different conversations at once – the brain struggles to combine information from different senses (sight, sound, touch) into a coherent picture.
  • Increased sensitivity to sensory noise: Imagine trying to hear someone speak in a very noisy room. For autistic individuals, the brain might have a harder time filtering out the “noise” and focusing on the important sensory “signal.”

Processing Strategies

The structural differences in the autistic brain,  contribute to the widely described characteristics of autism:

  1. Perceptual Processing: As mentioned above, this relates to how sensory information is handled. The “divisive normalization” issue means the brain might interpret sensory input differently, leading to unique ways of perceiving the world. For example, some autistic individuals might excel at tasks requiring fine detail, but struggle with integrating broader information.
  2. Social Communication and Interaction Deficits: This is a core symptom. Typical brain communication is like a symphony orchestra, with different sections playing together in harmony. In autism, some parts of the orchestra might not be playing in sync, or certain instruments might be too loud or too quiet. This “atypical functional connectivity” (how different brain areas communicate) affects social understanding.
    • “Underconnectivity” in large-scale networks: It’s like having weak internet signals between important brain regions that are supposed to work together for social interactions.
    • “Theory of Mind” (ToM) deficits: This is the ability to understand that others have their own thoughts, feelings, and perspectives. If the brain’s “social networks” are not communicating effectively, it can be harder to “read” other people.
  3. Restricted and Repetitive Behaviors (RRBs) and Interests: These behaviors, like repetitive movements or intense focus on specific topics, are also linked to brain differences. It’s like the brain getting “stuck” in certain patterns or having trouble shifting gears. This can involve issues with:
    • Inhibitory control: The brain’s ability to stop or regulate actions.
    • Frontostriatal circuits: Brain pathways involved in habits and routines.
  4. Emotion Regulation and Self-Awareness: Autistic individuals often find it challenging to recognize, express, and understand their own emotions, as well as those of others. This can make navigating social situations difficult.
  5. Cognitive Flexibility and Executive Function: This refers to the brain’s ability to adapt to new situations, switch tasks, and plan. In autism, there can be “cognitive inflexibility,” meaning difficulty with change and a preference for routines. This can be influenced by how the brain grows and develops.

Brain Development and Connectivity

Unusual brain growth trajectories in autism can disrupt how different brain regions connect and communicate. Imagine roads being built in unusual ways, leading to detours or dead ends. This “fall-off” in connectivity can lead to more localized processing rather than seamless communication across larger brain networks.

Tools for Understanding the Autistic Brain

Researchers are using advanced tools like “computational models” and “machine learning” to better understand autism. These are like sophisticated simulations that help scientists:

  • Predictive Models: Help with diagnosis and understanding how autism changes over time.
  • Identify Subgroups: Find distinct groups of autistic individuals based on their brain patterns and symptoms, which could lead to more personalized treatments.
  • Map Brain-Behavior Connections: Figure out which brain differences are linked to specific behaviors.

In essence, autism can be understood as a difference in how the brain computes and processes information, often due to imbalances in its internal “volume controls” and communication networks. This understanding, informed by genetics and brain development, opens doors for more precise diagnoses and tailored interventions for each individual on the autism spectrum.

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A moral tag on controlled substances in psychiatry

Posted in Clinical topics with tags , on February 27, 2013 by nvm.m

There are entire libraries out there filled with journal articles, monographs and pop science books discussing the controversies around the use and misuse of controlled medications in the medical profession.
Sometimes, however, short statements like the ones below may literally “speak volumes” about the subject. Behold  this “pearl”, from one anonymous child psychiatrist on Sermo:
“my colleagues are puzzled that I Rx stimulants but almost never benzodiazepines...
To me, benzodiazepines, weed, and alcohol are all substitutes for coping skills. Stimulants help compensate for deficient dopamine receptors that no amount of skills training will compensate for…”
This is a beautiful example of mainstream perception about these issues, and reminds me of a primary doctor who would never treat a fever, since it clearly denotes a lack of moral fiber, while he would always address hypothermia because none of the patient’s skills will compensate for the low body temperature.

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Psychotherapy as engineering

Posted in Clinical topics on August 21, 2011 by nvm.m

Most psychotherapies, probably due to tradition, tend to pay very little stock on the social dynamics around the individual who is receiving treatment, unless it is looking for, either an explanation for the symptomatology, or for an immediate vehicle to modify the present suffering. However, if we consider a patient as a part of a multidimensional, social and biological system, with local areas of complexity which often clash with each other in many surprising ways, we cannot limit to one layer alone. I usually see examples of unexpected conflicts in sometimes overlooked dimensions. The following is a simplified example.

Mr. P is a middle aged  male who presents complaining of “not being able to say the right things to people”. He also tends to worry too much and spend a lot of time “ruminating” about his conflicting relationships with close family members, especially his wife and children.

His past medical history is significant, with some major issues, however completely resolved. He does not seem to be physically strong, but, there is some inner energy beyond what would usually be expected. His gaze is direct and focused; he moves with speed and coordination for a man his age.

As opposed to many other patients looking for “someone to talk to”, he is not particularly verbose or circumstantial regarding his somewhat painful exchanges with his loved ones (he just describes them succintly, with precision). Anxiety is always in the background when he describes emotionally loaded segments of his life and also evident during our encounter, although mostly hidden below the surface.

His does not brag about it, but he has had access to high quality education, and has become (on his own) a financial expert.

Not surprisingly, the more success he had in the areas of engineering and finance, the more he focused he became on expanding his proficiency in those areas. As it usually happens, self esteem gradually gets to gravitate around these abilities, and interaction with other people becomes more and more centered on the corresponding areas. There is constant positive feedback from people around his proficiency as a financial whiz and a provider (for his family). This particular lifestyle has been typically analyzed from the perspective of ‘personality types’ and ‘object relations’. However, here I show that there is no need to resort to metaphysical constructs to conceptualize this.

When it comes to family interactions, there is need for open channels at many levels. All layers of communication should be equally available, and the constant nuances of both cognition and emotion* should be able to be expressed and perceived by all parties involved. This uninterrupted collective drift allows for sharing experiences and to relate to each other’s states of mind. Changes of state of each component of the system needs to be followed by the other members and, while this is taking place, all of them are internalizing (‘recording’) the trajectory (‘sequence’). Since the number of cognitive trajectories is finite, as is the length of each trajectory, then the group gets to accumulate its own particular ‘repertoire’ of trajectories which become their ‘culture’ (family culture or otherwise); that is what allows them to ‘bond’. That sort of multilayered interaction is what allows  us to consider another individual ‘a person’, and not just the bus driver, the teacher, the  mailman, etc. When the number of layers of communication is arbitrarily lowered, our perception of people as persons becomes degraded and they become just ‘the man in the toll booth’‘, ‘the waitress’, ‘the mailman’, and so forth. They become less and less human and more and more of a utilization object. In the most extreme case they become livestock (or, if you will, raw material for lye soap).

Admiration and kudos can become as addictive as any other experience. Receiving them can make someone crave for more. The object that triggers them may become the center of our life. J.L. Borges, during an interview close to the end of his life said, “there is only Literature”; Bobby Fischer, at the peak of his career as a world champion said, “Chess is life”. On the other hand, Nietzsche did not hide his contempt for a man that had gradually become “only an ear” (maybe his ex-friend Wagner?) and for the fact that the common folk did not only take this man for perfectly acceptable, but even for “a great man”. And it does not end here; there comes the fear (constant fear) of losing the treasured object (Literature, Chess, the Ear, etc); so, there are additional efforts to defend and preserve it. Hence Krishnamurti’s blunt statement, “a talent can become a man’s curse”.

Mr. P’s children (and probably other family members) got used to deal not with a man, but with (as he himself says) “a bank”. His feelings? They don’t matter, as long as he can sign his checks. Also, since “the bank” is always open, there is no need to develop their own financial skills.

Does it mean we should not uncover and cultivate our talents? Not exactly. We must develop them. We must use them constantly for altruistic purposes. And we must always remember that we do not own them (it is rather a lease).

Is there any hope for Mr. P? Yes. However, it will require some work to stop “being the bank”. He has depended on that role for too long; his self respect relies on it; without it, he is nothing. So, the task ahead is to shatter his uni-dimensional axiology and help him to rebuild a new one. The change required is deeper than what a casual look may suggest.

*  Emotion is an evolutionary sophistication “on top of the basic neural networks”, one may think, due to the fact that operationally it may be construed as a multiplication vector that is going to assign “weights” and “priorities” to the “basic computational processes”. All as a response to the problem of dealing with an unwieldy amount of information in order to improve the likelihood of survival. The funny thing is that emotion was present from the beginning (including the olfactory and the limbic system), and it was probably the appearance of further cognitive levels, with abstractions (or, as Maturana would say, ‘coordinations of coordinations of behavioral interactions’) void of direct emotional content being precisely the evolutionary novelty.

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Neurobiology and drug dinners

Posted in Clinical topics with tags , , , on November 8, 2009 by nvm.m

I have to confess that I’m currently attending drug dinners. The reason? My wife (also a physician) happens to like the food.
Even more shameful than attending them is writing about them. Why posting about one now? Sometimes you can hear about interesting problems even in prosaic events.
In this particular case the speaker brought up the old but still important issue of neuroprotection in stroke. Apparently, Lamotrigine may reduce the extension of the infarct when given shortly after the beginning of the process. I was aware of the use of Phenytoin experimentally for the same purpose in the old times (decades ago), with ambiguous results. It was found later on that there were different stages after the initial ischemic process, with a different type of intervention being useful for each stage. Phenytoin showed some limited efficacy on one of the early stages; however, at the end, the area of infarct was about the same as in controls. After a rather cursory search posterior to the drug dinner, it appeared to me that the neuroprotective power of Lamotrigine on an ischemic setting was equally controversial. In general, antiepileptic drugs have been good candidates for neuroprotective agents. It could be speculated that, since the effect of some of them (in this case Lamotrigine) is on voltage gated channels, they may help by curbing the excitotoxicity vicious cycle (NMDA receptors, calcium influx, further excitation, all of this enhanced by open potassium channels in the astroglia, which conforms a ionic syncitium when the pH is low).
It is always a pleasant surprise when, in a typically non-scientific event such a as a drug dinner, the speaker brings up, even en passant, a scientific topic.

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I like the Locum Tenens system

Posted in Clinical topics with tags , on July 4, 2008 by nvm.m

After finishing another successful assignment as a Locum doctor, I have to say that I find the system very appealing. Most of the time, the physician can choose the duration of the assignment, the clinical setting and the location, among the many offered by the companies that manage this system.

The physician turnover in hospitals all over the nation is very high; I recently read that it was 20% per year; different sources may probably disagree on the exact figure, but they will surely agree that it is above what you would usually expect. That strongly denotes a problem in the industry. Although financial incentives for physicians are good motivators to accept job offers, there is need for more to keep the new employee. What forces clinicians to leave the institutions? I speculate that it is quality of life.

For example, physicians are usually considered “exempt employees”, meaning that they have a variable daily schedule and are not required to punch time cards. This is supposed to be a privilege. The concept looks progressive because of its apparent flexibility and may probably apply very nicely to workers like programmers, writers or artists; you may come to work and leave at different times without being micromanaged, as long as you complete your projects in time and fulfill your duties. The physician, however, despite being an exempt employee, is required to be in the hospital at a specific time, usually 7:30 or 8:00 in the morning; what is really variable is the finish time, which is usually well beyond that of other employees; personally, I seldom left the hospital before 6 PM and met colleagues who would never leave before 9 PM. That obviously means that the “exempt employee” status is a sleight of hand to avoid having to pay the physician overtime.

Working hours are just one aspect of many that make current hospital jobs unattractive in the long run. But I think it is the administrators’ job to do their homework and figure it out by themselves. I don’t think it is as much a matter of insight as it is a matter of decision; I believe they know that it would be a lot cheaper to improve the permanent doctors’ conditions (and hire more of them) instead of getting a continuous flow of Locum physicians; I also believe that they somehow sense what has to be done to improve efficiency, decrease their department overhead and increase the workers’ satisfaction; it is not rocket science. What actually stops them from carrying out the necessary changes is probably fear to angry the establishment, since such changes would entail treading into the terrifying land of the unconventional. In the meantime, I believe that the Locum companies are going to keep flourishing during the following years, providing care for the areas with no permanent physicians.

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Better schizophrenia outcomes in developing countries

Posted in Clinical topics with tags , , , on April 10, 2008 by nvm.m

Schizophrenia outcome, as measured with a number of assessment instruments, has consistently been found to be better in so called third world communities [1-5]. Apparently, the course of change of a developing country into the industrial model seems to worsen the prognosis of schizophrenic patients overall [6]. The use of psychotropic medication has been ruled out as a factor [7-9].

Many explanations purported for these findings range from internal flaws of the methodology used for all the studies to a hypothetical diagnostic and treatment bias in the industrial world towards more severe cases. Actually, some articles question the initial results [10, 11]. Denial is usually an initial response when research results do not match commonly accepted opinions. It is a normal reaction.

A few workers dare to mention the cultural fabric of the patients’ community as a crucial factor [12]. In this vein, it is worth mentioning the encouraging results on a group of patients who availed themselves of a traditional resource in India [13, 14]. All this reminds me of Fritz Schumacher‘s ideas . In a highly technological society like ours, we tend to overlook the subtle cultural nuances that may work for or against us during the healing process. Maybe, in the long run, ethical and spiritual values may weigh more than the drug in fashion at the time.

References:

1. Mathews, M., B. Basil, and M. Mathews, Better outcomes for schizophrenia in non-Western countries. Psychiatr Serv, 2006. 57(1): p. 143-4.

2. Kulhara, P. and S. Chakrabarti, Culture and schizophrenia and other psychotic disorders. Psychiatr Clin North Am, 2001. 24(3): p. 449-64.

3. Jablensky, A., Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci, 2000. 250(6): p. 274-85.

4. Davidson, L. and T.H. McGlashan, The varied outcomes of schizophrenia. Can J Psychiatry, 1997. 42(1): p. 34-43.

5. Kendell, R.E., Long-term followup studies: a commentary. Schizophr Bull, 1988. 14(4): p. 663-7.

6. Douki, S., et al., [Schizophrenia and culture: reality and perspectives based on the Tunisian experience]. Encephale, 2007. 33(1): p. 21-9.

7. Kurihara, T., et al., Clinical outcome of patients with schizophrenia without maintenance treatment in a nonindustrialized society. Schizophr Bull, 2002. 28(3): p. 515-24.

8. Srinivasan, T.N., S. Rajkumar, and R. Padmavathi, Initiating care for untreated schizophrenia patients and results of one year follow-up. Int J Soc Psychiatry, 2001. 47(2): p. 73-80.

9. Srinivasa Murthy, R., et al., Community outreach for untreated schizophrenia in rural India: a follow-up study of symptoms, disability, family burden and costs. Psychol Med, 2005. 35(3): p. 341-51.

10. Cohen, A., et al., Questioning an axiom: better prognosis for schizophrenia in the developing world? Schizophr Bull, 2008. 34(2): p. 229-44.

11. Patel, V., et al., Is the outcome of schizophrenia really better in developing countries? Rev Bras Psiquiatr, 2006. 28(2): p. 149-52.

12. Luhrmann, T.M., Social defeat and the culture of chronicity: or, why schizophrenia does so well over there and so badly here. Cult Med Psychiatry, 2007. 31(2): p. 135-72.

13. Halliburton, M., The importance of a pleasant process of treatment: lessons on healing from South India. Cult Med Psychiatry, 2003. 27(2): p. 161-86.

14. Raguram, R., et al., Traditional community resources for mental health: a report of temple healing from India. Bmj, 2002. 325(7354): p. 38-40.

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Can psychologists prescribe psychotropics?

Posted in Clinical topics with tags , on April 3, 2008 by nvm.m

The pressure from psychologists to prescribe psychotropics seems to keep increasing, according to the APA. The psychiatrists’ resistance is fierce.

I don’t recall observing this sort of struggle in other specialties, e.g. between neurologists and clinical psychologists. I wonder if we are asking the wrong question above. Perhaps we should ask if psychiatrists are sophisticated enough to distance themselves from other groups who aspire to prescribe drugs.

Do we know enough about the mechanisms of action of psychotropic drugs? Do we have any solid knowledge of psychiatric pathophysiology? Sadly, the answer to these questions is no.

It’s not only a matter of increasing research funding. The average psychiatrist has already shifted his/her focus from the medical aspects of psychiatry to the more social and behavioral aspects, where he/she is guaranteed to find serious competition from other professionals who come with solid and extensive training in areas like psychotherapy, where the purely medical background has only minor relevance. On the other hand, while discussing medications in psychiatric circles, neurophysiological, molecular or computational/cognitive aspects are only casually addressed, if ever. There is already a significant rift between neuroscience and the practice of psychiatry. This fact may be a contributing factor for other health workers’ eagerness to replace psychiatrists in the prescription area.

Partially relinquishing their medical status through their cognitive choices puts psychiatrists at a feeble position to hold their ground in these matters.

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