TAP Psychopharmacology Bulletin - New Horizons / 2026 February

Behavioral and affective symptoms are managed with antidepressants, antipsychotics, and supportive interventions such as exercise, cognitive rehabilitation, balanced nutrition, environmental modifications, and caregiver support.

Current Therapeutic Approaches

For the AH therapy, Aducanumab and lecanemab have received FDA approval and demonstrated reductions in amyloid plaque burden, and donanemab followed with FDA approval in 2024. However, the clinical benefits of these agents remain limited, and concerns regarding their safety profiles continue to be discussed. Tau- targeted therapies, including immunotherapy-based anti-tau antibodies and vaccine approaches, are currently under clinical investigation. Immunotherapy and vaccine-based approaches aim to stimulate the immune system to recognize and clear pathological tau proteins, thereby reducing tau aggregation and intercellular spread. Strategies targeting tau phosphorylation seek to inhibit the enzymes responsible for abnormal phosphorylation, preventing neurofibrillary tangle formation and neuronal damage.

Another promising direction in Alzheimer’s treatment is drug repurposing. In this context, the tyrosine kinase inhibitor nilotinib, originally developed for chronic myeloid leukemia, has been proposed to reduce amyloid plaque and hyperphosphorylated tau accumulation and to help limit hippocampal volume loss.

Advances in understanding the role of neuroinflammation in the pathogenesis of Alzheimer’s disease have stimulated interest in developing new therapeutic strategies. These strategies include TNF-α inhibitors, approaches that modulate microglial activity, and interventions targeting the gut microbiota. Additionally, neuroprotective agents such as NMDA receptor modulators, stem cell therapies, and growth factors are being investigated for their potential to preserve synaptic plasticity and limit neuronal injury.

Non-pharmacological interventions also play an important role in treatment. Neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial pulse stimulation (TPS) are currently under investigation and are often complemented by lifestyle interventions including physical activity, dietary modification, and cognitive training. Additionally, the therapeutic potential of agents such as lithium, metformin, levetiracetam, and sodium benzoate is also being investigated. Finally, to enhance targeted drug delivery, advanced delivery systems are being developed. These advances show a clear shift in Alzheimer’s treatment from symptom-focused care toward a more innovative, multidisciplinary approach that directly addresses the disease’s underlying pathology.

Conclusion

Alzheimer’s disease remains a complex and multifactorial neurodegenerative disorder for which a definitive cure has not yet been achieved. Recent advances in disease- modifying therapies targeting amyloid-β, tau, neuroinflammation, and neuroprotective mechanisms are gradually approaching broader clinical use and offer the potential to influence disease progression rather than only relieve symptoms. However, long-term data on efficacy and safety are still required. Moving forward, the integration of pharmacological, biological, and non-pharmacological strategies is expected to support more comprehensive and personalized treatment approaches, marking a promising new phase in the management of Alzheimer’s disease.

Nevertheless, the profound, life- altering, and indefinite impact of an autism diagnosis on families often drives parents to search desperately for a concrete cause or someone to blame for their child's condition. Consequently, even in the face of overwhelming and incontrovertible scientific evidence to the contrary, the scapegoating of vaccines persists at a societal level, sustained by fear, misinformation, and the human desire for a simple explanation to a complex biological condition.

Acetaminophen Use During Pregnancy

While research on the etiology of autism continues, a new review was published in September 2025 examining the relationship between acetaminophen use during pregnancy and autism. Because of methodological heterogeneity, no meta-analysis could be conducted; instead, the Navigation Guide methodology was applied. The review examined 46 publications, eight of which (six original) evaluated the acetaminophen–autism association. The results suggested a possible link, but the authors clearly emphasized that methodological limitations and biases prevent any conclusion of causality.

In this context, the factor of “confounding by indication” is particularly important. Pregnant women do not use acetaminophen randomly; it is typically taken for medical reasons such as fever, inflammation, infection, or autoimmune processes— conditions that themselves may increase the prenatal risk of autism. Therefore, assessing the acetaminophen–autism relationship in isolation can lead to misleading interpretations. Twin studies and GWAS findings indicate that 70–90% of autism risk is attributable to genetic factors.

Environmental influences shape this risk through interaction with genetic susceptibility. It is crucial to distinguish causation from correlation: the simultaneous occurrence of two variables does not prove that one causes the other. For example, both ice cream sales and shark attacks increase during the summer months, but this does not mean that ice cream consumption causes shark attacks. It is evident that science must continue to make progress in understanding the causes and treatment of autism.

Expanding prospective longitudinal studies, investigating gene–environment interactions, and developing biomarker research will strengthen the knowledge base in this field. Each claim not grounded in scientific evidence, however, risks placing additional blame on mothers of autistic children. Referring to acetaminophen—used as an antipyretic during pregnancy and long regarded as the relatively safe option— has placed yet another burden on mothers of autistic children.

Conclusion

As research on autism continues, efforts aimed at preventing stigmatization, disseminating accurate information, facilitating access to special education, and improving the quality of life of individuals with autism and their families should not be overlooked.

In this context, developing a risk- communication strategy that protects both maternal health and fetal development while also strengthening public trust should be one of the most important goals in the period ahead.

Although quetiapine did not worsen motor symptoms, its potential association with cognitive decline has contributed to a growing clinical preference for pimavanserin. It provides particular added value in patients who are motor-vulnerable, cognitively impaired, or at high risk if dopaminergic therapy is modified.

Findings regarding pimavanserin in dementia-related psychosis are more heterogeneous. In Alzheimer’s disease cohorts, efficacy appears modest and short-lived. However, the phase 3 HARMONY relapse- prevention trial, which included multiple dementia subtypes, demonstrated that continuation of pimavanserin reduced relapse risk by nearly two-thirds. Early termination of the study and the heterogeneous sample have limited the regulatory translation of these results.

As a result, pimavanserin currently lacks formal approval for dementia psychosis. Nevertheless, in settings such as Lewy body dementia—where both psychosis and parkinsonism frequently coexist. It may be considered off-label with careful risk–benefit assessment and cardiac monitoring.

A theoretical advantage of pimavanserin in schizophrenia was its potential to modulate glutamatergic/ dopaminergic pathways without D2 blockade.

The phase 2 ADVANCE study found statistically significant but clinically modest improvements in Negative Symptom Assessment-16 (NSA-16) scores.
The confirmatory phase 3 trial failed to meet its primary outcomes, leading to discontinuation of the development program.Similarly, early encouraging results from the CLARITY phase 2 trial in treatment-resistant major depressive disorder were not replicated in subsequent phase 3 studies. Consequently, industry-sponsored development of pimavanserin outside the PDP indication has been halted.

Clinical Positioning and Practical Considerations

In contemporary practice, pimavanserin is increasingly recognized as a first-line therapy in PDP, particularly favored for its motor-sparing properties. It offers an alternative to the stepwise strategy of initiating quetiapine followed by clozapine if response is inadequate.
In dementia-related psychosis, a cautious approach is warranted. If off-label use is contemplated, clinicians should ensure thorough patient and caregiver education concerning expected benefits, QTc- prolongation risk, fall potential, and treatment costs. Once symptoms stabilize, abrupt discontinuation should be avoided to reduce relapse risk.

In schizophrenia and major depressive disorder, current evidence does not support routine clinical use. In such populations, pimavanserin should be limited to experimental or compassionate-use scenarios.

Pimavanserin represents an innovative pharmacological strategy. Its well-established efficacy and motor tolerability in PDP have already strengthened its role in neuropsychiatric practice. In dementia psychosis, its potential remains promising yet inconclusive; in schizophrenia and depression, its role appears limited. Notably, pimavanserin is generally well tolerated even in older and frail patients. Future research may better define its positioning. Based on current evidence, however, its principal role is firmly established in the management of Parkinson’s disease psychosis.

Guanfacine, as a selective α2A- adrenergic receptor agonist, activates postsynaptic α2A receptors located on the dendritic spines of pyramidal glutamatergic neurons in the prefrontal cortex. This activation leads to the inhibition of the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel signaling pathway (cAMP-HCN), thereby reducing "synaptic noise" and ensuring the selective strengthening of task-relevant neural signals. As a result, working memory processes, sustained attention, and impulse control are executed more effectively. Unlike stimulant medications, guanfacine modulates dopaminergic activity indirectly, thus exhibiting a more stabilizing pharmacological profile with a lower risk of anxiety, irritability, or insomnia. Furthermore, it provides physiological composure, offering a significant advantage in cases presenting with difficulties in anger management and agitation.

Randomized controlled trials demonstrate that the drug provides significant improvements in behavioral regulation, attention span, and impulse control when used both as monotherapy and as an adjunct to stimulant treatments. In clinical practice, the addition of guanfacine can provide distinct behavioral tranquility and emotional stability in cases that show a partial response to stimulants or where treatment is limited by side effects. Sedation is generally mild and may be considered a compliance-enhancing feature in most cases. Cardiovascular side effects are rare when dose titration is performed carefully. In these respects, guanfacine stands out as a frequently preferred agent in clinical practice for child and adolescent cases targeting behavioral stability, serving as either a complementary or alternative option to stimulant therapy.

It contributes to the preservation of neuronal network integrity by supporting intercellular communication and interaction.
Furthermore, it undertakes critical functions in the development and plasticity of the central nervous system by participating in neuronal survival, neurite outgrowth, and synaptogenesis processes.
In cells undergoing apoptosis, PS is translocated to the outer surface of the cell membrane, functioning as an "eat me" signal recognized by macrophages, ensuring that phagocytosis occurs effectively. In addition to contributing to the neuronal message transmission capacity in brain cells, it provides a protective effect against oxidative stress by exhibiting antioxidant properties at the cellular level.

Dosage and Administration

It can be administered in divided doses, morning and evening. The ideal dose is 150–200 mg/day, and it is recommended to be taken with food to facilitate absorption.
The FDA has validated that a daily dose of 300 mg is safe for use for up to 6 months. It has been stated that Phosphatidylserine is proven safe in sensitive groups and healthy children. In adults, the daily dose may be increased up to 400 mg.
Orally administered (PS) has high bioavailability in humans. Following absorption, it can easily cross the blood-brain barrier to access the central nervous system.

A meta-analysis published in 2022 evaluated the effect of phosphatidylserine (PS) supplementation on cognitive functions in elderly individuals.
Participants were administered 100– 300 mg of PS daily for periods ranging from 6 weeks to 6 months, and significant improvements were observed, particularly in the domain of short-term memory. It was reported that PS slowed cognitive decline and enhanced cognitive performance in individuals with mild cognitive impairment. In a study conducted on Major Depressive Disorder, the group receiving citicoline showed higher remission rates and a more rapid and significant reduction in Hamilton Depression Rating Scale scores compared to the placebo group. In a group of healthy adolescents aged 13–19 years, citicoline supplementation administered at doses of 250 mg and 500 mg for 28 days resulted in significant improvements in attention tests and motor speed. In another study involving healthy adults, participants were given a caffeine-based beverage containing 250 mg of citicoline. Continuous Performance Test results showed faster reaction times and better visuospatial processing in the citicoline-caffeine group. EEG analyses observed significant increases in P450 waves related to working memory and attention. These findings suggest that citicoline may positively affect cognitive functions. Both compounds possess pharmacological neuroprotective potential and stand out with a safe usage profile in children and adolescents.

Recent systematic reviews suggest that blinding integrity is rarely assessed in psychiatric RCTs. An important distinction in unblinding is between benign unblinding (blinding is broken because the treatment effect is genuinely strong) and malicious unblinding (blinding is broken due to side effects or treatment-specific cues).
Whereas benign unblinding may not threaten trial validity, malicious unblinding can introduce substantial bias in estimates of efficacy and tolerability. To make this distinction, it is necessary to evaluate whether blinding failed and, crucially, why it failed.

Critiques of Assessing Blinding Integrity

Determining blinding integrity in psychiatric RCTs is methodologically and ethically debated. The concept of equipoise refers to a genuine uncertainty on the part of the researcher that either treatment arm could be equally beneficial. However, asking participants or assessors to guess treatment allocation may undermine this balance; side effects or perceived efficacy can amplify expectancy responses and observer bias. When the rationale behind guesses is not elicited, it becomes difficult to understand why blinding was compromised. Moreover, testing blinding only at the end of the study may miss changes occurring during the trial.
In summary, the very methods used to assess blinding can themselves contribute to the erosion of blinding.

In psychiatric RCTs, assessment of blinding integrity is frequently neglected. Reported rates of blinding assessment range from approximately 1% to 7%. When blinding is tested, unblinding is often observed in active-treatment arms, whereas blinding tends to be better preserved in placebo arms.
Assessing blinding integrity is not merely a methodological detail; it is critical for the validity and reliability of trial findings. At the same time, the process of assessing blinding poses its own challenges: equipoise may be disrupted, and the clinical meaning of certain blinding metrics is not always clear.

He played a foundational role in shaping modern diagnostic frameworks, contributing to both the revision processes for DSM 5 and ICD 11 work-groups on obsessive-compulsive and related disorders.
His publication record is prodigious: hundreds of peer-reviewed papers, dozens of edited volumes (among them the influential book Problems of Living: Perspectives from Philosophy, Psychiatry, and Cognitive Affective Science), and mentoring that has shaped a new generation of global mental-health scientists.

Stein’s work earned him top honors: including the Max Hamilton Memorial Award for contributions to psychopharmacology, the MRC “Platinum Award,” and the World Federation of Societies of Biological Psychiatry Lifetime Achievement Award. Because he bridged neurobiology, clinical care and philosophy; his passing is a profound loss. But his legacy lives on: in his writings, in the many students and colleagues he inspired, and in the lives of countless patients helped by his work.