Neurosteroids and their Therapeutic Potential: Remembering the Contribution of Dr. Sabina Luchetti, Netherlands Institute for Neuroscience, Amsterdam, Netherlands.

This article traces the career of Dr. Sabina Luchetti (1969-2021), a noted physician (medical doctor, specialized in Neurology at Tor Vergata University of Rome, Italy), a dedicated neuroscientist (Ph.D. in Neuroscience at Tor Vergata University and IRCCS Santa Lucia of Rome), and a member of a renowned Netherlands group (senior researcher at Professor Swaab Laboratory of the Netherlands Institute for Neuroscience, Amsterdam, Netherlands), working in the field of brain function and diseases. She is particularly involved in the study of natural compounds, such as neurosteroids and their biosynthetic pathways in neurodegenerative and neuroinflammation- related disorders, working on post-mortem human brains. This editorial outlines Dr. Luchetti's wide range of interests, discloses her superior fund of knowledge, and recollects her humanitarian spirit, all of which contribute to creating a great sense of belonging to any group of researchers whom she worked with. The impact of Dr. Luchetti's work will continue to be felt for many years. From the bench to the bedside, her work has indirectly contributed to shedding light on the neurosteroids' potential therapeutic effects, considering that neurosteroids and their analogues (some of which are over-the-counter) are now used to treat depression, epilepsy, and substance abuse disorders. Moreover, the potential therapeutic effects of allopregnanolone with respect to its capability to promote neuroregeneration and neuroprotection are a promising basis for future treatment of neurodegenerative diseases.

The "Hysterical Psychosis" Dilemma: A Narrative Review.

BACKGROUND: Hysteria in its most severe expression may reach psychotic manifestations. Such symptomatology has been occasionally described by various authors starting from the 19th century and defined as "hysterical psychosis" (HP) by Hollender and Hirsch in 1964. Currently, diagnostic psychiatric manuals such as DSM and ICD do not include the diagnosis of HP, although this term is commonly used in clinical practice. This raises a well-known problem with case definition due to an inconsistent use of terminology. SUMMARY: Here, we propose a review of the literature that aims to highlight the clinical features of HP endorsed by the majority of authors, such as histrionic premorbid personality, acute reactive onset, short duration, altered state of consciousness, unstable delusions, typical hallucinations, labile mood, lack of flat affect. In the discussion, we focus on the differential diagnosis between HP and other diagnoses such as brief psychosis and schizophrenia, trying to point out aspects of distinction and continuity. KEY MESSAGES: The debate about this nosographic entity still remains a huge dilemma and needs further contributions.

The Symbolism in a Case of Hysterical Psychosis.

The authors take inspiration from a case of hysterical psychosis to illustrate a typical condition of this evocative disease: the symbolic language of hysteria, conjurer of archetypical images. The authors encourage the clinician not to decode such aspects in rational analytical terms, rather to have a more wide-open approach that promotes the emergence of the individual unconscious, reconnecting with the collective imagination. This approach could help psychiatrists better understand a subject's inner experiences and interpersonal behavior.

Why Use Nutraceutical Strategies for the Irritable Bowel Syndrome?

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder, often stress-related, identified by many abdominal symptoms, the most important of which is chronic visceral abdominal pain. Therefore, IBS commonly impairs the quality of life of patients, moreover, it is frequently linked to depressive and anxiety symptoms. The treatment of IBS primarily focuses on symptoms relief. Unfortunately, up to now, no efficacious therapies have been found. Therefore, it would be important to develop new anti- IBS interventions. The aim of this brief review is to summarize the current evidence of nutraceutical supplementation in IBS treatment, with probiotics, prebiotics, synbiotics, butyrate, palmitoylethanolamide and colostrum. Since nutraceutics are over-the-counter products, the review has the purpose to better inform the medicinal chemist and the practitioner about the possible beneficial mechanisms and the many advantages that these therapies offer. All of these compounds present multiple mechanisms of action, such as restoring the physiological microbiota, potentiating gastrointestinal barrier's function, immunomodulatory, anti-inflammatory and antinociceptive activities. From the literature data, it results that these compounds are not only capable of improving IBS symptomatology, but mainly display an optimal safety and tolerability profile. Although extensive studies must be carried out to reinforce the evidence from the so far limited clinical trials, the supplementation with these compounds may be useful considering the warnings of prescription medicines for special populations of patients, such as elders, youngsters, or patients who need combination therapy. Finally, the nutraceutical approach may improve adherence to treatment, given its better acceptance by the patients compared to pharmacological therapy.

The Emergency Department's management of a severe acute psychomotor agitation: a rare case of an adult presentation of Rasmussen's Syndrome?

We report a severe acute psychomotor agitation treated in the Emergency Department. We hypothesized to be a rare case of an adult presentation of Rasmussen's Syndrome.

Diagnostic and therapeutic challenges in neuroleptic malignant syndrome: a severe medical case.

Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic medical emergency usually associated with the use of dopamine antagonists, commonly typical antipsychotic drugs. However, it has been observed that it can occur with atypical antipsychotics as well. NMS is characterized by altered consciousness, fever, rigidity, autonomic instability and high creatine phosphokinase (CPK) blood levels. Here, we report a case of a 44-year-old female patient with history of a treatment-resistant bipolar disorder. She was admitted to our psychiatric ward for severe psychomotor agitation and treated with a therapy based on typical and atypical antipsychotics. During the course of the hospitalization she developed NMS. In this case, the diagnosis was delayed due to the slow and insidious symptom presentation, therefore requiring a differential diagnosis. Autoimmune NMDA receptor encephalitis, catatonic syndrome and malignant catatonia have been excluded. The patient met all the DSM-5 criteria for NMS: exposure to dopamine-blocking agent, severe muscle rigidity, fever, diaphoresis, dysphagia, altered level of consciousness, mutism, tremors, tachycardia, high or labile blood pressure, leukocytosis, high creatine phosphokinase. Since robust evidence-based protocols are lacking, here we discuss the relevance of this case in order to highlight the hurdles of a prompt diagnosis, clinical management of associated complications and treatment possibilities for such emergency.

Vitamin D and N-Acetyl Cysteine Supplementation in Treatment-Resistant Depressive Disorder Patients: A General Review.

Major Depressive Disorder (MDD) is often a lifetime disabling mental illness as individuals with MDD might not benefit from standard-therapy, including both pharmacological and psychosocial interventions. Novel therapies are, therefore, required. It was shown by recent preclinical and clinical studies that the dysfunction of glutamatergic neurotransmission might be involved in the pathophysiology of MDD. Furthermore, neuroimmune alterations could have a significant role in the pathogenesis of MDD. Vitamin D is a neurosteroid hormone essential for several metabolic processes, immune responses, and for regulating neurotrophic-neuroprotective processes, neurotransmission and synaptic plasticity. Recent studies have also shown Vitamin D deficiency in patients with severe psychiatric disorders, including MDD. Lately, clinical studies have shown the neuroprotective action of N-acetyl cysteine (NAC) through the modulation of inflammatory pathways and via the modulation of synaptic release of glutamate in cortico-subcortical brain regions; the cysteine-glutamate antiporter. This paper reviews the therapeutic use of Vitamin D and NAC and among individuals with refractory MDD to the first- line pharmacological interventions, reviewing the clinical studies published in the last decade. A detailed summary of the current evidence in this area aims to better inform psychiatrists and general practitioners on the potential benefits of Vitamin D and NAC supplementation for this disorder. Nutraceutical supplementation with Vitamin D and NAC in treatment-resistant MDD patients may be important not only for improving depressive clinical manifestations but also for their safety and tolerability profile. This is of great interest, especially considering the need for treating special populations affected by MDD, such as youngsters and elders. Finally, the nutraceutical approach represents a good choice, considering its better compliance by the patients compared to traditional psychopharmacological treatment.

N-Acetyl Cysteine and Vitamin D Supplementation in Treatment Resistant Obsessive-compulsive Disorder Patients: A General Review.

OBJECTIVE: Obsessive-compulsive Disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. This demonstrates the need for more targeted therapeutics. Recent preclinical and clinical studies have implicated the dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. Moreover, there are studies suggesting that neuroimmune abnormalities may play an important role in the pathogenesis of OCD. N-acetyl cysteine (NAC) is a safe and readily available agent that would modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. The modulation of inflammatory pathways may also play a role in the benefits seen following NAC treatment. Therefore NAC can be considered a neuroprotective agent. METHODS: This paper explores the role of NAC in the treatment of OCD conditions refractory to first-line pharmacological interventions, reviewing the clinical studies published in the last decade. RESULTS: The possible benefit mechanisms of NAC for this disorder will be discussed, as well as the role of vitamin D supplementation, given its specific property of stimulating the formation of glutathione in the brain. CONCLUSION: Nutraceutical supplementation in treatment resistance OCD may be important not only for improving obsessive-compulsive symptomatology, but also from a psychological perspective, given its better acceptance by the patients compared to pharmacological treatment.

Neurosteroid and neurotransmitter alterations in Parkinson's disease.

Parkinson's disease (PD) is associated with a massive loss of dopaminergic cells in the substantia nigra leading to dopamine hypofunction and alteration of the basal ganglia circuitry. These neurons, are under the control, among others, of the excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. An imbalance between these systems may contribute to excitotoxicity and dopaminergic cell death. Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of several neurotransmitter systems. The substantia nigra of the human brain expresses high concentrations of allopregnanolone (3α, 5αtetrahydroprogesterone), a neurosteroid that positively modulates the action of GABA at GABAA receptors and of 5α-dihydroprogesterone, a neurosteroid acting at the genomic level. This article reviews the roles of NS acting as neuroprotectants and as GABAA receptor agonists in the physiology and pathophysiology of the basal ganglia, their impact on dopaminergic cell activity and survival, and potential therapeutic application in PD.

Neurosteroids as neuromodulators in the treatment of anxiety disorders.

Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment but have a slow onset of action. Neurosteroids are powerful allosteric modulators of GABA(A) and glutamate receptors. However, they also modulate sigma receptors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance. Moreover, novel drugs interfering with neurosteroidogenesis such as ligands of the translocator protein (18 kDa) may represent an attractive pharmacological option for novel anxiolytics which lack the unwarranted side effects of benzodiazepines. Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders.

Mirtazapine does not influence tetrahydrodeoxycorticosterone levels in depressed patients.

BACKGROUND: Among the neuroactive steroids, 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) is at least in part produced in the adrenal gland and is therefore under the control of the hypothalamic-pituitary-adrenocortical (HPA) system. The antidepressant mirtazapine has been shown to attenuate HPA axis activity and to increase the concentrations of 3alpha-reduced metabolites of progesterone in depressed patients. In the present study, the impact of mirtazapine on 3alpha,5alpha-THDOC levels was investigated in relation to clinical response in depressed patients. METHOD: A total of 23 drug-free inpatients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 08:00 h and were quantified for 3alpha,5alpha-THDOC levels. RESULTS: 3alpha,5alpha-THDOC levels were not correlated with demographic and clinical parameters such as age and severity of depression. Moreover, 5-week treatment with mirtazapine did not influence the 3alpha,5alpha-THDOC in the depressed patients, neither in responders nor in non-responders. CONCLUSION: Putative increasing effects of mirtazapine on 3alpha-reduced neuroactive steroids such as 3alpha,5alpha-THDOC which may be mediated via an impact on the neurosteroidogenic enzyme 3alpha-hydroxysteroid dehydrogenase seem to be counterbalanced by the mirtazapine-induced inhibition of ACTH secretion which directly influences the 3alpha,5alpha-THDOC release of the adrenal cortex.

Changes in CCK-4 induced panic after treatment with the GABA-reuptake inhibitor tiagabine are associated with an increase in 3alpha,5alpha-tetrahydrodeoxycorticosterone concentrations.

There is evidence that gamma-amino-butyric acid type A (GABA(A))-receptor modulating neuroactive steroids play a role in the pathophysiology of panic disorder. Antidepressant treatment has been suggested to stabilize the concentrations of neuroactive steroids. In this pilot study we investigated neuroactive steroid concentrations during GABAergic treatment, which might represent an alternative anxiolytic pharmacotherapeutic strategy. Neuroactive steroid concentrations were determined in 10 healthy subjects treated with tiagabine. To evaluate the anxiolytic effects of tiagabine a cholecystokinin-tetrapeptide (CCK-4) challenge was performed before and after treatment. Treatment with tiagabine led to a significant increase in 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) from 0.49 to 1.42 nmol/l (Z=-2.80, p=.005), which was significantly correlated with a decrease of panic symptoms in the CCK-4 challenge. Thus, it might be hypothesized that the anxiolytic effects of GABAergic treatment might in part be mediated by their influence on 3alpha,5alpha-THDOC concentrations.

Effects of combination treatment with mood stabilizers and mirtazapine on plasma concentrations of neuroactive steroids in depressed patients.

Antidepressants such as SSRIs or mirtazapine have been demonstrated to increase the concentrations of 3alpha-reduced neuroactive steroids throughout several weeks of treatment. However, no data are available on the impact of mood stabilizers such as lithium or carbamazepine on neuroactive steroid levels in depressed patients. Study 1 was performed in 26 drug-free depressed inpatients who were treated with either mirtazapine monotherapy (n=13) or combination therapy with mirtazapine and addition of lithium (n=13). Twenty drug-free depressed inpatients were included in study 2, receiving either mirtazapine monotherapy (n=10) or combination treatment with mirtazapine and carbamazepine (n=10). Plasma samples were taken weekly at 0800 h in the morning and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. In study 1, the mirtazapine-induced rises in 3alpha,5alpha-tetrahydroprogesterone and 3alpha,5beta-tetrahydroprogesterone were abolished by additional lithium administration, as compared to mirtazapine monotherapy. In study 2, the mirtazapine-evoked increase in 3alpha,5alpha-tetrahydroprogesterone was reversed after additional administration of carbamazepine, presumably due to lowered mirtazapine levels after induction of cytochrome P450 enzymes. Apparently, the mood stabilizers lithium and carbamazepine do not enhance but rather reverse the increase in plasma concentrations of 3alpha-reduced neuroactive steroids in depressed patients pretreated with antidepressants such as mirtazapine.

Comparative non-radioactive RT-PCR assay: an approach to study the neurosteroids biosynthetic pathway in humans.

Polymerase chain reaction (PCR) is a powerful tool for qualitative evaluation of nucleic acid expression. PCR has been widely applied to measure DNA and RNA messages expression. Neurosteroids synthesized in the nervous system are potent modulators of synaptic activity and have been implicated in several neuropsychiatric disorders. To examine the possibility of an altered expression of the neurosteroidogenic metabolic enzymes in neurological diseases (like Parkinson's disease, PD) we developed a comparative non-radioactive RT-PCR assay to detect the mRNA levels of the peripheral benzodiazepine receptor, the 5alpha-reductase type 1 and 3alpha-hydroxysteroid-oxidoreductase type 1 and 2 in lymphocytes obtained from PD patients. The results were compared with that obtained from simultaneous quantification of progesterone, 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone in the plasma and cerebro-spinal fluid of the same individuals using a gas chromatography mass spectrometry (GC/MS) technique. We found a significant decrease of the rate-limiting enzyme 5alpha-R1 along with a significant decrease in plasma and CSF of the 3alpha,5alpha-tetrahydroprogesterone and of the 5alpha-dihydroprogesterone. Comparative RT-PCR assay, along with complimentary techniques (i.e. GC/MS), has the sensitivity, selectivity and dynamic range to allow specific and reliable quantization of the enzymes involved in the neurosteroids pathway and represent a valuable tool to assess their expression in human neuropsychiatric conditions.

Neuropsychopharmacological properties of neuroactive steroids in depression and anxiety disorders.

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABAA) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety- and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of 3alpha-reduced neuroactive steroids have been observed during major depression. This disequilibrium can be corrected by successful treatment with antidepressant drugs. However, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition independently from the clinical response. Further research is needed to clarify whether enhancement of neuroactive steroid levels might represent a new therapeutical approach in the treatment of affective disorders. Nevertheless, the first studies investigating the therapeutical effects of exogenously administered dehydroepiandosterone revealed promising results in the treatment of major depression. In addition, in various anxiety disorders alterations of neuroactive steroid levels have been observed. In panic disorder, in the absence of panic attacks, neuroactive steroid composition is opposite to that seen in depression, which may represent counter-regulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimentally induced panic attacks, there was a pronounced decline in GABAergic neuroactive steroids, which might contribute to the pathophysiology of panic attacks. In conclusion, neuroactive steroids contribute to the pathophysiology of affective disorders and the mechanisms of action of antidepressants. They are important endogenous modulators of depression and anxiety and may provide a basis for the development of novel therapeutic agents in the treatment of affective disorders.