Stephen Stahl

In collaboration with and
Thought-provoking articles by Stephen Stahl (Trends in Psychopharmacology, Essential PsychopharmaStahlogy, Second messanger) have been a popular feature on over the years.
We are happy to announce that, in collaboration with CNS Spectrums, a new series of articles by Stephen Stahl, Brainstorms, is now available free of charge to visitors to

See video interview of Stephen Stahl explaining the goals of CNS Spectrums

Available "Brainstorms"  


Psychiatric Pharmacogenomics: How to Integrate into Clinical Practice Pharmacogenomic testing can be integrated into modern mental health practices to help select psychotropic drugs for individuals who have failed first-line evidence-based treatments. PDF


Dextromethorphan-quinidine–responsive pseudobulbar affect (PBA): psychopharmacological model for wide-ranging disorders of emotional expression? The symptoms of emotional dysregulation associated with the syndrome known as pseudobulbar affect (PBA) can be effectively treated by the sigma, glutamate, and serotonergic agent dextromethorphan combined with quinidine. PDF

Parkinson’s disease psychosis as a serotonin-dopamine imbalance syndrome
Parkinson’s disease psychosis (PDP) is theoretically a serotonin-dopamine imbalance syndrome due to disruption of the normal balance between the serotonergic and dopaminergic neurotransmitter systems in key brain circuits. PDF

Mechanism of action of pimavanserin in Parkinson’s disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors
Pimavanserin, a novel agent approved for the treatment of Parkinson’s disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors. PDF

Mechanism of action of suvorexant
Suovrexant is a novel hypnotic and is the only agent clinically available that works by blocking orexin-ergic mechanisms. PDF

Mechanism of action of cariprazine
Cariprazine is a new therapeutic agent recently approved for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar disorder, and is under investigation for the treatment of both bipolar depression and major depressive disorder. PDF

Mechanism of action of brexpiprazole: comparison with aripiprazole
Brexpiprazole is a new therapeutic agent that was recently approved for the treatment of schizophrenia and for the adjunctive treatment of major depressive disorder. Brexpiprazole has features that both overlap and contrast with a related molecule, aripiprazole, and these features are discussed here. PDF


Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): actions at serotonin receptors may enhance downstream release of four pro-cognitive neurotransmitters
Vortioxetine is an antidepressant with multiple pharmacologic modes of action that enhance release of dopamine, norepinephrine, acetylcholine, and histamine. PDF

Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): modifying serotonin’s downstream effects on glutamate and GABA (gamma amino butyric acid) release PDF

Is impulsive violence an addiction? The Habit Hypothesis
Impulsive violence may be the behavioral consequence of inefficient information processing within specific neuronal networks. Analogous to the hypothetical pathophysiology of addiction, maladaptations within reward pathways may shift goal-directed behaviors to impulsive reactions and then to compulsive habits, in order to create impulsive violence. PDF

Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): blocking 5HT3 receptors enhances release of serotonin, norepinephrine, and acetylcholine
Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. 5HT3 receptor antagonism is one of these actions, and this leads to increased release of norepinephrine (NE), acetylcholine (ACh), and serotonin (5HT) within various brain circuits PDF

Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors)
Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites—or nodes—where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks. PDF

Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder
Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire. PDF


Mechanism of action of tasimelteon in non-24 sleep-wake syndrome: treatment for a circadian rhythm disorder in blind patients
Many individuals with total blindness can develop a circadian rhythm disorder—called non-24 sleep wake syndrome—because they cannot detect light to resynchronize their sleep–wake cycles. A new melatonin 1 and melatonin 2 agonist tasimelteon improves sleep in these patients, resetting their circadian sleep–wake clocks. PDF

Deconstructing violence as a medical syndrome: mapping psychotic, impulsive, and predatory subtypes to malfunctioning brain circuits
Violence is a major management issue for forensic mental health systems. Violence can be approached as a medical syndrome and deconstructed into psychotic, impulsive, and predatory subtypes, which are hypothetically mapped onto corresponding malfunctioning brain circuits. Rational management of violence balances treatment with security, while targeting each subtype of violence with approaches unique to the psychotic, impulsive, and predatory forms of violence. PDF

Clozapine: Is Now the Time for More Clinicians to Adopt This Orphan?
Although many patients with schizophrenia fail to respond adequately to trials of 2 or more antipsychotics, utilization of clozapine for these patients remains low, despite recommendations for its use by accepted treatment guidelines. Some experts estimate that 5–10 times more patients could benefit from clozapine than who are now receiving it. Learning how to manage the unique side effect profile of clozapine can potentially remove barriers to prescribing this agent and thus unlock its unique therapeutic efficacy for more patients. PDF

Mechanism of action of agomelatine: a novel antidepressant exploiting synergy between monoaminergic and melatonergic properties
A striking and unexpected pharmacologic synergy has been shown between antagonist actions at serotonergic 5HT2C receptors, and agonist actions at melatonergic receptors by agomelatine, a drug that has both of these properties. PDF

Mechanism of action of the SPARI vilazodone: serotonin 1A partial agonist and reuptake inhibitor
Vilazodone is an antidepressant with a novel mechanism of pharmacologic action: serotonin partial agonist reuptake inhibitor (SPARI) PDF

Long-acting injectable antipsychotics: shall the last be first?
A paradigm shift is afoot in which the “last shall be first,” namely, use of long-acting injectable (LAI) antipsychotics, rather than being reserved for use only at the last stages of schizophrenia, may be shifting to first-line treatment of early episodes of this illness. PDF


Role of alpha1 adrenergic antagonism in the mechanism of action of iloperidone: reducing extrapyramidal symptoms
The low incidence of extrapyramidal side effects associated with the atypical antipsychotic iloperidone may be linked to its unique binding profile of high affinity antagonism of both a1 adrenergic receptors and serotonin 2A receptors. PDF

Mechanism of action of dextromethorphan/quinidine: comparison with ketamine
Reports of rapid-onset but short-duration antidepressant effects in patients with treatment-resistant mood disorders after intravenous administration of ketamine have prompted efforts to find an agent with ketamine's properties that can be administered orally in repeated doses in order to sustain that action. One candidate for this is dextromethorphan, and here the pharmacologic mechanism of action is compared and contrasted with that of ketamine. PDF

Mechanism of action of ketamine
Ketamine induces rapid-onset and short-duration improvement in depressive and suicidal symptoms in both treatment-resistant unipolar depression and bipolar depression, and also reduces chronic pain after short intravenous infusions. In order to develop long-acting oral agents with the same clinical effects, the pharmacologic mechanism of action must be understood, and the leading hypotheses are discussed here. PDF

Classifying psychotropic drugs by mode of action and not by target disorder
Psychotropic drugs are traditionally classified by the first disorder they are proven to target (eg, as antidepressants or antipsychotics). However, these names are becoming increasingly confusing, as many drugs have multiple therapeutic actions. A more rational nomenclature categorizes psychotropic drugs by their pharmacologic mode of action. PDF

The last Diagnostic and Statistical Manual (DSM): replacing our symptom-based diagnoses with a brain circuit-based classification of mental illnesses
Current psychiatric diagnoses are defined “top-down” based upon clinical phenomenology, but may give way to defining mental illnesses “bottom-up” based upon genetic and molecular factors that regulate information processing in neuronal circuits, and that can be visualized with neuroimaging techniques. PDF

Off-label prescribing: best practice or malpractice?
Standards for the practice of medicine are increasingly being confused with standards for the sale and reimbursement of medicines. Authority for prescribing of psychotropic drugs, whether on-label or off-label, is determined by the standard of medical care set by practitioners, not by regulators of the pharmaceutical industry. PDF

“Brainstorms”, written by Dr. Stephen Stahl, has been an ongoing feature in other journals for the past 15 years, and it is now published exclusively in CNS Spectrums. Presented as an editorial commentary, “Brainstorms” provides the background of a current topic, along with a brief review, and it addresses an ongoing controversy or evolving point of view pertaining to that topic. In addition, illustrations are often included, both to set the material in its proper context and to enable readers to more clearly understand the subject matter.

CNS Spectrums aims to be the premiere journal covering all aspects of clinical neurosciences, neurotherapeutics and neuropsychopharmacology. Launched in 1996, it was relaunched in 2012 with the current editor-in-chief, Stephen M. Stahl, MD. The journal focuses on cross-disciplinary reviews, original research articles, commentaries, and opinion pieces, and it also addresses recent advances and controversial issues that are relevant to the practicing clinician. Subject coverage spans the full spectrum of neuropsychiatry, focusing on translational issues and those issues that cross the traditional boundaries between neurology and psychiatry.

For more information about CNS Spectrums, please visit its homepage.

Updated April 2017
Site conceived and produced by NeuroBiz Consulting & Communications
Copyright © Mike Briley & Chantal Moret 2017