What is Neuropsychopharmacology?

Introduction

Neuropsychopharmacology, an interdisciplinary science related to psychopharmacology (study of effects of drugs on the mind) and fundamental neuroscience, is the study of the neural mechanisms that drugs act upon to influence behaviour.

It entails research of mechanisms of neuropathology, pharmacodynamics (drug action), psychiatric illness, and states of consciousness. These studies are instigated at the detailed level involving neurotransmission/receptor activity, bio-chemical processes, and neural circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of “how” and “why”, and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic (non-psychoactive) pharmacology-based treatments. Developments in neuropsychopharmacology may directly impact the studies of anxiety disorders, affective disorders, psychotic disorders, degenerative disorders, eating behaviour, and sleep behaviour.

Brief History

Drugs such as opium, alcohol, and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era knowledge of how the substances actually worked was quite limited, most pharmacological knowledge being more a series of observation than a coherent model. The first half of the 20th century saw psychology and psychiatry as largely phenomenological, in that behaviours or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the behavioural branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as “software” errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields – until several developments after World War II began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as MAO inhibitors, tricyclic antidepressants, thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which could directly affect brain circuitry and neurotransmitter levels were the prefrontal lobotomy, and electroconvulsive therapy, the latter of which was conducted without muscle relaxants and both of which often caused the patient great physical and psychological injury.

The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the Hungarian College of Neuropsychopharmacology. This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.

Overview

An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a neurochemical basis at the fundamental level, and certain circuit pathways in the central nervous system at a higher level. Thus the understanding of nerve cells or neurons in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern clinical and research methods such as genetic manipulation in animal subjects, imaging techniques such as functional magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10-10 M such as found with extrastriatal D1 receptor for dopamine.

One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuropathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop drugs which act on very specific receptors within a neurotransmitter system. These “hyperselective-action” drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximising the efficacy (or technically the potency) of the drug within the clinical target and minimising adverse effects. However, there are some cases when some degree of pharmacological promiscuity is tolerable and even desirable, producing more desirable results than a more selective agent would. An example of this is Vortioxetine, a drug which is not particularly selective as a serotonin reuptake inhibitor, having a significant degree of serotonin modulatory activity, but which has demonstrated reduced discontinuation symptoms (and reduced likelihood of relapse) and greatly reduced incidence of sexual dysfunction, without loss in antidepressant efficacy.

The groundwork is currently being paved for the next generation of pharmacological treatments, which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new neurons – the study of which, in addition to neurotrophic factors, may hold hope for neurodegenerative diseases like Alzheimer’s, Parkinson’s, ALS, and types of chorea. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week.

Neurotransmission

So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the action potential may affect the firing of as many as a thousand other neurons in a process called neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an EEG device.

By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. These features are:

  • The synthesis and storage of neurotransmitter substances;
  • The transport of synaptic vesicles and subsequent release into the synapse;
  • Receptor activation and cascade function; and
  • Transport mechanisms (reuptake) and/or enzyme degradation.

The more recent advances involve understanding at the organic molecular level; biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterisation of a large number of very specific subtypes of receptors. For the six more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at neurotransmitter) there are at least 29 major subtypes of receptor. Further “sub-subtypes” exist together with variants, totalling in the hundreds for just these 6 transmitters (refer to serotonin receptor, for example). It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.

It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the transmembrane ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of lesser importance Mg++ and Cl. The concentration differences between the inside and outside of the cell determine the membrane voltage.

Precisely how these currents are controlled has become much clearer with the advances in receptor structure and G-protein coupled processes. Many receptors are found to be pentameric clusters of five transmembrane proteins (not necessarily the same) or receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.

The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying gene transcription. The synthesis of cellular proteins from nuclear DNA has the same fundamental machinery for all cells; the exploration of which now has a firm basis thanks to the Human Genome Project which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level. Gene expression determines protein structures through type II RNA polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity.

Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.

Drugs

The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. “dirty drug”) and safe to consume. The 2005 Physicians’ Desk Reference lists twice the number of prescription drugs as the 1990 version. Many people by now are familiar with “selective serotonin reuptake inhibitors“, or SSRIs which exemplify modern pharmaceuticals. These SSRI antidepressant drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The FDA has approved drugs which selectively act on each of the major neurotransmitters such as NE reuptake inhibitor antidepressants, DA blocker anti-psychotics, and GABA agonist tranquilisers (benzodiazepines).

New endogenous chemicals are continually identified. Specific receptors have been found for the drugs THC (cannabis) and GHB, with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of narcolepsy. Orexin agonism may explain the antinarcoleptic action of the drug modafinil which was already being used only a year prior.

The next step, which major pharmaceutical companies are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1 antagonists, and 5HT2c antagonists. Another is the proposal of new routes of exploration for antipsychotics such as glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.

Modern studies are revealing details of mechanisms of damage to the nervous system such as apoptosis (programmed cell death) and free-radical disruption. Phencyclidine has been found to cause cell death in striatopallidal cells and abnormal vacuolisation in hippocampal and other neurons. The hallucinogen persisting perception disorder (HPPD), also known as post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an excitotoxic response of 5HT2 interneurons (Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself). As for MDMA, aside from persistent losses of 5HT and SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function.

Neural Circuits

It is a not-so-recent discovery that many functions of the brain are somewhat localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioural, and genetic correlates of receptor action, completing the knowledge of neural signalling (refer to Human Cognome Project). The signal paths of neurons are hyperorganised beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts.

Almost all drugs with a known potential for abuse have been found to modulate activity (directly or indirectly) in the mesolimbic dopamine system, which includes and connects the ventral tegmental area in the midbrain to the hippocampus, medial prefrontal cortex, and amygdala in the forebrain; as well as the nucleus accumbens in the ventral striatum of the basal ganglia. In particular, the nucleus accumbens (NAc) plays an important role in integrating experiential memory from the hippocampus, emotion from the amygdala, and contextual information from the PFC to help associate particular stimuli or behaviours with feelings of pleasure and reward; continuous activation of this reward indicator system by an addictive drug can also cause previously neutral stimuli to be encoded as cues that the brain is about to receive a reward. This happens via the selective release of dopamine, a neurotransmitter responsible for feelings of euphoria and pleasure. The use of dopaminergic drugs alters the amount of dopamine released throughout the mesolimbic system, and regular or excessive use of the drug can result in a long-term downregulation of dopamine signalling, even after an individual stops ingesting the drug. This can lead the individual to engage in mild to extreme drug-seeking behaviours as the brain begins to regularly expect the increased presence of dopamine and the accompanying feelings of euphoria, but how problematic this is depends highly on the drug and the situation.

Significant progress has been made on central mechanisms of certain hallucinogenic drugs. It is at this point known with relative certainty that the primary shared effects of a broad pharmacological group of hallucinogens, sometimes called the “classical psychedelics”, can be attributed largely to agonism of serotonin receptors. The 5HT2A receptor, which seems to be the most critical receptor for psychedelic activity, and the 5HT2C receptor, which is a significant target of most psychedelics but which has no clear role in hallucinogenesis, are involved by releasing glutamate in the frontal cortex, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. 5HT2A activity has a net pro-dopaminergic effect, whereas 5HT2C receptor agonism has an inhibitory effect on dopaminergic activity, particularly in the prefrontal cortex. One hypothesis suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory postsynaptic potentials, a process antagonised by serotonin itself through 5HT1 receptors, which may explain why SSRIs and other serotonin-affecting drugs do not normally cause a patient to hallucinate. However, the fact that many classical psychedelics do in fact have significant affinity for 5HT1 receptors throws this claim into question. The head twitch response, a test used for assessing classical psychedelic activity in rodents, is produced by serotonin itself only in the presence of beta-Arrestins, but is triggered by classical psychedelics independent of beta-Arrestin recruitment. This may better explain the difference between the pharmacology of serotonergic neurotransmission (even if promoted by drugs such as SSRIs) and that of classical psychedelics. Newer findings, however, indicate that binding to the 5HT2A-mGlu2 heterodimer is also necessary for classical psychedelic activity. This, too, may be relevant to the pharmacological differences between the two. While early in the history of psychedelic drug research it was assumed that these hallucinations were comparable to those produced by psychosis and thus that classical psychedelics could serve as a model of psychosis, it is important to note that modern neuropsychopharmacological knowledge of psychosis has progressed significantly since then, and we now know that psychosis shows little similarity to the effects of classical psychedelics in mechanism, reported experience or most other respects aside from the surface similarity of “hallucination”.

Circadian rhythm, or sleep/wake cycling, is centred in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with melanopsin cells in the eye which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABAergic neurons from the SCN inhibit the paraventricular nucleus, which signals the superior cervical ganglion (SCG) through sympathetic fibres. The output of the SCG, stimulates NE receptors (β) in the pineal gland which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback pathway. Therefore, light inhibits the production of melatonin which “entrains” the 24-hour cycle of SCN activity. The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things.

Research

Research in the field of neuropsychopharmacology encompasses a wide range of objectives. These might include the study of a new chemical compound for potentially beneficial cognitive or behavioural effects, or the study of an old chemical compound in order to better understand its mechanism of action at the cell and neural circuit levels. For example, the addictive stimulant drug cocaine has long been known to act upon the reward system in the brain, increasing dopamine and norepinephrine levels and inducing euphoria for a short time. More recently published studies however have gone deeper than the circuit level and found that a particular G-protein coupled receptor complex called A2AR-D2R-Sigma1R is formed in the NAc following cocaine usage; this complex reduces D2R signalling in the mesolimbic pathway and may be a contributing factor to cocaine addiction. Other cutting-edge studies have focused on genetics to identify specific biomarkers that may predict an individual’s specific reactions or degree of response to a drug or their tendency to develop addictions in the future. These findings are important because they provide detailed insight into the neural circuitry involved in drug use and help refine old as well as develop new treatment methods for disorders or addictions. Different treatment-related studies are investigating the potential role of peptide nucleic acids in treating Parkinson’s disease and schizophrenia while still others are attempting to establish previously unknown neural correlates underlying certain phenomena.

Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the American College of Neuropsychopharmacology (ACNP), the European College of Neuropsychopharmacology (ECNP), and the Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus. The ECNP publishes European Neuropsychopharmacology, and as part of the Reed Elsevier Group, the ACNP publishes the journal Neuropsychopharmacology, and the CINP publishes the journal International Journal of Neuropsychopharmacology with Cambridge University Press. In 2002, a recent comprehensive collected work of the ACNP, “Neuropsychopharmacology: The Fifth Generation of Progress” was compiled. It is one measure of the state of knowledge in 2002, and might be said to represent a landmark in the century-long goal to establish the basic neurobiological principles which govern the actions of the brain.

Many other journals exist which contain relevant information such as Neuroscience. Some of them are listed at Brown University Library.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Neuropsychopharmacology >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is a Dosage Form?

Introduction

Dosage forms (also called unit doses) are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration (such as a capsule shell, for example), and apportioned into a particular dose. For example, two products may both be amoxicillin, but one is in 500 mg capsules and another is in 250 mg chewable tablets.

The term unit dose can also sometimes encompass non-reusable packaging as well (especially when each drug product is individually packaged), although the US Food and Drug Administration (FDA) distinguishes that by unit-dose “packaging” or “dispensing”. Depending on the context, multi(ple) unit dose can refer to distinct drug products packaged together, or to a single drug product containing multiple drugs and/or doses. The term dosage form can also sometimes refer only to the pharmaceutical formulation of a drug product’s constituent drug substance(s) and any blends involved, without considering matters beyond that (like how it is ultimately configured as a consumable product such as a capsule, patch, etc.). Because of the somewhat vague boundaries and unclear overlap of these terms and certain variants and qualifiers within the pharmaceutical industry, caution is often advisable when conversing with someone who may be unfamiliar with another person’s use of the term.

Depending on the method/route of administration, dosage forms come in several types. These include many kinds of liquid, solid, and semisolid dosage forms. Common dosage forms include pill, tablet, or capsule, drink or syrup, among many others. In naturopathy, dosages can take the form of decoctions and herbal teas, as well as the more conventional methods previously mentioned. A liquid dosage form is the liquid form of a dose of a chemical compound used as a drug or medication intended for administration or consumption.

The route of administration (ROA) for drug delivery is dependent on the dosage form of the substance in question. Various dosage forms may exist for a single particular drug, since some medical conditions such as being unconscious can restrict ROA. For example, persistent nausea, especially with vomiting, may make it difficult to use an oral dosage form, and in such a case, it may be necessary to use an alternative route such as inhalational, buccal, sublingual, nasal, suppository or parenteral instead. Additionally, a specific dosage form may be a requirement for certain kinds of drugs, as there may be issues with various factors like chemical stability or pharmacokinetics. As an example, insulin cannot be given orally because upon being administered in this manner, it is extensively metabolized in the gastrointestinal tract (GIT) before reaching the blood stream, and is thereby incapable of sufficiently reaching its therapeutic target destinations. The oral and intravenous doses of a drug such as paracetamol will differ for the same reason.

Oral

  • Pills, i.e. tablets or capsules.
  • Liquids such as syrups, solutions, elixers, emulsions, and tinctures.
  • Liquids such as decoctions and herbal teas.
  • Orally disintegrating tablets.
  • Lozenges or candy (electuaries).
  • Thin films (e.g. Listerine Pocketpaks, nitroglycerin) to be placed on top of or underneath the tongue as well as against the cheek.
  • Powders or effervescent powder or tablets, often instructed to be mixed into a food item.
  • Plants or seeds prepared in various ways such as a cannabis edible.
  • Pastes such as high fluoride toothpastes.
  • Gases such as oxygen (can also be delivered through the nose).

Ophthalmic

  • Eye drops.
  • Lotions.
  • Ointments.
  • Emulsions.

Inhalation

  • Aerosolised medication.
  • Dry-powder Inhalers or metered dose inhalers.
  • Nebuliser-administered medication.
  • Smoking.
  • Vaporiser-administered medication.

Unintended Ingredients

Talc is an excipient often used in pharmaceutical tablets that may end up being crushed to a powder against medical advice or for recreational use. Also, illicit drugs that occur as white powder in their pure form are often cut with cheap talc. Natural talc is cheap but contains asbestos while asbestos-free talc is more expensive. Inhaled talc that has asbestos is generally accepted as being able to cause lung cancer if it is inhaled. The evidence about asbestos-free talc is less clear, according to the American Cancer Society.

Injection

  • Parenteral.
  • Intradermally-administered (ID).
  • Subcutaneously-administered (SC).
  • Intramuscularly-administered (IM).
  • Intraosseous administration (IO).
  • Intraperitoneally-administered (IP).
  • intravenously-administered (IV).
  • Intracavernously-administered (ICI).

These are usually solutions and suspensions.

Unintended Ingredients

Safe

Eye drops (normal saline in disposable packages) are distributed to syringe users by needle exchange programs.

Unsafe

The injection of talc from crushed pills has been associated with pulmonary talcosis in intravenous drug users.

Topical

  • Creams, liniments, balms (such as lip balm or antiperspirants and deodorants), lotions, or ointments, etc.
  • Gels and hydrogels.
  • Ear drops.
  • Transdermal and dermal patches to be applied to the skin.
  • Powders.

Unintended Use

  • It is not safe to calculate divided doses by cutting and weighing medical skin patches, because there’s no guarantee that the substance is evenly distributed on the patch surface. For example, fentanyl transdermal patches are designed to slowly release the substance over 3 days. It is well known that cut fentanyl transdermal consumed orally have cause overdoses and deaths.
  • Single blotting papers for illicit drugs injected from solvents in syringes may also cause uneven distribution across the surface.

Other

  • Intravaginal administration:
    • Vaginal rings.
    • Capsules and tablets.
    • Suppositories.
  • Rectal administration (enteral):
    • Suppositories.
    • Suspensions and solutions in the form of enemas.
    • Gels.
  • Urethral.
  • Nasal sprays.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dosage_form >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is the Inverse Benefit Law?

Introduction

The inverse benefit law states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively a drug is marketed. Two Americans, Howard Brody and Donald Light, have defined the inverse benefit law, inspired by Tudor Hart’s inverse care law.

A drug effective for a serious disorder is less and less effective as it is promoted for milder cases and for other conditions for which the drug was not approved. Although effectiveness becomes more diluted, the risks of harmful side effects persist, and thus the benefit-harm ratio worsens as a drug is marketed more widely. The inverse benefit law highlights the need for comparative effectiveness research and other reforms to improve evidence-based prescribing.

State of Affairs

The law is manifested through 6 basic marketing strategies:

  • Reducing thresholds for diagnosing disease;
  • Relying on surrogate endpoints;
  • Exaggerating safety claims;
  • Exaggerating efficacy claims;
  • Creating new diseases; and
  • Encouraging unapproved uses.

Impact

This is the reason why organisations like “Worst Pill, Best Pill” recommend not to use/prescribe new medications before being in the market for at least ten years (except in the case of important new drugs that treat previously unsolved problems).

Agencies of drugs, committee of ethics and organisations of patients’ safety should consider:

  • Requiring that clinical trials run long enough to pick up evidence of side effects and record all adverse reactions, including in subjects who drop out.
  • Paying companies more for new drugs in proportion to how much better they are for patients than existing drugs, and marketing according to the value of the new drugs (ratio of benefits to harms and marketing).
  • Considering that market could be a force against the best use of medications.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Inverse_benefit_law >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

Can Lorazepam be Considered to be a Clinically Effective Means of Treating the Acutely Agitated Patient?

Research Paper Title

Treatment of Agitation With Lorazepam in Clinical Practice: A Systematic Review.

Background

Acute agitation is a frequent occurrence in both inpatient and outpatient psychiatric settings, and the use of medication to calm a patient may be warranted to mitigate the situation. Lorazepam is a benzodiazepine that is widely used for management of acute agitation. Despite its widespread use, there is remarkably little clinical evidence for the benefits of lorazepam in acute agitation.

Methods

The researchers performed a systematic review with focus on lorazepam, including all randomised clinical trials on lorazepam in mental and behavioural disorders, excluding studies on dementia and paediatric patients and in mixed conditions.

Results

A total of 11 studies met inclusion criteria, and all were in patients with mental and behavioural disorders. Most trials generally found improvements across a variety of outcomes related to agitation, although there was some disparity if specific outcomes were considered.

In the five studies with haloperidol, the combination of lorazepam and haloperidol was superior to either agent alone, but with no differences between monotherapy with the individual agents.

Conclusions

In the study comparing lorazepam to olanzapine, olanzapine was superior to lorazepam, and both were superior to placebo.

As expected, the safety of lorazepam among the different studies was consistent with its well-characterised profile with dizziness, sedation, and somnolence being the most common adverse events.

Based on this structured review, lorazepam can be considered to be a clinically effective means of treating the acutely agitated patient.

Reference

Amore, M., D’Andrea, M. & Fagiolini, F. (2021) Treatment of Agitation With Lorazepam in Clinical Practice: A Systematic Review.

Book: A Straight-talking Introduction to Children’s Mental Health Problems

Book Title:

A Straight-talking Introduction to Children’s Mental Health Problems (Straight Talking Introductions).

Author(s): Sami Timimi (Author), Richard Bentall (Editor), and Pete Sanders (Editor).

Year: 2009.

Edition: First (1st).

Publisher: PCCS Books.

Type(s): Paperback and Kindle.

Synopsis:

Rates of diagnosis of psychiatric disorders such as ADHD, and the subsequent prescription of psychiatric drugs in children, have increased alarmingly over recent years. Yet diagnoses are supported by very little scientific evidence and the effectiveness and safety of drugs for children is highly questionable. Unlike medications, psychotherapeutic or ‘talking therapies’ with children, adolescents and their families have established themselves as both safe and effective. Here, Sami Timimi arms you with some of the information you’ll need to make informed choices about a child’s diagnosis and treatment. He provides an honest account of the dangers of medicating children or adolescents and discusses alternative therapies. He also describes practical advice on things parents can try themselves, common pitfalls to avoid, and how to find the professionals you need.

Book: A Straight Talking Introduction to Psychiatric Drugs: The Truth About How They Work and How to Come Off Them

Book Title:

A Straight Talking Introduction to Psychiatric Drugs: The Truth About How They Work and How to Come Off Them (The Straight Talking Introduction Series).

Author(s): Joanna Moncrieff.

Year: 2020.

Edition: Second (2nd), Revised Edition.

Publisher: PCCS Books.

Type(s): Paperback and Kindle.

Synopsis:

In an era when more people are taking psychiatric drugs than ever before, Joanna Moncrieff’s explosive book challenges the claims for their mythical powers. Drawing on extensive research, she demonstrates that psychiatric drugs do not ‘treat’ or ‘cure’ mental illness by acting on hypothesised chemical imbalances or other abnormalities in the brain. There is no evidence for any of these ideas. Moreover, any relief the drugs may offer from the distress and disturbance of a mental disorder can come at great cost to people’s physical health and their ability to function in day-to-day life. And, once on these drugs, coming off them can be very difficult indeed. This book is a wake-up call to the potential damage we are doing to ourselves by relying on chemical cures for human distress. Its clear, concise explanations will enable people to make a fully informed decision about the benefits and harms of these drugs and whether and how to come off them if they so choose.

Principles for Improving Investment in Translational Neuroscience Aimed at Psychiatric Drug Discovery

Research Paper Title

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology.

Background

There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology.

Methods

Based on a review of the relevant literature, the researchers formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery.

Results

The researchers propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery:

  1. Consider incorporating the NIMH Research Domain Criteria (RDoC) approach;
  2. Engage the power of translational and systems neuroscience approaches;
  3. Use disease-relevant experimental perturbations;
  4. Identify molecular targets via genomic analysis and patient-derived pluripotent stem cells;
  5. Embrace holistic neuroscience: a partnership with psychoneuroimmunology;
  6. Use translational measures of neuronal activation;
  7. Validate the reproducibility of findings by independent collaboration; and
  8. Learn and reflect.

They provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities.

Conclusions: We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

Reference

Tricklebank, M.D., Robbins, T.W., Simmons, C. & Wong, E.H.F. (2021) Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology. Psychopharmacology (Berl). doi: 10.1007/s00213-021-05787-x. Online ahead of print.

Book: Best Practices and Barriers to Engaging People with Substance Use Disorders in Treatment

Book Title:

Best Practices and Barriers to Engaging People with Substance Use Disorders in Treatment.

Author(s): Peggy O’Brien, Erika Crable, Catherine Fullerton, and Lauren Hughey.

Year: March 2019.

Edition: First (1st).

Publisher: US Department of Health and Human Services.

Type(s): eBook.

Synopsis:

In 2015, 20.8 million people aged 12 years or older (7.8% of the United States population) had a substance use disorder (SUD) in the previous year. Approximately 75% of this group, or 15.7 million Americans, had an alcohol use disorder,
2.0 million had a prescription opioid use disorder (OUD), and about 0.6 million had a heroin use disorder.

Since 1999, opioid-related overdose deaths in the United States have quadrupled, with more than 15,000 individuals experiencing prescription drug-related overdose deaths in 2015. Even though evidence-based SUD treatments are effective, rates of treatment receipt are quite low. In 2015, only 18% of the population with SUDs, or 3.7 million people, received SUD treatment – a number that has not increased significantly since 2002.

Only about 48% of patients who enter SUD treatment actually complete it.

You can access the book, for free, here.

Book: Approaches to Drug Abuse Counselling

Book Title:

Approaches to Drug Abuse Counselling.

Author(s): National Institute on Drug Abuse (NIDA).

Year: 2000.

Edition: First (1st).

Publisher: US Government Printing Office.

Type(s): eBook.

Synopsis:

Dual disorders recovery counselling (DDRC) is an integrated approach to treatment of patients with drug use disorders and comorbid psychiatric disorders.

The DDRC model, which integrates individual and group addiction counselling approaches with psychiatric interventions, attempts to balance the focus of treatment so that both the patient’s addiction and psychiatric issues are addressed.

The DDRC model is based on the assumption that there are several treatment phases that patients may go through.

You can access the book, for free, here.

Book: Integrating Behavioural Therapies with Medications in the Treatment of Drug Dependence

Book Title:

Integrating Behavioural Therapies With Medications in the Treatment of Drug Dependence (National Institute on Drug Abuse Research Monograph Series).

Author(s): Lisa Simon Onken (PhD), Jack D. Blaine (MD), and John J. Boren (PhD.

Year: 1995.

Edition: First (1st).

Publisher: US Government Printing Office.

Type(s): eBook.

Synopsis:

It is no revelation that drug dependence is a complex problem with behavioural, cognitive, psychosocial, and biological dimensions and may be treated with behavioural therapy (including behaviour therapy, psychotherapy, and counselling), and, where available, pharmacotherapy.

Drug use can be reduced behaviourally with appropriate manipulation of reinforcements within the environment (Higgins et al. 1993). Continued improvements over time in drug use can be initiated by cognitive behavioural psychotherapies to modify cognitions that perpetuate drug use (Carroll et al., submitted for publication), and a reduced likelihood of
relapse has been engendered by specialised training approaches (Rohsenow et al., in press).

Methadone, of course, has long been recognised as an effective pharmacotherapy to reduce opiate use, and its biological mechanism of action is well understood.

You can access the book, for free, here.