What is anxiolytic related stress disorder? #MentalHealthAwareness
By Ibani Kapur, Farooq Ali Khan, Abhishek Kumar, Raamesh Gowri Raghavan, and Sukant Khurana* (*to whom correspondence should be addressed)
Anxiety
Anxiety is a condition marked by an extensive level of reactivity to external stimuli and can affect the cognitive, physiological and behavioural aspects of a person.(4) It also disrupts social and occupational functioning. (5) According to numerous community surveys conducted, this disorder forms a major percentage of mental health disorders affecting the population.(5) It is a fact that most childhood symptoms of anxiety continue through adulthood therefore a corrective action taken at the right time is essential.
Anxiety disorders and inflammation
Inflammation is caused in the brain through the activation of brain microglia which expresses pro-inflammatory cytokines(PIC) and other inflammatory mediators. Some PICs can directly modulate levels of serotonin through induction of indoleamine 2,3-dioxygenase, which leads to tryptophan and serotonin depletion, and production of tryptophan catabolites including kynurenine and quinolinic acid. These substances are anxiogenic and depressogenic, and are known to induce oxidative stress and impair normal mitochondrial respiratory mechanisms.(6) Serotonin is a kind of neurotransmitter which regulates amygdala. The serotonin in amygdala is associated with a higher risk of anxiety. It has been shown through animal studies that extremely high ssri (selective serotonin re uptake inhibitors) administration, decreases the serotonin synthesis.
Class of drugs used
Benzodiazepines are a class of drugs used commonly for conditions like anxiety, insomnia , epilepsy, pre-surgical stress. However, there exists a risk from long time exposure to these drugs. A European database was used to understand the pattern of BZD prescription.
1a) Benzodiazepine advantages-(3)
1) Wide therapeutic effect
2) less systemic toxicity
3) few drug-drug interactions
4) Do not influence their own or other drugs metabolism
1b) However, the drawbacks cannot be overlooked since these include
certain severe conditions like
1) sedative effects
2) interaction with alcohol
3) memory impairment
The solution to these disabling effects is improvement of serotonergic activity by agents that act as specific serotonin receptors (3). 5- Hydroxytryptamine (5-HT) is a major class of serotonin receptor system which is further subdivided into different categories like 5-HT(1,2,3). 5-HT(1) is divided into (1A,1B,1C,1D). Drugs like buspirone, ipsapirone,gepirone and SM-3997 are selective for the 5-HT(1A) site.
Epidemiology
A study was conducted as part of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium) (http://www.imi-protect.eu/), a European consortium in the field of pharmacoepidemiology and pharmacovigilance. So as to enable a comparison in pharmacological studies across different countries, this study was conducted. Seven databases were used in the study. The seven databases represented five European countries. (7) The population consisted of patients in the databases during the period from January 1 2001 until December 31 2009. One of the databases Bavarian database, the study period was for a short duration of 2004–2008. Anxiolytic was under the classification of drugs as N05BA, benzodiazepine derivative Hypnotics under N05CD, hypnotics and sedatives — benzodiazepine derivatives N05CF (hypnotics and sedatives — benzodiazepine-related drugs or Z-drugs).
outcome of the study-
The prevalence rates of BZD’s were analysed by age and sex. It was observed that in patients over 50 years of age, the age specific prevalence rates were 1.5 to 2 times higher for women than men. Also, there was a decrease in use in older ages ( 60 years and older) while it remained stable among the younger age groups.(7) The prescription of BZD’s as anxiolytics was found to be four times higher than that of hypnotics (including BZDs, Z-drugs and clomethiazole when available) in BIFAP (i.e. 1439.3 vs. 363.2 per 10000 person-years for 2008), 1.3- times higher in the Bavarian database (i.e. 347.8 vs. 266.4 per 10000 person-years for 2008) and 1.5-times higher in the Mondriaan-AHC database (i.e. 666.7 vs. 457.0 per 10 000 person-years for 2008), whereas in the UK databases, CPRD and THIN, and in DKM, the prevalence for hypnotics prescriptions outweighed that of anxiolytics, by a factor of approximately 1.2 (i.e. 355.6 vs. 302.8, 359.6 vs. 291.5 and 523.5 vs. 436.7, per 10000 person-years respectively for 2008). Almost no differences were observed in the Mondriaan-NPCRD databases. Trends over time were essentially similar for both anxiolytics and hypnotics.(7)
4 to 8 percent of the US population is affected by anxiety disorders. Children and adolescents up to 25 percent are affected by anxiety disorders
Period prevalence rates of BZDs use according to the ATC classification: anxiolytics (N05BA) — left graph and Hypnotics (N05CD,N05CF and N05CM02) — right graph
Diagram Reference — Exposure to benzodiazepines (anxiolytics, hypnotics and related
drugs) in seven European electronic healthcare databases: a crossnational
descriptive study from the PROTECT-EU Project
Links related to Anxiety
Correlation between stress and memory
The effect that a stressful event or encounter can have on memory has been overlooked at times. Memory encompasses a series of processes namely consolidation, retrieval,extinction and reconsolidation. Glucocorticoid hormones are a type of hormones which are found to be effective in controlling the modulatory effect that stress has on consolidation and retrieval of memory.(1) The activation of hypothalamus–pituitary–adrenal (HPA) axis during a stressful encounter is responsible for the release of these hormones. On release, they travel to the brain and bind to mineral corticoid receptors (MRs) and glucocorticoid receptors (GRs) which leads to their activation or effect on human physiology and behaviour. These receptors due to majorly being expressed in the hypothalamus, continue to be studied to a greater extent in this region. However, other regions of the brain have been found to be as effective in studying memory processes as well.
1) Different memory stages and effect of glucocorticoids
‘Selection is the very keel on which our mental ship is built. And in the
case of memory its utility is obvious. If we remembered everything, we
should on most occasions be as ill off as if we remembered nothing.’
(William James, 1890)
A MAN WE MET RECENTLY was only a few blocks from Oklahoma
City’s Alfred R. Murrah building when the deadly bomb exploded on 19
April, 1995. He described that experience as ‘engraved’ in his brain, saying, ‘I’ll have that memory forever’.(2)
Adrenaline effects on memory appear to be mediated by the activation of peripheral BETA-adrenergic receptors(2). Under low-arousing conditions, administration of yohimbine, a drug that stimulates noradrenaline release, enables glucocorticoid-induced memory enhancement. Tests for understanding retrieval in humans , there was administration of cortisone (at a dose resulting in high physiological cortisol levels) 1 hour before retention testing impaired the recall of words learned 24 hours earlier.
Comparable to memory consolidation, glucocorticoid effects on memory retrieval seem to be more prominent in men than in women who use oral contraceptives
2) Anxiety and cognition and psychophysiology
The cognitive bias theory does not clearly specify the link between cognition and psychophysiology with the development of anxiety. While cognitive bias refers to the deviation or shift from thinking rationally , autonomic arousal is the arousal or reaction which occurs in the body in response to physiological reactions. It is believed that cognitive bias may worsen or increase autonomic reactivity to produce anxiety. This relationship needs to be understood and examined in youth.(4) Autonomic arousal disorder is a disorder characterized by persistent or recurrent symptoms other than pain that are mediated by the autonomic nervous system and not a part of a general medical condition. Symptoms may involve various systems or organs including palpitations (cardiovascular), hyperventilation (respiratory), vomiting (gastrointestinal), urinary frequency (urogenital), or flushing (dermal). In earlier classifications (DSM-I, DSM-II, and DSM-III), such symptoms were considered conversion symptoms, psychosomatic symptoms, or psychophysiological disorders.
Price variation of the drugs in India
Currently, benzodiazepines and the Selective serotonin reuptake inhibitors (SSRIs) are the drugs leading the pharmaceutical industry for treatment of common anxiety disorders. An analysis was conducted on different anxiolytic brands and their price variations were recorded in India. The prices of a total of 17 drugs (11 single drug therapy and 6 combination therapy), available in 33 different formulations of anxiolytic drugs were analyzed. These 33 different formulations were manufactured by different pharmaceutical companies.(8) Some commonly used drugs include Alprazolam 1mg a minimum price of 11Rs, maximum of 36Rs, % Price variation 227.27. Out of 26 single drug formulations analyzed, maximum percentage variation in prices were seen with diazepam (5 mg) 371.42% followed by clonazepam (0.5 mg) 350%, lorazepam (1mg) 328.57%, alprazolam (0.25 mg) 320% and clobazam (20 mg) 318.18%.
Outcome of the survey
The size of the pharmaceutical industry in India stands at US$ 20 billion. The Indian pharmaceutical manufacturing facilities registered with the US Food and Drug Administration (FDA) stood at 523 which was highest for any country outside the US.10 There is marketing of the same drug under different brand names. In India, a large number of different drug formulations are available at different prices.11 Other factors contributing to these price variations are government regulations and pricing policies, cost of raw materials, distribution and promotion, target return on investment.(8)
Alcohol as an anxiolytic
It is a well known fact that most people resort to alcohol consumption when under the influence of stress. The property of alcohol making it the most preferred drink during times of anxiety can be attributed to its mitigation of stress induced anxiety like behaviours proven in rodents.(7) However, moderate consumption of alcohol, using zebra fish as a model has shown to exhibit this property. Thereby, making it a suitable candidate as an anxiolytic. In the field of neuroscience, zebrafish is considered as a novel model organism. The procedure that was involved to inflict anxiety upon the zebra fish was exposing the fishes to a a handling condition at a frequency much higher than would otherwise be employed in habituating the fishes to their test environment (7). Ethanol between 0 to 1 percent was another factor that was considered.
Diagnostic tools that assess anxiety(4)
Anxiety Disorders Interview Schedule for Children, Version IV (ADIS-IV;
Silverman, Saavedra, & Pina, 2001). The ADIS-IV is a semi-structured
diagnostic interview that assesses the major DSM-IV disorders,
including anxiety
Clinical Global Impressions — Severity (CGI-S; Guy, 1976) is a clinicianrated
dimensional measure of psychopathology severity. The CGI-S
ranges from 1(“not at all ill”) to 7 (“extremely ill”)
Wide-Range Achievement Test — 4th Edition Reading Subtest (WRAT-4;
Wilkinson & Robertson, 2006) is a well-established academic
achievement test with validated standardized scores for youth according
to age and grade.
References
(1) Stress, glucocorticoids and memory: implications for treating fearrelated
disorders
Dominique de Quervain1–3, Lars Schwabe4 and Benno Roozendaal5,6
(2) Mechanisms of emotional arousal and lasting declarative memory
Larry Cahill and James L. McGaugh
(3) Serotonin-1A Anxiolytics: An Overview
John P. Feighner, William F. Boyer
(4) Thinking anxious, feeling anxious, or both? Cognitive bias moderates
the relationship between anxiety disorder status and sympathetic
arousal in youth
Running head: Cognitive Bias and Sympathetic Arousal
Michelle Rozenman, Ph.D., Allison Vreeland, B.A., & John Piacentini,
Ph.D. Division of Child & Adolescent Psychiatry
UCLA Semel Institute for Neuroscience & Human Behavior
(5) The Age of Onset of Anxiety Disorders: A Meta-analysis
L’age de De ́but des Troubles Anxieux: Une Me ́ta-analyse
Jasmijn M. de Lijster, MSc1, Bram Dierckx, PhD1, Elisabeth M.W.J.
Utens, PhD1, Frank C. Verhulst, PhD1, Carola Zieldorff, MSc1, Gwen C.
Dieleman, MSc1,
and Jeroen S. Legerstee, PhD1
(6) Exercising the worry away: How inflammation, oxidative and nitrogen
stress mediates the beneficial effect of physical activity on anxiety
disorder symptoms and behaviours
S. Moylana,∗, H.A. Eyreb,c, M. Maesd, B.T. Bauneb, F.N. Jackaa, M.
Berka,e,f,g
(7) Exposure to benzodiazepines (anxiolytics, hypnotics and related
drugs) in seven European electronic healthcare databases: a crossnational
descriptive study from the PROTECT-EU Project
Consuelo Huerta1*, Victoria Abbing-Karahagopian2, Gema Requena3,
Belén Oliva1, Yolanda Alvarez4,
Helga Gardarsdottir2,5, Montserrat Miret6, Cornelia Schneider7, Miguel
Gil1, Patrick C. Souverein2, Marie L. De Bruin2, Jim Slattery4, Mark C.
H. De Groot2, Ulrik Hesse8, Marietta Rottenkolber9, Sven
Schmiedl10,11, Dolores Montero1, Andrew Bate12, Ana Ruigomez13,
Luis Alberto García-Rodríguez13, Saga Johansson14, Frank de
Vries2,15,16,
Raymond G. Schlienger17, Robert F. Reynolds18, Olaf H. Klungel2,19
and Francisco José de Abajo3,20
(8)Analysis of price variation amongst different formulations of anxiolytic
drugs available in Indian market
Vihang S. Chawan, Sagar V. Badwane*, Kalpesh V. Gawand, Maheshi
U. Chhaya
About:
ploring the interface of science and art. He is also championing a massive anti-depression and suicide prevention effort with Dr. Khurana and Farooq Ali Khan.
You can know more about Raamesh at:
https://sites.google.com/view/raameshgowriraghavan/home and https://www.linkedin.com/in/raameshgowriraghavan/?ppe=1
Dr. Sukant Khurana runs an academic research lab and several tech companies. He is also a known artist, author, and speaker. You can learn more about Sukant at www.brainnart.com or www.dataisnotjustdata.com and if you wish to work on biomedical research, neuroscience, sustainable development, artificial intelligence or data science projects for public good, you can contact him at skgroup.iiserk@gmail.com or by reaching out to him on linkedin https://www.linkedin.com/in/sukant-khurana-755a2343/.
Here are two small documentaries on Sukant and a TEDx video on his citizen science effort.