Tag: Treatment

How Common Is Addiction Alongside Mental Health Disorders?

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Introduction

According to a range of US governmental agencies devoted to healthcare studies, addiction and mental health disorders are deeply intertwined. It is not uncommon for someone seeking treatment for substance use to also be managing symptoms of depression, anxiety, trauma, or another psychiatric condition. 

This combination is referred to as a co-occurring disorder or dual diagnosis. In Arizona specifically, the latest research from the Arizona Department of Human Services relays the following: 71 % of Arizona treatment providers reported offering dual‑diagnosis/co‑occurring services.

Understanding how common these conditions are, and how they interact, is key to getting the right help. Whether you are researching for a loved one or trying to make sense of your own experience, we provide a brief outline for you in this article.

We will review what you need to know about the prevalence, causes, and treatment of addiction alongside mental health disorders.

According to the Substance Abuse and Mental Health Services Administration, genetics  significantly influence both mental illness and substance use disorders (SUDs). Shared genetic factors – such as those affecting brain reward systems – can increase risk for both conditions.

The Overlap Between Addiction and Mental Illness

Addiction does not occur in a vacuum. Many individuals who struggle with drugs or alcohol also experience underlying mental health conditions.

According to the National Institute on Drug Abuse “About half of the people who experience a substance use disorder also experience a mental illness at some point during their lifetime, and vice versa.”

In Arizona, this rate tends to be even higher. According to SAMHSA’s 2019 Behavioural Health Barometer, Arizona reports that 4-5% of adults experienced both SUD and any mental illness. These percentages surpass the national average of 3.8%.

Why Do These Conditions Co-Occur?

There are several reasons why mental health disorders and addiction commonly appear together:

  • Self-medication: SAMHSA explains that mental health problems can lead some individuals to misuse substances “as a form of self‑medication” to alleviate distressing symptoms like anxiety or depression.
  • Shared risk factors: Genetics contribute significantly, according to the National Centre for Biotechnology Information: Epigenetic changes triggered by trauma or stress can modify gene expression in ways that increase sensitivity to both mental health issues and substance use.
  • Addiction-induced symptoms: SAMHSA states that substances “can cause people with an addiction to experience one or more symptoms of a mental health problem.” These symptoms may mirror anxiety, depression, psychosis, or mood disturbances during intoxication or withdrawal—and may persist until diagnosed and treated appropriately.

The relationship is rarely one-directional. Sometimes addiction leads to worsening mental health. Other times, unresolved trauma or an undiagnosed condition paves the way for substance use.

Common Mental Health Conditions Seen with Addiction

While co-occurring disorders can take many forms, certain psychiatric conditions are more frequently associated with substance use disorders.

Depression and Substance Use

Depression is among the most common co-occurring disorders. Nationally, SAMHSA states that depression is one of the most frequent mental–substance use co-occurring disorders, underscoring how individuals may self-medicate depressive symptoms with alcohol or sedatives, which then exacerbate depression over time.

Anxiety Disorders

Generalised anxiety disorder, panic disorder, and social phobia frequently appear alongside alcohol use, benzodiazepine misuse, or stimulant addiction. These substances can seem like a quick escape from anxiety but often reinforce the cycle of fear and dependence. 

The National Institute of Mental Health confirms that GAD and social anxiety disorder are “commonly associated with alcohol and substance misuse”.

Post-Traumatic Stress Disorder (PTSD)

PTSD is closely linked to addiction, especially among veterans, first responders, and survivors of abuse. Arizona has a large population of military personnel and veterans who may face both PTSD and addiction, requiring trauma-informed, dual diagnosis care. 

The US Air Force Medical Service materials state: withdrawal and stress can trigger PTSD symptoms (like flashbacks or hyperarousal), reinforcing substance use through emotional conditioning.

Bipolar Disorder

SAMHSA emphasizes that co-occurring SUD and bipolar symptoms create clinical ambiguity, often obscuring whether substance use or mood fluctuations came first. 

Substance use can make it harder to diagnose and treat bipolar disorder accurately. During manic episodes, individuals may take risks with drugs or alcohol. 

During depressive episodes, they may self-isolate or engage in harmful use patterns.

Schizophrenia and Psychotic Disorders

Though less common, individuals with schizophrenia or schizoaffective disorder can also struggle with substance use. According to the NCBI, NIDA and SAMHSA note that schizophrenia and other psychotic disorders, including schizoaffective disorder, are “highly prevalent” comorbid conditions with SUDs.

Specialized care is essential, particularly when symptoms of psychosis overlap with those caused by drug use (such as methamphetamine-induced psychosis, which has become more common in parts of Arizona). According to the Department of Justice,  Methamphetamine abuse is increasing in Arizona, making more persons at risk for methamphetamine-induced psychosis.

Recognising the Signs of a Co-Occurring Disorder

It can be challenging to identify a co-occurring disorder—especially because addiction can mimic or mask psychiatric symptoms. Here are some warning signs SAMHSA indicates that a dual diagnosis might be present:

  • Sudden mood swings or emotional numbness.
  • Isolation from family and friends.
  • Risky behaviour that escalates over time.
  • Trouble managing daily responsibilities.
  • Using substances to sleep, relax, or feel normal.
  • History of trauma or prior psychiatric diagnosis.

In many cases, individuals with co-occurring disorders will not fully respond to addiction treatment alone unless their mental health needs are also addressed.

The Importance of Integrated Treatment in Arizona

When both mental health and substance use disorders are present, integrated treatment is essential. This means treating both conditions at the same time, in the same setting, by the same clinical team.

Why Integrated Treatment Works

Research and clinical experience consistently show that individuals with co-occurring disorders do better when they receive:

  • A comprehensive psychiatric evaluation.
  • Medication management (when appropriate).
  • Individual and group therapy focused on dual diagnosis.
  • Psychoeducation about the interaction between mental health and addiction.
  • Trauma-informed care and relapse prevention strategies.

In Arizona, dual diagnosis treatment is offered by specialized providers who understand the unique cultural and logistical barriers residents may face—especially those in rural areas or on AHCCCS (Arizona’s Medicaid programme). For support using AHCCCS, those struggling can find an accredited facility that handles trauma and addiction treatment in Phoenix.

Access to Care in Arizona

Arizona has expanded mental health and substance use services through various public and private efforts, including:

  • AHCCCS coverage for dual diagnosis treatment at both inpatient and outpatient levels.
  • Designated behavioural health facilities offering psychiatric stabilization and addiction care under one roof.
  • Outreach efforts in underserved communities and tribal regions.

Still, waitlists and transportation issues remain barriers for some individuals, making early intervention all the more important.

Addressing Stigma Around Dual Diagnosis

Stigma remains one of the biggest obstacles to care. Some people may feel ashamed to seek help for either addiction or mental health concerns—let alone both at once. Families may misunderstand the symptoms and assume their loved one just needs “more willpower.”

The truth is that co-occurring disorders are medical conditions, not moral failings. Treatment works, and recovery is possible. In fact, when both mental health and addiction are addressed together, individuals are more likely to achieve long-term stability and improved quality of life.

What to Look for in a Dual Diagnosis Programme

If you or someone you care about in Arizona is dealing with both addiction and mental health challenges, finding the right treatment setting is key.
Look for programmes that offer:

  • Medical detox with psychiatric support.
  • A licensed mental health team (psychiatrists, therapists, counsellors).
  • Evidence-based therapies like CBT, DBT, and EMDR.
  • Support groups focused on co-occurring disorders.
  • A structured discharge and aftercare plan.

Ask whether the programme accepts your insurance, especially if you are using AHCCCS, Health Choice, or another Arizona-based plan.

When to Seek Help

You don’t need to have everything “figured out” to start. Many people begin treatment unsure of whether they have a co-occurring diagnosis – and that is okay. A quality provider will help you uncover the full picture through assessment and ongoing care.

If substance use is interfering with your ability to function, and you have noticed symptoms of anxiety, depression, trauma, or mood instability, it is time to reach out. Waiting for things to get worse only increases the risk of crisis or overdose.

Summary

No matter where you are in the process: searching for answers, feeling stuck, or finally ready to act – help is available. With the right support, healing from both addiction and mental health struggles is not only possible but deeply rewarding.

If you are exploring options for dual diagnosis care in Arizona, do not hesitate to ask questions. A conversation with the right provider can open the door to lasting change: for you or your loved one.

What is Phenylpiracetam?

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Introduction

Phenylpiracetam, also known as fonturacetam (INNTooltip International nonproprietary name) and sold under the brand names Phenotropil, Actitropil, and Carphedon among others, is a stimulant and nootropic medication used in Russia and certain other Eastern European countries in the treatment of cerebrovascular deficiency, depression, apathy, and attention, and memory problems, among other indications. It is also used in Russian cosmonauts to improve physical, mental, and cognitive abilities. The drug is taken by mouth.

Side effects of phenylpiracetam include sleep disturbances among others. The mechanism of action of phenylpiracetam was originally unknown. However, it was discovered that (R)-phenylpiracetam is a selective atypical dopamine reuptake inhibitor in 2014. In addition, phenylpiracetam interacts with certain nicotinic acetylcholine receptors. Chemically, phenylpiracetam is a racetam and phenethylamine and is structurally related to piracetam.

Phenylpiracetam was first described by 1983. It was approved for medical use in Russia in 2003. Development of (R)-phenylpiracetam (code name MRZ-9547) in the West as a potential treatment for fatigue related to Parkinson’s disease began by 2014.

Brief History

Phenylpiracetam was first described in the scientific literature by 1983. It was developed in 1983 as a medication for Soviet cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina (Валентина Ивановна Ахапкина). Subsequently, it became available as a prescription drug in Russia. It was approved in 2003 for treatment of various conditions.

Pilot-cosmonaut Aleksandr Serebrov described being issued and using phenylpiracetam, as well as it being included in the Soyuz spacecraft’s standard emergency medical kit, during his 197-days working in space aboard the Mir space station. He reported:

“the drug acts as the equalizer of the whole organism, “tidying it up”, completely excluding impulsiveness and irritability inevitable in the stressful conditions of space flight.”

Medical Uses

Phenylpiracetam is used in the treatment of a variety of different medical conditions. It is specifically approved in Russia for treatment of cerebrovascular deficiency, depression, apathy, attention deficits, and memory decline. It is used to improve symptoms following encephalopathy, brain injury, and glioma surgery. The drug has been reported to improve symptoms of depression, anxiety, asthenia, and fatigue, as well as to improve cognitive performance and memory. It also has anticonvulsant effects and has been used as an add-on therapy in epilepsy.

Phenylpiracetam is typically prescribed as a general stimulant or to increase tolerance to extreme temperatures and stress.

Clinical use of phenylpiracetam has shown to be more potent than piracetam and is used for a wider-range of indications.

A few small clinical studies have shown possible links between prescription of phenylpiracetam and improvement in a number of encephalopathic conditions, including lesions of cerebral blood pathways, traumatic brain injury and certain types of glioma.

Clinical trials were conducted at the Serbsky State Scientific Centre for Social and Forensic Psychiatry. The Serbsky Centre, Moscow Institute of Psychiatry, and Russian Centre of Vegetative Pathology are reported to have confirmed the effectiveness of phenylpiracetam describing the following effects: improvement of regional blood flow in ischemic regions of the brain, reduction of depressive and anxiety disorders, increase the resistance of brain tissue to hypoxia and toxic effects, improving concentration and mental activity, a psycho-activating effect, increase in the threshold of pain sensitivity, improvement in the quality of sleep, and an anticonvulsant action, though with the side effect of an anorexic effect in extended use.

Available Forms

Phenylpiracetam is available in the form of 100 mg oral tablets.

Contraindications

Phenylpiracetam has a number of contraindications, such as individual intolerance.

Side Effects

Side effects of phenylpiracetam include insomnia or sleep disturbances, psychomotor agitation, flushing, a feeling of warmth, and increased blood pressure, among others.

Overdoses

Overdose has not been reported.

Pharmacology

Pharmacodynamics

Phenylpiracetam is a racetam and is described as a stimulant. Racetams have a variety of different pharmacological activities and have varying effects. For example, phenylpiracetam is a stimulant, piracetam is a nootropic, and levetiracetam is an anticonvulsant. The mechanisms of action of most racetams, with some exceptions, are unknown.

Phenylpiracetam is a racemic mixture.4-Phenylpiracetam is the most active enantiomer and is much more potent in stimulating locomotor activity than (S)-phenylpiracetam, which is ineffective. However, (S)-phenylpiracetam retains some activity in most pharmacological tests. On the other hand, in one animal test, the passive avoidance test, (S)-phenylpiracetam appeared to be antagonistic of (R)-phenylpiracetam.

Dopamine Reuptake Inhibitor

Experiments performed on Sprague-Dawley rats in a European patent for using phenylpiracetam to treat sleep disorders showed an increase in extracellular dopamine levels after administration. The patent asserts discovery of phenylpiracetam’s action as a dopamine reuptake inhibitor as its basis.

The peculiarity of this invention compared to former treatment approaches for treating sleep disorders is the so far unknown therapeutic efficacy of (R)-phenylpiracetam, which is presumably based at least in part on the newly identified activity of (R)-phenylpiracetam as the dopamine re-uptake inhibitor

Both enantiomers of phenylpiracetam, (R)-phenylpiracetam and (S)-phenylpiracetam, have been described in peer-reviewed research as dopamine transporter (DAT) inhibitors in rodents, confirming the patent claim. Their actions at the norepinephrine transporter (NET) vary: (R)-phenylpiracetam acts as a dual norepinephrine–dopamine reuptake inhibitor (NDRI), with 11-fold lower affinity for the NET than for the DAT, whereas the (S)-enantiomer is selective for the DAT. However, whereas (R)-phenylpiracetam stimulates locomotor activity, (S)-phenylpiracetam does not do so. This variation in effects has also been seen with other dopamine reuptake inhibitors.

Other atypical dopamine reuptake inhibitors include modafinil, mesocarb (Sydnocarb), and solriamfetol.

Other Actions

Phenylpiracetam binds to α4β2 nicotinic acetylcholine receptors in the mouse brain cortex with an IC50Tooltip half-maximal inhibitory concentration of 5.86 μM.

Racetams generally, but including phenylpiracetam, have been described as AMPA receptor potentiators.

Animal Studies

Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anxiolytic, and anticonvulsant effects.

Phenylpiracetam has been shown to reverse the sedative or depressant effects of the benzodiazepine diazepam, increases operant behaviour, inhibits post-rotational nystagmus, prevents retrograde amnesia, and has anticonvulsant properties in animal models.

In Wistar rats with gravitational cerebral ischemia, phenylpiracetam reduced the extent of neuralgic deficiency manifestations, retained the locomotor, research, and memory functions, increased the survival rate, and lead to the favouring of local cerebral flow restoration upon the occlusion of carotid arteries to a greater extent than did piracetam.

In tests against a control, Sprague-Dawley rats given free access to less-preferred rat chow and trained to operate a lever repeatedly to obtain preferred rat chow performed additional work when given methylphenidate, dextroamphetamine, and phenylpiracetam. Rats administered 100 mg/kg phenylpiracetam performed, on average, 375% more work than rats given placebo, and consumed little non-preferred rat chow. In comparison, rats administered 1mg/kg dextroamphetamine or 10 mg/kg methylphenidate performed, on average, 150% and 170% more work respectively, and consumed half as much non-preferred rat chow.

Present data show that (R)-phenylpiracetam increases motivation, i.e. the work load, which animals are willing to perform to obtain more rewarding food. At the same time consumption of freely available normal food does not increase. Generally this indicates that (R)-phenylpiracetam increase motivation […] The effect of (R)-phenylpiracetam is much stronger than that of methylphenidate and amphetamine.

Pharmacokinetics

The pharmacokinetics of phenylpiracetam in humans are unpublished. In any case, the drug is described as having an oral bioavailability of approximately 100%, as having an onset of action of less than 1 hour, as not being metasbolised, as being excreted unchanged about 40% in urine and 60% in bile and sweat, and as having an elimination half-life of 3 to 5 hours. In rodents, its absorption occurs within 1 hour with oral administration or intramuscular injection and its elimination half-life is 2.5 to 3 hours.

Chemistry

Phenylpiracetam, also known as 4-phenylpiracetam, is a racetam (i.e. a 2-oxo-1-pyrrolidine acetamide derivative) and the 4-phenyl-substituted analogue of piracetam. In contrast to piracetam and most other racetams however, phenylpiracetam contains β-phenylethylamine within its chemical structure and hence can additionally be conceptualised as a substituted phenethylamine.

Phenylpiracetam is a racemic mixture of (R)- and (S)-enantiomers, (R)-phenylpiracetam (MRZ-9547) and (S)-phenylpiracetam.

Derivatives

RGPU-95 (4-chlorophenylpiracetam) is a derivative of phenylpiracetam described as having 5- to 10-fold greater potency. Cebaracetam (CGS-25248; ZY-15119) is a derivative of RGPU-95 in which the terminal amide has been replaced with a 2-piperazinone moiety.

Methylphenylpiracetam, including all four of its stereoisomers (especially the (4R,5S)-enantiomer E1R), is a positive allosteric modulator of the sigma σ1 receptor. It is currently the only known racetam demonstrating σ1 receptor modulation. Whereas phenylpiracetam stimulates locomotor activity in animals, the E1R enantiomer of methylphenylpiracetam does not do so at doses of up to 200 mg/kg.

Phenylpiracetam hydrazide is a hydrazide derivative of phenylpiracetam described as having anticonvulsant effects.

Other derivatives of phenylpiracetam have also been developed and studied.

Society and Culture

Availability

While not prescribed as a pharmaceutical in the West, in Russia and certain other Eastern European countries it is available as a prescription medicine under brand names including Phenotropil (also spelled Fenotropil, Phenotropyl, and Fenotropyl), Actitropil, and Nanotropil, among others.

Phenylpiracetam is not scheduled by the United States Drug Enforcement Administration (DEA) as of 2016.

Manufacturer

Phenylpiracetam is manufactured by the pharmaceutical companies Valenta Pharm and Pharmstandard (Pharmstandart) in Russia.

Doping in Sport

Phenylpiracetam has stimulant effects and may be used as a doping agent in sport. As a result, it is on the list of stimulants banned for in-competition use by the World Anti-Doping Agency (WADA). This list is applicable in all Olympic sports. Owing to its unique stimulant properties among racetams, phenylpiracetam is the only racetam on the WADA prohibited list.

Research

Phenylpiracetam has been studied in the treatment of stroke and glaucoma.

The more active enantiomer of phenylpiracetam, (R)-phenylpiracetam, was under development for fatigue related to Parkinson’s disease. However, no recent development has been reported. There was also interest in the compound for fatigue related to depression and other conditions, but this was not pursued. 6-Phenylpiracetam has been identified as a selective atypical dopamine reuptake inhibitor (DRIs), and similarly to other DRIs, shows pro-motivational effects in animals and reverses motivational deficits.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Phenylpiracetam >; 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 Oxyprothepin Decanoate?

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Introduction

Oxyprothepin decanoate, sold under the brand name Meclopin, is a typical antipsychotic which was used in the treatment of schizophrenia in the Czech Republic but is no longer marketed.

Outline

It is administered by depot injection into muscle.

The medication has an approximate duration of 2 to 3 weeks.

The history of oxyprothepin decanoate has been reviewed.

What is Perphenazine Enanthate?

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Introduction

Perphenazine enanthate, sold under the brand name Trilafon Enantat among others, is a typical antipsychotic and a depot antipsychotic ester which is used in the treatment of schizophrenia and has been marketed in Europe.

Outline

It is formulated in sesame oil and administered by intramuscular injection and acts as a long-lasting prodrug of perphenazine.

Perphenazine enanthate is used at a dose of 25 to 200 mg once every 2 weeks by injection, with a time to peak levels of 2 to 3 days and an elimination half-life of 4 to 7 days.

What is Oxcarbazepine?

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Introduction

Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalised seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.

Common side effects include nausea, vomiting, dizziness, drowsiness, double vision and trouble with walking. Serious side effects may include anaphylaxis, liver problems, pancreatitis, suicide ideation, and an abnormal heart beat. While use during pregnancy may harm the baby, use may be less risky than having a seizure. Use is not recommended during breastfeeding. In those with an allergy to carbamazepine there is a 25% risk of problems with oxcarbazepine. How it works is not entirely clear.

Oxcarbazepine was patented in 1969 and came into medical use in 1990. It is available as a generic medication. In 2022, it was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Brief History

First made in 1966, it was patent-protected by Geigy in 1969 through DE 2011087. It was approved for use as an anticonvulsant in Denmark in 1990, Spain in 1993, Portugal in 1997, and eventually for all other EU countries in 1999. It was approved in the US in 2000. In September 2010, Novartis, of which Geigy are part of its corporate roots, pleaded guilty to marketing Trileptal for the unapproved uses of neuropathic pain and bipolar disorder.

Medical Uses

Neurology

Oxcarbazepine is an anticonvulsant used to reduce the occurrence of epileptic episodes, and is not intended to cure epilepsy. Oxcarbazepine is used alone or in combination with other medications for the treatment of focal (partial) seizures in adults. In paediatric populations, it can be used by itself for the treatment of partial seizures for children 4 years and older, or in combination with other medications for children 2 years and older. There is some evidence to support its effectiveness in reducing seizure frequency when used as an add-on therapy for drug-resistant focal epilepsy but there are concerns over tolerability.

Psychiatry

Oxcarbazepine (brand name Trileptal), has been historically used off-label by psychiatrists as a mood stabiliser. However, due to the limited data supporting efficacy it is typically reserved for patients for whom other medications have not worked or are contraindicated.

Side Effects

Side effects are dose-dependent. The most common include dizziness, blurred or double vision, nystagmus, ataxia, fatigue, headaches, nausea, vomiting, sleepiness, difficulty in concentration, and mental sluggishness. The incidence of movement disorders appears to be lower compared to carbamazepine.

Other, rare, side effects of oxcarbazepine include severe low blood sodium (hyponatremia), anaphylaxis / angioedema, hypersensitivity (especially if experienced with carbamazepine), toxic epidermal necrolysis, Stevens–Johnson syndrome, and thoughts of suicide.

Measurement of serum sodium levels should be considered in maintenance treatment or if symptoms of hyponatremia develop. Low blood sodium is seen in 20–30% of people taking oxcarbazepine, and 8–12% of those experience severe hyponatremia. Some side effects, such as headaches, are more pronounced shortly after a dose is taken and tend to fade with time (60 to 90 minutes). Other side effects include stomach pain, tremor, rash, diarrhoea, constipation, decreased appetite, and dry mouth. Photosensitivity is a potential side-effect and people could experience severe sunburns as a result of sun exposure.

Oxcarbazepine may lead to hypothyroxinemia. The well-known reduction in free and total thyroxine concentration may be due to both peripheral and central mechanisms.

Pregnancy

Oxcarbazepine is pregnancy category C in the US. There is limited data supporting its safety in pregnancy. Several alternative medications with similar efficacy profiles provide significantly more robust data to support safety during pregnancy. However limited recent research shows similar rates of foetal malformations in exposed pregnancies to the general non-teratogen exposed population. Careful consideration of the risks, benefits, alternatives, and expert advise is needed when considering Oxcarbazepine use during pregnancy.

Historically Oxcarbazepine was considered to be teratogenic in humans due to animal studies which have shown increased foetal abnormalities in pregnant rats and rabbits exposed to oxcarbazepine during pregnancy. Additionally it’s similar structure of to carbamazepine, raised concern as it is teratogenic in humans (pregnancy category D).

Breastfeeding

Oxcarbazepine and its metabolite licarbazepine are both present in human breast milk and thus, some of the active drug can be transferred to a nursing infant. When considering whether to continue this medication in nursing mothers, the impact of the drug’s side effect profile on the infant should be weighed against its anti-epileptic benefit for the mother.

Interactions

Oxcarbazepine, licarbazepine and many other common drugs influence each other through interaction with the cytochrome P450 family of enzymes. This leads to a cluster of dozens of common drugs interacting with one another to varying degrees, some of which are especially noteworthy.

Oxcarbazepine and licarbazepine are potent inhibitors of CYP2C19 and thus have the potential to increase plasma concentration of drugs, which are metabolised through this pathway. Other antiepileptics, which are CYP2C19 substrates and thus may be metabolised at a reduced rate when combined with oxcarbazepine, include diazepam, hexobarbital, mephenytoin, methylphenobarbital, nordazepam, phenobarbital, phenytoin, and primidone.

In addition, oxcarbazepine and licarbazepine are CYP3A4 and CYP3A5 inducers and thus have the potential to decrease the plasma concentration of CYP3A4 and CYP3A5 substrates, including calcium channel antagonists against high blood pressure and oral contraceptives. However, whether the extent of CYP3A4/5 induction at therapeutic doses reaches clinical significance is unclear.

Pharmacology

Oxcarbazepine is a prodrug, which is largely metabolised to its pharmacologically active 10-monohydroxy derivative licarbazepine (sometimes abbreviated MHD). Oxcarbazepine and MHD exert their action by blocking voltage-sensitive sodium channels, thus leading to the stabilisation of hyper-excited neural membranes, suppression of repetitive neuronal firing and diminishment propagation of synaptic impulses. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of high-voltage activated calcium channels.

Pharmacokinetics

Oxcarbazepine has high bioavailability upon oral administration. In a study in humans, only 2% of oxcarbazepine remained unchanged, 70% were reduced to licarbazepine; the rest were minor metabolites. The half-life of oxcarbazepine is considered to be about 2 hours, whereas licarbazepine has a half-life of nine hours. Through its chemical difference to carbamazepine metabolic epoxidation is avoided, reducing hepatic risks. Licarbazepine is metabolised by conjugation with Glucuronic acid. Approximately 4% are oxidised to the inactive 10,11-dihydroxy derivative. Elimination is almost completely renal, with faeces accounting to less than 4%. 80% of the excreted substances are to be attributed to licarbazepine or its glucuronides.

Pharmacodynamics

Both oxcarbazepine and licarbazepine were found to show anticonvulsant properties in seizure models done on animals. These compounds had protective functions whenever tonic extension seizures were induced electrically, but such protection was less apparent whenever seizures were induced chemically. There was no observable tolerance during a four weeks course of treatment with daily administration of oxcarbazepine or licarbazepine in electroshock test on mice and rats. Most of the antiepileptic activity can be attributed to licarbazepine. Aside from its reduction in side effects, it is presumed to have the same main mechanism as carbamazepine, sodium channel inhibition, and is generally used to treat the same conditions.

Pharmacogenetics

The human leukocyte antigen (HLA) allele B*1502 has been associated with an increased incidence of Stevens–Johnson syndrome and toxic epidermal necrolysis in people treated with carbamazepine, and thus those treated with oxcarbazepine might have similar risks. People of Asian descent are more likely to carry this genetic variant, especially some Malaysian populations, Koreans (2%), Han Chinese (2–12%), Indians (6%), Thai (8%), and Philippines (15%). Therefore, it has been suggested to consider genetic testing in these people prior to initiation of treatment.

Structure

Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon–carbon double bond on the dibenzazepine ring at the 10 position (10-keto). This difference helps reduce the impact on the liver of metabolising the drug, and also prevents the serious forms of anaemia or agranulocytosis occasionally associated with carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as carbamazepine — sodium channel inhibition (presumed to be the main mechanism of action) – and is generally used to treat the same conditions.

Oxcarbazepine is a prodrug which is activated to licarbazepine in the liver.

Research

Antiepileptics are a key pharmacological therapy used in the treatment of bipolar disorder. Research has investigated the use of oxcarbazepine as a mood stabiliser in bipolar disorder, with further evidence needed to fully assess its suitability. Oxcarbazepine used in conjunction with lithium has been shown to be effective in the maintenance phase.

It may be beneficial in trigeminal neuralgia.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Oxcarbazepine >; 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 are Psychoplastogens?

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Introduction

Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration.

Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin (the active metabolite of psilocybin), DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.

Etymology and Nomenclature

The term psychoplastogen comes from the Greek roots psych- (mind), -plast (molded), and -gen (producing) and covers a variety of chemotypes and receptor targets. It was coined by David E. Olson in collaboration with Valentina Popescu, both at the University of California, Davis.

The term neuroplastogen is sometimes used as a synonym for psychoplastogen, especially when speaking to the biological substrate rather than the therapeutic.

Chemistry

Psychoplastogens come in a variety of chemotypes and chemical families, but, by definition, are small-molecule drugs. Ketamine has been described as, “the prototypical psychoplastogen”.

Pharmacology

Psychoplastogens exert their effects by promoting structural and functional neural plasticity through diverse targets including, but not limited to, 5-HT2A, NMDA, and muscarinic receptors. Some are biased agonists. While each compound may have a different receptor binding profile, signalling appears to converge at the tyrosine kinase B (TrkB) and mammalian target of rapamycin (mTOR) pathways. Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset.

Due to their rapid and sustained effects, psychoplastogens could potentially be dosed intermittently. In addition to the neuroplasticity effects, these compounds can have other epiphenomena including sedation, dissociation, and hallucinations.

Psychedelics show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances. Single doses of DMT, 5-MeO-DMT, psilocybin, and DOI have been found to produce robust and long-lasting increases in neuroplasticity in animals. Likewise, repeated doses of LSD for 7 days increased neuroplasticity. However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation. In addition, DOI has been found to decrease brain-derived neurotrophic factor (BDNF) levels in the hippocampus. The effects of psychedelics on neuroplasticity appear to be dependent on serotonin 5-HT2A receptor activation, as they are abolished in 5-HT2A receptor knockout mice. Non-hallucinogenic serotonin 5-HT2A receptor agonists, like tabernanthalog and lisuride, have also been found to increase neuroplasticity, and to a magnitude comparable to psychedelics.

In terms of neurogenesis, DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and 25I-NBOMe decreased hippocampal neurogenesis. 5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by sigma σ1 receptor antagonists.

Approved Medical Uses

Several psychoplastogens have either been approved or are in development for the treatment of a variety of brain disorders associated with neuronal atrophy where neuroplasticity can elicit beneficial effects.

Esketamine, sold under the brand name Spravato and produced by Janssen Pharmaceuticals, was approved by the FDA in March 2019 for the treatment of Treatment-Resistant Depression (TRD) and suicidal ideation. As of 2022, it is the only psychoplastogen approved in the US for the treatment of a neuropsychiatric disorder. Esketamine is the S(+) enantiomer of ketamine and functions as an NMDA receptor antagonist.

Clinical Development

Other psychoplastogens that are being investigated in the clinic include:

  • MDMA-assisted psychotherapy is being investigated for treatment of PTSD. A recent placebo controlled Phase 3 trial found that 67% of participants in the MDMA+therapy group no longer met the diagnostic criteria for PTSD whereas 32% of those in the placebo+therapy group no longer met PTSD threshold. MDMA-assisted psychotherapy is also currently in Phase 2 trials for eating disorders, anxiety associated with life-threatening illness, and social anxiety in autistic adults.
  • Psilocybin, a compound in psilocybin mushrooms that serves as a prodrug for psilocin, is currently being investigated in clinical trials of Hallucinogen-Assisted Therapy for a variety of neuropsychiatric disorders. To date studies have explored the utility of psilocybin in a variety of diseases, including TRD, smoking addiction, and anxiety and depression in people with cancer diagnoses.
  • LSD is being tested in phase 2 trials for cluster headaches and anxiety.
  • DMT is being studied for depression.
  • 5-MeO-DMT is being studied for depression and eating disorders.
  • Ibogaine and Noribogaine are being studied for addiction.

List of Known Psychoplastogens

  • Substituted tryptamines: psilocin (including psilocybin and 4-AcO-DMT/psilacetin), DMT, and 5-MeO-DMT.
  • Ergolines: LSD and lisuride.
  • Substituted phenethylamines: DOI, MDMA, methylone, and mescaline.
  • Dissociatives: ketamine (including esketamine and arketamine).
  • Iboga-derivatives: ibogaine, noribogaine, tabernanthine, and tabernanthalog (DLX-007).
  • Zalsupindole (DLX-001; AAZ-A-154) and DLX-159.
  • Scopolamine.
  • Rapastinel.
  • Tropoflavin (7,8-DHF) (including R7 and R13).
  • LY-341495.
  • Isoflurane.

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What was STAR*D?

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Introduction

Sequenced Treatment Alternatives to Relieve Depression (STARD) was a collaborative study on the treatment of depression, funded by the National Institute of Mental Health. Its main focus was on the treatment of depression in patients where the first prescribed antidepressant proved inadequate. A key feature of the study was its aim to be more generalisable to real clinical situations; this was done through the use of minimal exclusion criteria, incorporating patient preference, and not blinding the treatments (i.e. the patient and clinician both knew what treatment the patient was receiving).

The STARD trial included remission (the near-absence of symptoms, rather than simply a reduction in symptoms) as an outcome measure, as there is evidence that patients with depression who achieve remission function better and are less prone to relapse than those who achieve only partial improvement in symptoms.

This report had profound impact on the promotion of antidepressants but later accused of having been subjected to multiple levels of fraud.

Trial

The STAR*D trial enrolled 4,041 outpatients with nonpsychotic depression at 23 psychiatric and 18 primary care sites. The trial was completed in 2006, and data from it has been available since 2008.

The trial involved four different treatment levels, and patients were encouraged to enter the next level of treatment if they failed to achieve remission or response (50% reduction in symptoms) after a specified number of weeks.

In level one, patients received the selective serotonin reuptake inhibitor (SSRI) citalopram for up to 14 weeks, with adjustment of the dose being managed by their own physicians. If patients achieved remission or response during that time period, they could enter a 12-month naturalistic follow-up, during which time the researchers did not have any influence over the treatment plan. Non-remitters were encouraged to enter level two.

In level two, there were seven different treatment options, and cognitive behavioural therapy (CBT) was included as the psychotherapy option. There were three combination options (either an antidepressant or CBT added to citalopram), and four switch options (to either a different antidepressant or CBT). Those who remitted or responded were offered 12-month naturalistic follow-up; non-remitters after two medication trials were encouraged to enter level 3; other non-remitters entered level 2A, which involved a second antidepressant trial.

In level three, patients were offered the addition of lithium or triiodothyronine (a thyroid hormone) to their antidepressant, or a switch to another antidepressant (mirtazapine or nortriptyline). This continued for 12 weeks.

Level four consisted of the monoamine oxidase inhibitor tranylcypromine or a combination of venlafaxine and mirtazapine.

Results

For level one, the remission rate was 28-33% (depending on the symptom scale used), and the response rate was 47%. Higher remission rates were seen in patients who were Caucasian, female, employed, or had higher levels of income or education. Lower remission rates were seen in those with longer depressive episodes, co-occurring anxiety or substance use disorders, and more physical illness.

For level two, patients who received CBT, either alone or combined with citalopram, had similar response and remission rates compared to those who were receiving medication(s) only; however, for those patients who remained on citalopram, those who had another antidepressant added achieved remission more rapidly than those who had CBT added. Among the patients who were switched to a different antidepressant, there was no significant difference among the different antidepressants.

For level three, the remission rates based on the HAM-D symptom scale were 12.3% for mirtazapine and 19.8% for nortriptyline, although the difference was not large enough for statistical significance. The remission rates based on the HAM-D in the combination strategy were 15.9% for lithium and 24.7% for triiodothyronine, but the difference was not statistically significant. However, more patients receiving lithium than triiodothyronine left the study due to side effects.

For level four, the average remission rate was 13%, with no statistically significant difference between tranylcypromine and the venlafaxine/mirtazapine combination. More patients receiving tranylcypromine left the study due to side effects.

Overall, the study findings indicate that patients who do not achieve remission or response after several weeks of citalopram treatment could achieve those outcomes by the end of 14 weeks. The STAR*D researchers state that their data “suggest that a patient with persistent depression can get well after trying several treatment strategies, but his or her odds of beating the depression diminish as additional treatment strategies are needed.” With failed treatment at a higher step, the chances of remission were smaller – and this decrease was particularly significant after level two. For those who did achieve full remission, there was a decreased chance of relapse at 12-month (naturalistic) follow-up compared to those patients who only responded.

A reanalysis published in 2023 concluded that STAR*D’s cumulative remission rate was approximately half of that reported.

Criticism

Criticism of bias has been raised by certain researchers about the STAR*D trial:

  • The research contract provided for the assessment of depression by the HRSD and IDS-C30 scales. Instead, depression was assessed using an ex-nihilo study scale (QIDS-SR), which was used for both medical decision-making and scientific evaluation.
  • STAR*D changed the inclusion and exclusion criteria for subjects during the study, so 931 subjects were included when they met the exclusion criteria, and 370 subjects were excluded while they met the inclusion criteria. These changes resulted in an increase in the average score of the subjects: according to the inclusion and exclusion criteria provided by the original protocol, the remission rate was 38%; according to the inclusion and exclusion criteria implemented retrospectively, the remission rate is 67%.
  • Only 7% of subjects in remission remained stable and stayed in the study until the end. This represents only 3% of subjects according to the original inclusion and exclusion criteria (108 out of 3,671). This has not been specified.

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An Overview of the Pharmacology of Antidepressants

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Introduction

The pharmacology of antidepressants is not entirely clear.

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine). It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All antidepressants that have entered the market before 2011 have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.

Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid (within 2 hours), robust and sustained (lasting for up to a fortnight) antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don’t directly influence mood, but influence emotional perception biases.[9]

Monoamine Hypothesis

In 1965, Joseph Schildkraut published a review article stating that several researchers had found an association between depression and deficiency of the catecholamine family of monoamine neurotransmitters, which they had begun calling the “catecholamine hypothesis”, also known as the monoamine hypothesis.

By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain.

Serotonin levels in the human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response. Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin levels in the brain and symptoms of depression have not been linked.

Although there is evidence that antidepressants inhibit the reuptake of serotonin, norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants, and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants.

While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2A receptors, suggesting it is too simplistic to say serotonin is a “happy neurotransmitter”. In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again – the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behaviour. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.

Hypothalamic-Pituitary-Adrenal Axis

One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not known whether this HPA axis dysregulation is reactive or causative for depression. A 2003 briefing suggests that the mode of action of antidepressants may be in regulating HPA axis function.

A 2011 study combines aspects of the HPA axis theory and the neurogenic theory (see below). The researchers showed that mice under unpredictable chronic mild stress (a well-known animal model of depression) have impaired hippocampal neurogenesis and greatly reduced ability of the hippocampus to regulate the HPA axis, causing anhedonia as measured by the Cookie Test. Administration of fluoxetine (an SSRI) without removing the stressor causes increased hippocampal neurogenesis, normalisation of the HPA axis, and improvement of anhedonia. If X-ray irradiation is used on the hippocampus before drug treatment to prevent neurogenesis, no improvement of anhedonia occurs. However, if an irradiated mouse is given a corticotropin-releasing factor 1 antagonist – a drug that directly targets the HPA axis – anhedonia is improved. Combined with the fact that irridiation without stressing does not impair hippocampal control of the HPA axis, the authors conclude that fluoxetine works by improving hippocampal neurogenesis, which then helps restore the HPA axis, in turn leading to improvements in depression symptoms such as anhedonia.

Neurogenic Adaptations

The neurogenic hypothesis states that molecular and cellular mechanisms underlying the regulation of adult neurogenesis is required for remission from depression and that neurogenesis is mediated by the action of antidepressants. A broader view is that antidepressants help by increasing neuroplasticity in general.

Chronic use of SSRI antidepressant increased neurogenesis in the hippocampus of rats and mice. Other antidepressant treatments also appear associated with hippocampal neurogenesis and/or neuroplasticity: electroconvulsive therapy, which is known to be highly effective for depression, is associated with higher BDNF expression in the hippocampus as well as global rewiring; lithium and valporate, two mood stabilisers occasionally used as add-on treatment, are associated with increased survival and proliferation of neurons. Ketamine (see also esketamine), a new fast-acting antidepressant, can increase the number of dendritic spines and restore aspects of functional connectivity after a single infusion.

Other animal research suggests that long term drug-induced antidepressants effects modulate the expression of genes mediated by clock genes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).

The delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, MAOIs, TCAs, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolised by cyclic nucleotide phosphodiesterases (PDEs).

Studies on human patients have used imaging approaches to measure the changes in density and volume of specific brain areas. The grey matter volume of parts of the brain are differently increased or decreased by SSRI use. It appears possible to use brain imaging to predict which patients are likely to respond to SSRI antidepressants.

Anti-Inflammatory and Iimmunomodulation

Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system.

Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes, may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones. SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10), as well as TNF-alpha and interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.

These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

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What is Oxazepam?

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Introduction

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety, insomnia, and to control symptoms of alcohol withdrawal syndrome.

It is a metabolite of diazepam, prazepam, and temazepam, and has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, sedative, and skeletal muscle relaxant properties compared to other benzodiazepines.

It was patented in 1962 and approved for medical use in 1964.

Medical Uses

Oxazepam is an intermediate-acting benzodiazepine with a slow onset of action, so it is usually prescribed to individuals who have trouble staying asleep, rather than falling asleep. It is commonly prescribed for anxiety disorders with associated tension, irritability, and agitation. It is also prescribed for drug and alcohol withdrawal, and for anxiety associated with depression. Oxazepam is sometimes prescribed off-label to treat social phobia, post-traumatic stress disorder, insomnia, premenstrual syndrome, and other conditions.

Side Effects

The side effects of oxazepam are similar to those of other benzodiazepines, and may include dizziness, drowsiness, headache, memory impairment, paradoxical excitement, and anterograde amnesia, but does not affect transient global amnesia.[citation needed] Withdrawal effects due to rapid decreases in dosage or abrupt discontinuation of oxazepam may include abdominal and muscle cramps, seizures, depression, insomnia, sweating, tremors, or nausea and vomiting.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence and Withdrawal

Oxazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction, and benzodiazepine withdrawal syndrome. Withdrawal from oxazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur, though, at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.

Contraindications

Oxazepam is contraindicated in myasthenia gravis, chronic obstructive pulmonary disease, and limited pulmonary reserve, as well as severe hepatic disease.

Special Precautions

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders. Benzodiazepines including oxazepam are lipophilic drugs and rapidly penetrate membranes, so rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines in late pregnancy, especially high doses, may result in floppy infant syndrome.

Pregnancy

Oxazepam, when taken during the third trimester, causes a definite risk to the neonate, including a severe benzodiazepine withdrawal syndrome including hypotonia, reluctance to suck, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Interactions

As oxazepam is an active metabolite of diazepam, an overlap in possible interactions is likely with other drugs or food, with exception of the pharmacokinetic CYP450 interactions (e.g. with cimetidine). Precautions and following the prescription are required when taking oxazepam (or other benzodiazepines) in combinations with antidepressants or opioids. Concurrent use of these medications can interact in a way that is difficult to predict. Drinking alcohol when taking oxazepam is not recommended. Concomitant use of oxazepam and alcohol can lead to increased sedation, memory impairment, ataxia, decreased muscle tone, and, in severe cases or in predisposed patients, respiratory depression and coma.

Overdose

Oxazepam is generally less toxic in overdose than other benzodiazepines. Important factors which affect the severity of a benzodiazepine overdose include the dose ingested, the age of the patient, and health status prior to overdose. Benzodiazepine overdoses can be much more dangerous if a coingestion of other CNS depressants such as opiates or alcohol has occurred. Symptoms of an oxazepam overdose include:

  • Respiratory depression
  • Excessive somnolence
  • Altered consciousness
  • Central nervous system depression
  • Occasionally cardiovascular and pulmonary toxicity
  • Rarely, deep coma

Pharmacology

Oxazepam is an intermediate-acting benzodiazepine of the 3-hydroxy family; it acts on benzodiazepine receptors, resulting in increased effect of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system. The half-life of oxazepam is between 6 and 9 hours. It has been shown to suppress cortisol levels. Oxazepam is the most slowly absorbed and has the slowest onset of action of all the common benzodiazepines according to one British study.

Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain similar drugs. It may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather, it is simply metabolised by glucuronidation, so oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this respect. Preferential storage of oxazepam occurs in some organs, including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of oxazepam during pregnancy and breast feeding is recommended, as oxazepam is excreted in breast milk.

Two milligrams of oxazepam equates to 1 mg of diazepam according to the benzodiazepine equivalency converter, therefore 20 mg of oxazepam according to BZD equivalency equates to 10 mg of diazepam and 15 mg oxazepam to 7.5 mg diazepam (rounded up to 8 mg of diazepam). Some BZD equivalency converters use 3 to 1 (oxazepam to diazepam), 1 to 3 (diazepam to oxazepam) as the ratio (3:1 and 1:3), so 15 mg of oxazepam would equate to 5 mg of diazepam.

Chemistry

Oxazepam exists as a racemic mixture. Early attempts to isolate enantiomers were unsuccessful; the corresponding acetate has been isolated as a single enantiomer. Given the different rates of epimerisation that occur at different pH levels, it was determined that there would be no therapeutic benefit to the administration of a single enantiomer over the racemic mixture.

Frequency of Use

Oxazepam, along with diazepam, nitrazepam, and temazepam, were the four benzodiazepines listed on the pharmaceutical benefits scheme and represented 82% of the benzodiazepine prescriptions in Australia in 1990–1991. It is in several countries the benzodiazepine of choice for novice users, due to a low chance of accumulation and a relatively slow absorption speed.

Society and Culture

Misuse

Oxazepam has the potential for misuse, defined as taking the drug to achieve a high, or continuing to take the drug in the long term against medical advice. Benzodiazepines, including diazepam, oxazepam, nitrazepam, and flunitrazepam, accounted for the largest volume of forged drug prescriptions in Sweden from 1982 to 1986. During this time, a total of 52% of drug forgeries were for benzodiazepines, suggesting they were a major prescription drug class of abuse.

However, due to its slow rate of absorption and its slow onset of action, oxazepam has a relatively low potential for abuse compared to some other benzodiazepines, such as temazepam, flunitrazepam, or triazolam. This is similar to the varied potential for abuse between different drugs of the barbiturate class.

Legal Status

Oxazepam is a Schedule IV drug under the Convention on Psychotropic Substances.

Brand Names

Oxazepam is marketed under many brand names worldwide, including: Alepam, Alepan, Anoxa, Anxiolit, Comedormir, durazepam, Murelax, Nozepam, Oksazepam, Opamox, Ox-Pam, Oxa-CT, Oxabenz, Oxamin, Oxapam, Oxapax, Oxascand, Oxaze, Oxazepam, Oxazépam, Oxazin, Oxepam, Praxiten, Purata, Selars, Serax, Serepax, Seresta, Séresta, Serpax, Sobril, Tazepam, Vaben, and Youfei.

It is also marketed in combination with hyoscine as Novalona and in combination with alanine as Pausafrent T.

Environmental Concerns

In 2013, a laboratory study which exposed European perch to oxazepam concentrations equivalent to those present in European rivers (1.8 μg/L) found that they exhibited increased activity, reduced sociality, and higher feeding rate. In 2016, a follow-up study which exposed salmon smolt to oxazepam for seven days before letting them migrate observed increased intensity of migratory behaviour compared to controls. A 2019 study associated this faster, bolder behaviour in exposed smolt to increased mortality due to a higher likelihood of being predated on.

On the other hand, a 2018 study from the same authors, which kept 480 European perch and 12 northern pikes in 12 ponds over 70 days, half of them control and half spiked with oxazepam, found no significant difference in either perch growth or mortality. However, it suggested that the latter could be explained by the exposed perch and pike being equally hampered by oxazepam, rather than the lack of an overall effect. Lastly, a 2021 study built on these results by comparing two whole lakes filled with perch and pikes – one control while the other was exposed to oxazepam 11 days into experiment, at concentrations between 11 and 24 μg/L, which is 200 times greater than the reported concentrations in the European rivers. Even so, there were no measurable effects on pike behaviour after the addition of oxazepam, while the effects on perch behaviour were found to be negligible. The authors concluded that the effects previously attributed to oxazepam were instead likely caused by a combination of fish being stressed by human handling and small aquaria, followed by being exposed to a novel environment.

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What is Opipramol?

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Introduction

Opipramol, sold under the brand name Insidon among others, is an anxiolytic and tricyclic antidepressant (TCA) that is used throughout Europe. Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is not a monoamine reuptake inhibitor like most other TCAs, and instead acts primarily as a sigma-1 receptor agonist. It was developed by Schindler and Blattner in 1961.

Brief History

Opipramol was developed by Geigy. It first appeared in the literature in 1952 and was patented in 1961. The drug was first introduced for use in medicine in 1961. Opipramol was one of the first TCAs to be introduced, with imipramine marketed in the 1950s and amitriptyline marketed in 1961.

Medical Uses

Opipramol is typically used in the treatment of generalised anxiety disorder (GAD) and somatoform disorders. Preliminary studies suggest that opipramol shows potential clinical significance in the treatment of severe sleep bruxism.

Contraindications

  • In patients with hypersensitivity to opipramol or another component of the formulation
  • Acute alcohol, sedative, analgesic, and antidepressant intoxications
  • Acute urinary retention
  • Acute delirium
  • Untreated narrow-angle glaucoma
  • Benign prostatic hyperplasia with residual urinary retention
  • Paralytic ileus
  • Pre-existing higher-grade atrioventricular blockages or diffuse supraventricular or ventricular stimulus conduction disturbances
  • Combination with monoamine oxidase inhibitor (MAOI)

Pregnancy and Lactation

Experimental animal studies did not indicate injurious effects of opipramol on the embryonic development or fertility. Opipramol should only be prescribed during pregnancy, particularly in the first trimester, for compelling indication. It should not be used during lactation and breastfeeding, since it passes into breast milk in small quantities.

Side Effects

Frequently (≥1% to <10%) reported adverse reactions with opipramol, especially at the beginning of the treatment, include fatigue, dry mouth, blocked nose, hypotension, and orthostatic dysregulation.

Adverse reactions reported occasionally (≥0.1% to <1%) include dizziness, stupor, micturition disturbances, vigilance, accommodation disturbances, tremor, weight gain, thirst, allergic skin reactions (rash, urticaria), abnormal ejaculation, erectile impotence, constipation, transient increases in liver enzymes, tachycardia, and palpitations.

Rarely (≥0.01% to <0.1%) reported adverse reactions include excitation, headache, paraesthesia especially in elderly patients, restlessness, sweating, sleep disturbances, oedema, galactorrhoea, urine blockage, nausea and vomiting, fever, collapse conditions, stimulation conducting disturbances, intensification of present heart insufficiency, blood profile changes particularly leukopenia, confusion, delirium, stomach complaints, taste disturbance, and paralytic ileus especially with sudden discontinuation of a longer-term high-dose therapy.

Very rarely (<0.01%) reported adverse reactions include seizures, motor disorders (akathisia, dyskinesia, ataxia), polyneuropathy, glaucoma, anxiety, hair loss, agranulocytosis, severe liver dysfunction after long-term treatment, jaundice, and chronic liver damage.

Overdose

Symptoms of intoxication from overdose include drowsiness, insomnia, stupor, agitation, coma, transient confusion, increased anxiety, ataxia, convulsions, oliguria, anuria, tachycardia or bradycardia, arrhythmia, AV block, hypotension, shock, respiratory depression, and, rarely, cardiac arrest.

Interactions

While opipramol is not a monoamine reuptake inhibitor, any irreversible MAOIs should still be discontinued at least 14 days before treatment. Opipramol can compete with other tricyclic antidepressants, beta blockers, antiarrhythmics (of class 1c), and other drugs for microsomal enzymes, which can lead to slower metabolism and higher plasma concentrations of these drugs. Co-administration of antipsychotics (e.g., haloperidol, risperidone) can increase the plasma concentration of opipramol. Barbiturates and anticonvulsants can reduce the plasma concentration of opipramol and thereby weaken its therapeutic effect.[3]

Pharmacology

Pharmacodynamics

Opipramol acts as a high affinity sigma receptor agonist, primarily of the σ1 subtype, but also of the σ2 subtype with lower affinity. In one study of σ1 receptor ligands that also included haloperidol, pentazocine, (+)-3-PPP, ditolylguanidine, dextromethorphan, SKF-10,047 ((±)-alazocine), ifenprodil, progesterone, and others, opipramol showed the highest affinity (Ki = 0.2–0.3) for the guinea pig σ1 receptor of all the tested ligands except haloperidol, which it was approximately equipotent with. The sigma receptor agonism of opipramol is thought to be responsible for its therapeutic benefits against anxiety and depression.

Unlike other TCAs, opipramol does not inhibit the reuptake of serotonin or norepinephrine. However, it does act as a high affinity antagonist of the histamine H1 receptor and is a low to moderate affinity antagonist of the dopamine D2, serotonin 5-HT2, and α1-adrenergic receptors. H1 receptor antagonism accounts for its antihistamine effects and associated sedative side effects. In contrast to other TCAs, opipramol has very low affinity for the muscarinic acetylcholine receptors and virtually no anticholinergic effects.

Sigma receptors are a set of proteins located in the endoplasmic reticulum. σ1 receptors play key role in potentiating intracellular calcium mobilisation thereby acting as sensor or modulator of calcium signalling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors cause neurotransmitter release. Opipramol is said to have a biphasic action, with prompt initial improvement of tension, anxiety, and insomnia followed by improved mood later. Hence, it is an anxiolytic with an antidepressant component. After sub-chronic treatment with opipramol, σ2 receptors are significantly downregulated but σ1 receptors are not.

Pharmacokinetics

Opipramol is rapidly and completely absorbed by the gastrointestinal tract. The bioavailability of opipramol amounts to 94%. After single oral administration of 50 mg, the peak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/mL. After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/mL. Therapeutic concentrations of opipramol range from 140 to 550 nmol/L. The plasma protein binding amounts to approximately 91% and the volume of distribution is approximately 10 L/kg. Opipramol is partially metabolised in the liver to deshydroxyethylopipramol. Metabolism occurs through the CYP2D6 isoenzyme. Its terminal half-life in plasma is 6–11 hours. About 70% is eliminated in urine with 10% unaltered. The remaining portion is eliminated through faeces.

Society and Culture

Generic Names

Opipramol is the English, German, French, and Spanish generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while opipramol hydrochloride is its USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name. Its generic name in Italian and its DCITTooltip Denominazione Comune Italiana is opipramolo and in Latin is opipramolum.

Brand Names

Opipramol is marketed under the brand names Deprenil, Dinsidon, Ensidon, Insidon, Insomin, Inzeton, Nisidana, Opipram, Opramol, Oprimol, Pramolan, and Sympramol among others.

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