Tag: MDD: Major Depressive Disorder

An Overview of Lithium (as a Medication)

Published on by Andrew MarshallLeave a comment

Introduction

Certain lithium compounds, also known as lithium salts, are used as psychiatric medication, primarily for bipolar disorder and for major depressive disorder. Lithium is taken orally (by mouth).

Common side effects include increased urination, shakiness of the hands, and increased thirst. Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. If levels become too high, diarrhoea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur. Lithium is teratogenic and can cause birth defects at high doses, especially during the first trimester of pregnancy. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied. The American Academy of Paediatrics lists lithium as contraindicated for pregnancy and lactation. The United States Food and Drug Administration (FDA categorises lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.

Lithium salts are classified as mood stabilisers. Lithium’s mechanism of action is not known.

In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer. Its use in the treatment of mental disorders began with Carl Lange in Denmark and William Alexander Hammond in New York City, who used lithium to treat mania from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established (on a different theoretical basis) in 1948 by John Cade in Australia. Lithium carbonate is on the World Health Organisation’s List of Essential Medicines, and is available as a generic medication. In 2022, it was the 212th most commonly prescribed medication in the United States, with more than 1 million prescriptions. It appears to be underused in older people, and in certain countries, for reasons including patients’ negative beliefs about lithium.

Brief History

Lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York City used lithium to treat mania from the 1870s onwards.

By the turn of the 20th century, as theory regarding mood disorders evolved and so-called “brain gout” disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, several lithium preparations were still produced for the control of renal calculi and uric acid diathesis. As accumulating knowledge indicated a role for excess sodium intake in hypertension and heart disease, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride). This practice and the sale of lithium itself were both banned in the United States in February 1949, following the publication of reports detailing side effects and deaths.

Also in 1949, the Australian psychiatrist John Cade and Australian biochemist Shirley Andrews rediscovered the usefulness of lithium salts in treating mania while working at the Royal Park Psychiatric Hospital in Victoria. They were injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine blocks them), they needed soluble urate for a control. They used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade and Andrews traced the effect to the lithium-ion itself, and after Cade ingested lithium himself to ensure its safety in humans, he proposed lithium salts as tranquilisers. He soon succeeded in controlling mania in chronically hospitalised patients with them. This was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades.

The rest of the world was slow to adopt this treatment, largely because of deaths that resulted from even relatively minor overdosing, including those reported from the use of lithium chloride as a substitute for table salt. Largely through the research and other efforts of Denmark’s Mogens Schou and Paul Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the US, this resistance was slowly overcome. Following the recommendation of the APA Lithium Task Force (William Bunney, Irvin Cohen (Chair), Jonathan Cole, Ronald R. Fieve, Samuel Gershon, Robert Prien, and Joseph Tupin[133]), the application of lithium in manic illness was approved by the FDA in 1970, becoming the 50th nation to do so.

Lithium has now become a part of Western popular culture. Characters in Pi, Premonition, Stardust Memories, American Psycho, Garden State, and An Unmarried Woman all take lithium. It’s the chief constituent of the calming drug in Ira Levin’s dystopian This Perfect Day. Sirius XM Satellite Radio in North America has a 1990s alternative rock station called Lithium, and several songs refer to the use of lithium as a mood stabiliser. These include: “Equilibrium met Lithium” by South African artist Koos Kombuis, “Lithium” by Evanescence, “Lithium” by Nirvana, “Lithium and a Lover” by Sirenia, “Lithium Sunset”, from the album Mercury Falling by Sting, and “Lithium” by Thin White Rope.

7 Up

As with cocaine in Coca-Cola, lithium was widely marketed as one of several patent medicine products popular in the late 19th and early 20th centuries and was the medicinal ingredient of a refreshment beverage. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-lime soft drink in 1920. The product, originally named “Bib-Label Lithiated Lemon-Lime Soda”, was launched two weeks before the Wall Street Crash of 1929. It contained the mood stabiliser lithium citrate, and was one of many patent medicine products popular in the late-19th and early-20th centuries. Its name was soon changed to 7 Up. All American beverage makers were forced to remove lithium from beverages in 1948. Despite the ban, in 1950, the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.

Medical Uses

In 1970, lithium was approved by the FDA for the treatment of bipolar disorder, which remains its primary use in the US. It is sometimes used when other treatments are not effective in a number of other conditions, including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label.

Bipolar Disorder

Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilise mood and prevent manic episodes, but it may also be helpful in the acute treatment of manic episodes. Although recommended by treatment guidelines for the treatment of depression in bipolar disorder, the evidence that lithium is superior to placebo for acute depression is low-quality; atypical antipsychotics are considered more effective for treating acute depressive episodes. Lithium carbonate treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level (representing a low therapeutic index), requiring close monitoring of blood levels of lithium carbonate during treatment. Within the therapeutic range there is a dose-response relationship. A limited amount of evidence suggests lithium carbonate may contribute to the treatment of substance use disorders for some people with bipolar disorder. Although it is believed that lithium prevents suicide in people with bipolar disorder, a 2022 systematic review found that:

“Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.”

Schizophrenic Disorders

Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone. The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.

Major Depressive Disorder

Lithium is widely prescribed as an adjunct treatment for depression.

Augmentation

If therapy with antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]) does not fully treat and discontinue the symptoms of major depressive disorder (MDD) (also known as refractory depression or treatment resistant depression [TRD]) then a second augmentation agent is sometimes added to the therapy. Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomised controlled trials and it has been prescribed (off-label) for this purpose since the 1980s. A 2019 systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated.

While SSRIs have been mentioned above as a drug class in which lithium is used to augment, there are other classes in which lithium is added to increase effectiveness. Such classes are antipsychotics (used for bipolar disorder) as well as antiepileptic drugs (used for both psychiatric and epileptic cases). Lamotrigine and topiramate are two specific antiepileptic drugs in which lithium is used to augment.

Monotherapy

There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants. A recent study concluded that lithium works best on chronic and recurrent depression when compared to modern antidepressant (i.e. citalopram) but not for patients with no history of depression. A 2019 systemic review found no evidence to support the use of lithium for monotherapy.

Prevention of Suicide

Lithium is widely believed to prevent suicide and is often used in clinical practice towards that end. However, meta-analyses, faced with evidence base limitations, have yielded differing results, and it therefore remains unclear whether or not lithium is efficacious in the prevention of suicide. However, some evidence suggests it is effective in significantly reducing the risk of self-harm and unintentional injury for bipolar disorder in comparison to no treatment and to antipsychotics or valporate. According to meta-analyses, the increased presence of lithium in drinking water is correlated with lower overall suicide rates, especially among men. It is noted that further testing is needed to confirm this benefit.

Alzheimer’s Disease

Alzheimer’s disease affects forty-five million people and is the fifth leading cause of death in the 65-plus population. There is no complete cure for the disease, currently. However, lithium is being evaluated for its effectiveness as a potential therapeutic measure. One of the leading causes of Alzheimer’s is the hyperphosphorylation of the tau protein by the enzyme GSK-3, which leads to the overproduction of amyloid peptides that cause cell death. To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme. Lithium also stimulates neurogenesis within the hippocampus, making it thicker. Yet another cause of Alzheimer’s disease is the dysregulation of calcium ions within the brain. Too much or too little calcium within the brain can lead to cell death. Lithium can restore intracellular calcium homeostasis by inhibiting the wrongful influx of calcium upstream. It also promotes the redirection of the influx of calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria.

In 2009, a study was performed by Hampel and colleagues that asked patients with Alzheimer’s to take a low dose of lithium daily for three months; it resulted in a significant slowing of cognitive decline, benefitting patients being in the prodromal stage the most. Upon a secondary analysis, the brains of the Alzheimer’s patients were studied and shown to have an increase in BDNF markers, meaning they had actually shown cognitive improvement. Another study, a population study this time by Kessing et al., showed a negative correlation between Alzheimer’s disease deaths and the presence of lithium in drinking water. Areas with increased lithium in their drinking water showed less dementia overall in their population.

Monitoring

Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.

Lithium concentrations in whole blood, plasma, serum, or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L) in well-controlled people, but may increase to 1.8–2.5 mmol/L in those who accumulate the drug over time and to 3–10 mmol/L in acute overdose.

Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4[a][b] to 1.2 mmol/L on samples taken 12 hours after the preceding dose.

Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months.

Given the risks of kidney malfunction, serum creatinine, and eGFR should be checked before lithium is instituted and monitored after 3–6 months at regular intervals. Patients who have a rise in creatinine on three or more occasions, even if their eGFR is > 60 ml/min/ 1.73m2 require further evaluation, including a urinalysis for haematuria, and proteinuria, a review of their medical history with attention paid to cardiovascular, urological, and medication history, and blood pressure control and management. Overt proteinuria should be further quantified with a urine protein-to-creatinine ratio.

Discontinuation

For patients who have achieved long-term remission, it is recommended to discontinue lithium gradually and in a controlled fashion.

Discontinuation symptoms may occur in patients stopping the medication including irritability, restlessness, and somatic symptoms like vertigo, dizziness, or lightheadedness. Symptoms occur within the first week and are generally mild and self-limiting within weeks.

Cluster Headaches, Migraine, and Hypnic Headache

Studies testing prophylactic use of lithium in cluster headaches (when compared to verapamil), migraine attacks, and hypnic headache indicate good efficacy.

Adverse Effects

The adverse effects of lithium include:

Very Common (> 10% incidence) Adverse Effects

  • Confusion
  • Constipation (usually transient, but can persist in some)
  • Decreased memory
  • Diarrhea (usually transient, but can persist in some)
  • Dry mouth
  • EKG changes – usually benign changes in T waves
  • Hand tremor (usually transient, but can persist in some) with an incidence of 27%. If severe, psychiatrist may lower lithium dosage, change lithium salt type or modify lithium preparation from long to short-acting (despite lacking evidence for these procedures) or use pharmacological help
  • Headache
  • Hyperreflexia — overresponsive reflexes
  • Leukocytosis — elevated white blood cell count
  • Muscle weakness (usually transient, but can persist in some)
  • Myoclonus — muscle twitching
  • Nausea (usually transient)
  • Polydipsia — increased thirst
  • Polyuria — increased urination
  • Renal (kidney) toxicity which may lead to chronic kidney failure, although some cases may be misattributed
  • Vomiting (usually transient, but can persist in some)
  • Vertigo

Common (1–10%) Adverse Effects

  • Acne
  • Extrapyramidal side effects — movement-related problems such as muscle rigidity, parkinsonism, dystonia, etc.
  • Euthyroid goitre — i.e. the formation of a goitre despite normal thyroid functioning
  • Hypothyroidism — a deficiency of thyroid hormone, though this condition is already common among patients with bipolar disorder.
  • Hair loss/hair thinning
  • Weight gain — 5% incidence, tends to start fast and then plateau. Usually ends at 1–2 kg.

Unknown Incidence

Sexual dysfunction
Hypoglycaemia
Glycosuria
In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.

In the average bipolar patient, chronic lithium use is not associated with cognitive decline.

Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.

Hypothyroidism

The rate of hypothyroidism is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary.

Because lithium competes with the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene. It increases the appetite and thirst (“polydypsia”) and reduces the activity of thyroid hormone (hypothyroidism). The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to cause renal dysfunction, although this does not appear to be common.

Lambert et al. (2016), comparing the rate of hypothyroidism in patients with bipolar disorder treated with 9 different medications, found that lithium users do not have a particularly high rate of hypothyroidism (8.8%) among BD patients – only 1.39 times the rate in oxcarbazepine users (6.3%). Lithium and quetiapine are not statistically different in terms of hypothyroidism rates. However, lithium users are tested much more frequently for hypothyroidism than those using other drugs. The authors write that there may be an element of surveillance bias in understanding lithium’s effects on the thyroid glands, as lithium users are tested 2.3-3.1 times as often. Furthermore, the authors argue that because hypothyroidism is common among BD patients regardless of lithium treatment, regular thyroid testing should be applied to all BD patients, not just those on lithium.

Pregnancy

Lithium is a teratogen, which can cause birth defects in a small number of newborns. Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defects including Ebstein’s anomaly if taken during pregnancy. Teratogenicity is affected by trimester and dose of Lithium. Most significantly affecting first-trimester cardiac development with greater effects at higher doses.

As the risks of stopping Lithium can be significant, patients are sometimes recommended to stay on this medicine while pregnant. Careful weighing of the risks and benefits should be made in consultation with a psychiatric physician.

For patients who are exposed to lithium, or plan to stay on the medication throughout their pregnancy, foetal echocardiography is routinely performed to monitor for cardiac anomalies.

While lithium is typically the most effective treatment, possible alternatives to Lithium include lamotrigine and second generation antipsychotics for the treatment of acute bipolar depression or for the management of bipolar patients with normal mood during pregnancy.

Breastfeeding

While only small amounts of Lithium are transmitted to the infant in breastmilk, there is limited data on the safety of Breastfeeding while on Lithium. Medical evaluation and monitoring of infants consuming breastmilk during maternal prescription may be indicated.

Kidney Damage

Lithium has been associated with several forms of kidney injury. It is estimated that impaired urinary concentrating ability is present in at least half of individuals on chronic lithium therapy, a condition called lithium-induced nephrogenic diabetes insipidus. Continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidus. In rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%.

Some reports of kidney damage may be wrongly attributed to lithium, increasing the apparent rate of this adverse effect. Nielsen et al. (2018), citing 6 large observational studies since 2010, argue that findings of decreased kidney function are partially inflated by surveillance bias. Furthermore, modern data does not show that lithium increases the risk of end-stage kidney disease. Davis et al. (2018), using literature from a wider timespan (1977–2018), also found that lithium’s association with chronic kidney disease is unproven with various contradicting results. They also find contradicting results regarding end-stage kidney disease.

A 2015 nationwide study suggests that chronic kidney disease can be avoided by maintaining the serum lithium concentration at a level of 0.6–0.8 mmol/L and by monitoring serum creatinine every 3–6 months.

Hyperparathyroidism

Lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. Lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia.

Interactions

Lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Lithium concentrations can also be increased with concurrent use of ACE inhibitors such as captopril, enalapril, and lisinopril.

Lithium is primarily cleared from the body through glomerular filtration, but some is then reabsorbed together with sodium through the proximal tubule. Its levels are therefore sensitive to water and electrolyte balance. Diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium. ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. This is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. Another possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body.

Some drugs can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include theophylline, caffeine, and acetazolamide. Additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium.

Lithium is known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others. Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.

High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported. Indeed, these and other antipsychotics have been associated with an increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.

Classical psychedelics such as psilocybin and LSD may cause seizures if taken while using lithium, although further research is needed.

Overdose

Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons who are taking lithium in which the lithium levels are affected by drug interactions in the body.

In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhoea, which may result in volume depletion. During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness.

In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status. During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific.

If the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. If the toxicity is severe, lithium may need to be removed from the body.

Mechanism of Action

The specific biochemical mechanism of lithium action in stabilising mood is unknown.

Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.

Unlike many other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations. Lithium may also increase the release of serotonin by neurons in the brain. In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarisation compared to no lithium treatment and the same depolarisation.

Lithium both directly and indirectly inhibits GSK3β (glycogen synthase kinase 3β) which results in the activation of mTOR. This leads to an increase in neuroprotective mechanisms by facilitating the Akt signalling pathway. GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. During mania, GSK-3β is activated via dopamine overactivity. GSK-3β inhibits the transcription factors β-catenin and cyclic AMP (cAMP) response element binding protein (CREB), by phosphorylation. This results in a decrease in the transcription of important genes encoding for neurotrophins. In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). The Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1.

Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signaling pathway in the central nervous system, which plays a crucial role in neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.

Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.

Although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is unlikely.

Oxidative Metabolism

Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder. Oxidative stress and reduced levels of antioxidants (such as glutathione) lead to cell death. Lithium may protect against oxidative stress by up-regulating complexes I and II of the mitochondrial electron transport chain.

Dopamine and G-Protein Coupling

During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. Lithium treatment alters the function of certain subunits of the dopamine-associated G-protein, which may be part of its mechanism of action.

Glutamate and NMDA Receptors

Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilisation and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission. The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and cesium.

GABA Receptors

GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid. Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins. Lithium’s regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood-stabilising effects.

Cyclic AMP Secondary Messengers

Lithium’s therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. The cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor-coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production. Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.

Inositol Depletion Hypothesis

Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2. This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction are affected by lithium. myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigate the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.

Neurotrophic Factors

Lithium’s actions on Gsk3 result in activation of CREB, leading to higher expression of BDNF. (Valproate, another mood stabilizer, also increases the expression of BDNF.) As expected of increased BDNF expression, chronic lithium treatment leads to increased grey matter volume in brain areas implicated in emotional processing and cognitive control. Bipolar patients treated with lithium also have higher white matter integrity compared to those taking other drugs.

Lithium also increases the expression of mesencephalic astrocyte-derived neurotrophic factor (MANF), another neurotrophic factor, via the AP-1 transcription factor. MANF is able to regulate proteostasis by interacting with GRP78, a protein involved in the unfolded protein response.

Salts and product names Lithium carbonate (Li2CO3) is the most commonly used form of lithium salts, a carbonic acid involving the lithium element and a carbonate ion. Other lithium salts are also used as medication, such as lithium citrate (Li3C6H5O7), lithium sulfate, lithium chloride, and lithium orotate. Nanoparticles and microemulsions have also been invented as drug delivery mechanisms. As of 2020, there is a lack of evidence that alternate formulations or salts of lithium would reduce the need for monitoring serum lithium levels or lower systemic toxicity.

As of 2017 lithium was marketed under many brand names worldwide, including Cade, Calith, Camcolit, Carbolim, Carbolit, Carbolith, Carbolithium, Carbolitium, Carbonato de Litio, Carboron, Ceglution, Contemnol, Efadermin (Lithium and Zinc Sulfate), Efalith (Lithium and Zinc Sulfate), Elcab, Eskalit, Eskalith, Frimania, Hypnorex, Kalitium, Karlit, Lalithium, Li-Liquid, Licarb, Licarbium, Lidin, Ligilin, Lilipin, Lilitin, Limas, Limed, Liskonum, Litarex, Lithane, Litheum, Lithicarb, Lithii carbonas, Lithii citras, Lithioderm, Lithiofor, Lithionit, Lithium, Lithium aceticum, Lithium asparagicum, Lithium Carbonate, Lithium Carbonicum, Lithium Citrate, Lithium DL-asparaginat-1-Wasser, Lithium gluconicum, Lithium-D-gluconat, Lithiumcarbonaat, Lithiumcarbonat, Lithiumcitrat, Lithiun, Lithobid, Lithocent, Lithotabs, Lithuril, Litiam, Liticarb, Litijum, Litio, Litiomal, Lito, Litocarb, Litocip, Maniprex, Milithin, Neurolepsin, Plenur, Priadel, Prianil, Prolix, Psicolit, Quilonium, Quilonorm, Quilonum, Téralithe, and Theralite.

Research

Tentative evidence in Alzheimer’s disease showed that lithium may slow progression. It has been studied for its potential use in the treatment of amyotrophic lateral sclerosis (ALS), but a study showed lithium had no effect on ALS outcomes.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Lithium_(medication) >; 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 Flesinoxan?

Published on by Andrew MarshallLeave a comment

Introduction

Flesinoxan (DU-29,373) is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class.

Outline

Originally developed as a potential antihypertensive drug, flesinoxan was later found to possess antidepressant and anxiolytic effects in animal tests. As a result, it was investigated in several small human pilot studies for the treatment of major depressive disorder (MDD), and was found to have robust effectiveness and very good tolerability. However, due to “management decisions”, the development of flesinoxan was stopped and it was not pursued any further.

In patients, flesinoxan enhances REM sleep latency, decreases body temperature, and increases ACTH, cortisol, prolactin, and growth hormone secretion.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Flesinoxan >; 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 Double Depression?

Published on by Andrew Marshall1 Comment

Introduction

Double depression refers to the co-existence of major depressive disorder (MDD) and persistent depressive disorder (PDD), the latter previously referred to as dysthymia. Research has shown that double depression tends to be more severe than either MDD or PDD alone and that individuals with double depression experience relapse more often than those with either MDD or PDD alone. However, there is some research that indicates few differences exist between double depression, MDD, and PDD; as a result, those researchers conclude that double depression is not a distinct disorder.

The literature that details the pharmaceutical treatment of double depression is sparse. Although there are studies that demonstrate that certain medications, such as selective serotonin reuptake inhibitors (SSRIs), are effective methods of treatment, those studies lack placebo controls; therefore, the studies’ conclusions are questionable.

Research has found that, as is the case with other depressive disorders, pharmaceutical and therapeutic treatments combined are more effective than the use of either form of treatment alone. Individuals with double depression tend to experience more functional impairment than those with either MDD or PDD alone. As a result, researchers emphasize the need for unique treatments for double depression to be developed and implemented.

Presentation

Individuals with double depression meet the DSM-5 classification criteria for both MDD and PDD. Goldney and Fisher (2004) determined that, in a sample of 3,010 individuals from southern portions of Australia calculated a prevalence rate of double depression of 2.2%. Jonas et al. (2003) reported a prevalence rate of double depression in the United States of 3.4%—based upon an assessment of 7,667 Americans. The prevalence rate of double depression can be compared to rates of PDD at 6.2%, major depressive episode (MDE) at 8.6%, and major depressive episode with severity (MDE-s) at 7.7%. Keller and Shapiro (1982) found that 26% of patients within a sample of 101 met the criteria for both MDD and PDD; however, the aforementioned sample is much smaller—and much more inclined to inaccuracies—than the samples (3,010 and 7,667) described above. Thus, double depression is less common than other forms of depression, but it is still a form of depression that warrants medical attention in the form of behavioral therapies; pharmaceutical treatments; or, both (Miller, Norman, and Keitner, 1999).

The characteristics of those with double depression tend to be more severe in nature than those associated with those who have either MDD or PDD. Levitt, Joffe, and MacDonald (1991) found that those with double depression experience fluctuations in mood at an earlier point in life, a more substantial number of depressive episodes, as well as co-morbid disorders of anxieties more often than their MDD-alone counterparts. Goldney and Fisher (2004) reported that individuals with double depression seek medical attention more often than those with either MDD or PDD alone. Leader and Klein (1996) found that individuals with double depression experience a more substantial level of social impairment, which includes factors such as leisure pursuits and relationship characteristics, than those with either MDD or PDD. Dixon and Thyer (1998) concluded that individuals with double depression experiences recoveries on a more frequent basis than their counterparts who have MDD alone (88% to 69%); however, individuals with double depression experience the most substantial rates of relapse of all of those who suffer from chronic depression. In addition, remission from MDD tends to happen faster than remission from PDD (Dixon & Thyer, 1998).

Miller, Norman, and Dow (1986) reported that individuals with double depression endure a more severe path of illness, but experience few differences with respect to social impairment compared to their MDD-alone counterparts. In addition, McCullough et al. (2000) found that, with the exception that patients with double depression tended to experience of more severe illness, few differences were apparent. Therefore, the conclusions drawn in previous research that are associated with the nature of the clinical presentation of double depression are mixed. Multiple scientists emphasize the need for additional research to determine adequate treatments for those with double depression, as depression is a disease that places a considerable burden upon communities and societies; furthermore, those researchers predict depression will be, in an economic sense, the second-most burdensome disease on societies come 2020.

Treatment

Research on pharmaceutical treatment of double depression in particular is sparse. Certain medications, such as fluoxetine, were found in numerous studies to be effective at reducing symptom severity; however, these studies involved open-label trials, double-blind randomised trials that lack placebo conditions, and small sample sizes. Thus, placebo-controlled trials are needed in order to determine adequate and unique treatments for double depression. In addition, the considerable burden depression places upon communities and societies (Goldney & Fisher, 2004) emphasizes the need for additional research into the treatment of chronic depression.

Hellerstein et al. (1994) theorised that antidepressant medications could be used to ameliorate both MDD and PDD; a pharmaceutical trial found that fluoxetine facilitated remission in 57.1% of patients after five months of treatment. In addition, Miller, Norman, and Keitner (1999) conducted an intervention in which one cohort received pharmaceutical treatment while another cohort received both pharmaceutical and therapeutic treatment. Their results indicated that those who received the combined intervention were more functional—in a social sense—as well as relieved of their depression than those who received the pharmaceutical intervention alone (Miller, Norman, & Keitner, 1999). However, the researchers found that the effect disappeared at both the 6 and 12-month follow-up assessments.

Vasile et al. (2012) conducted a pharmaceutical trial with 16 patients with double depression (who had comorbid alcohol dependence) who were treated and monitored for six months. Results showed that three antidepressants – venlafaxine, duloxetine, and milnacipran – were associated with substantial improvement; venlafaxine was the most effective of the three antidepressants.

Koran, Aboujaoude, and Gamel (2007) conducted a pharmaceutical trial with 24 adults who received duloxetine over the course of a 12-week period. Results showed that duloxetine was successful in the treatment of both PDD as well as double depression. However, the researchers’ trial was an open-label trial; as a result, the researchers called for a double-blind and placebo-controlled trial to be conducted in order to further validate the benefits the medication seems to provide.

In addition, Waslick et al. (1999) used duloxetine to treat 19 children and adolescents with either PDD or double depression; after eight weeks of pharmaceutical treatment, 11 of the patients failed to meet the classification criteria for one of the two disorders, which led to the conclusion that duloxetine was a medication that appeared to provide relief from PDD and double depression in children and adolescents. However, the aforementioned trial (in addition to Koran et al.’s (2007) trial) was an open-label trial, which the authors noted as a limitation.

Hirschfield et al. (1998) conducted a 12-week randomised controlled trial (RCT) that involved the administration of sertraline or imipramine, after which 324 of 623 patients either qualified for remission or experienced a substantive improvement in clinical presentation. In a double-blind, fixed-dose trial that involved the use of either the monoamine oxidase inhibitor (MAOI) moclobemide or the SSRI fluoxetine, Duarte, Mikkelsen, and DeliniStula (1996) were able to facilitate a minimum of a 50% score reduction on the Hamilton Depression Rating Scale (HDRS). 71% of cases that involved moclobemide – versus 38% of cases that involved fluoxetine – were determined to achieve the aforementioned desired outcome. As a result, the researchers concluded that both antidepressants were similar in their abilities to treat double depression in an effective fashion. However, the lack of a placebo control undermines the extent to which the results can be applied.

Marin, Kocsis, Frances, and Parides (1994) conducted an eight-week open trial that entailed the administration of desipramine to 42 individuals with double depression and 33 individuals with PDD. The researchers found that 70% of the PDD patients experienced a substantial improvement in clinical presentation; the proportion associated with the double depression-cohort was said to be similar. However, the lack of blindness as well as a placebo control notes a considerable limitation of the aforementioned research.

Goldney and Bain (2006) found that those who have double depression receive some form of treatment on a more substantial basis than their MDD-alone and PDD-alone counterparts. To elaborate, the authors measured that, in Australia, 41.4% of those evaluated with double depression received treatment three or more times over the course of the previous month, whereas 34.5% of those with MDD alone; 23.2% of those with PDD alone; and 10.3% of those who were not depressed received treatment three or more times over the course of the previous month (Goldney & Bain, 2006). In addition, the researchers concluded that those with double depression acquire a more substantial number of treatment visits per month (a mean of 4.3) when compared to their MDD-alone counterparts (a mean of 3.0); their PDD-alone counterparts (a mean of 2.6); and their non-depressed counterparts (a mean of 1.5).

Prognosis

Although double depression is less prevalent than either MDD or PDD, it is still a form of depression that warrants medical attention in the form of behavioural therapies; pharmaceutical treatments; or, both. Miller, Norman, and Keitner (1999) found that the use of both behavioural and pharmaceutical treatments was more effective on a short-term basis in the reduction of depression than the use of pharmaceutical treatments alone.

Klein, Shankman, and Rose (2008) determined that poor maternal-child relationship, histories of sexual abuse, co-morbid disorders of anxieties, and lower educational attainment predicted an increased HAM-D score after a decade; the researchers also determined that those same factors predicted, after a decade, increased functional impairment. In addition, the results showed that the life course of depression did not differ to a substantial extent between individuals with MDD-alone and double depression.

Hirschfield et al. (1998) conducted a 12-week RCT that involved the administration of sertraline or imipramine, in which the most notable predictors of treatment response were educational attainment and relationship status; in addition, the authors noted the apparent influence of intrinsic personal traits. However, Hirschfield et al. noted the limitation of a lack of a placebo control.

Klein, Taylor, Harding, and Dickstein (1988) reported that, via their assessment of clinical, familial, and socio-environmental characteristics of those with chronic depression, at a six-month follow-up, individuals with double depression experienced decreased rates of remission, increased manifestations of clinical depressive phenomena, increased functional impairment, and increased likelihood of the development and onset of a hypomanic episode than their MDD-alone counterparts; as a result, the authors underscore the importance of the creation of a distinct classification of double depression due to its unique episodic path.

Controversies

Previous research on the clinical presentation of double depression tends to be mixed. Numerous studies indicate that the course of double depression tends to be more severe in nature. In addition, numerous studies demonstrate that individuals with double depression seek medical attention to a more substantial extent than those with either MDD or PDD. However, Miller, Norman, and Dow (1986) determined that individuals with MDD or PDD versus individuals with double depression experienced similar levels of social impairment. In addition, McCullough and colleagues found that there were few additional differences overall between the characteristics of those with double depression versus those with either MDD or PDD.

Research on the course of double depression is also mixed. Klein, Taylor, Harding, and Dickstein (1988) found that remission in individuals with double depression is less probable than it is in individuals with either MDD or PDD; the researchers also noted that those with double depression are more prone to the development and onset of a hypomanic episode than those with either MDD or PDD. In addition, Klein, Shankman, and Rose (2008) and Hirschfield et al. (1998) both concluded that educational status predicted treatment outcome. However, Levitt, Joffe, and MacDonald (1991) demonstrated that the courses of the respective depressive disorders did not differ to a substantial extent. While Klein, Shankman, and Rose (2008) advocate for the creation of a distinct classification of double depression in the future edition(s) of the DSM, Levitt and colleagues (as well as McCullough and colleagues) seem to indicate that, due to the numerous similarities as well as limited differences between double depression and either MDD or PDD, the creation of such a classification would be inappropriate and incorrect. Remick, Sadovnick, Lam, Zis, and Yee (1996) determine that the heritable bases of MDD, PDD, and double depression are similar and that, as a result, the three disorders are unable to be differentiated.

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

Published on by Andrew Marshall2 Comments

Introduction

Milnacipran (trade names Ixel, Savella, Dalcipran, Toledomin) is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.

Brief History

Milnacipran was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed (as Ixel) for this indication in over 45 countries worldwide including several European countries such as Austria, Bulgaria, Finland, France, Portugal, and Russia. It is also available in Japan (as Toledomin) and Mexico (as Dalcipran). Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the United States and Canada in 2003 from the manufacturer Laboratoires Pierre Fabre.

In January 2009 the US Food and Drug Administration (FDA) approved milnacipran (under the brand name Savella) only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States. In July and November 2009, the European Medicines Agency refused marketing authorisation for a milnacipran product (under the brand name Impulsor) for the treatment of fibromyalgia.

Medical Uses

Depression

In a pooled analysis of 7 comparative trials with imipramine, milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs concluded a superior efficacy for milnacipran with similar tolerability for milnacipran and SSRIs. A more recent meta-analysis of 6 studies involving more than 1,000 patients showed no distinction between milnacipran and SSRIs in efficacy or discontinuation rates, including discontinuation for side effects or lack of efficacy. A meta-analysis of a total of 16 randomised controlled trials with more than 2200 patients concluded that there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressant agents. However, compared with TCAs, significantly fewer patients taking milnacipran dropped out due to adverse events. As with other antidepressants, 1 to 3 weeks may elapse before significant antidepressant action becomes clinically evident.

Impulse Control

Milnacipran was found to improve impulse control in rats, which has been linked to its activation of D1-like receptors in the infralimbic cortex. However, high doses of milnacipran did not show this effect, likely because of increased dopamine in the nucleus accumbens. Depression has been associated with increased impulsivity.

Fibromyalgia

During its development for fibromyalgia, milnacipran was evaluated utilizing a composite responder approach. To be considered as a responder for the composite ‘treatment of fibromyalgia’ endpoint, each patient had to show concurrent and clinically meaningful improvements in pain, physical function, and global impression of disease status. A systematic review in 2015 showed moderate relief for a minority of people with fibromyalgia. Milnacipran was associated with increased adverse events when discontinuing use of the drug.

Social Anxiety

There is some evidence that milnacipran may be effective for social anxiety.

Contraindications

Administration of milnacipran should be avoided in individuals with the following:

  • Known hypersensitivity to milnacipran (absolute contraindication)
  • Patients under 15 years of age (no sufficient clinical data)
  • Concomitant treatment with irreversible MAO inhibitors (e.g. tranylcypromine (Parnate), phenelzine (Nardil), >10 mg selegiline) or digitalis glycosides is an absolute contraindication.

Administration of milnacipran should be done with caution in individuals with the following:

  • Concomitant treatment with parenteral epinephrine, norepinephrine, with clonidine, reversible MAO-A Inhibitors (such as moclobemide, toloxatone) or 5-HT1D-agonists (e.g. triptan migraine drugs)
  • Advanced renal disease (decreased dosage required)
  • Hypertrophy of the prostate gland (possibly urination hesitancy induced), with hypertension and heart disease (tachycardia may be a problem) as well as with open angle glaucoma.

Milnacipran should not be used during pregnancy because it may cross the placenta barrier and no clinical data exists on harmful effects in humans and animal studies. Milnacipran is contraindicated during lactation because it is excreted in the milk, and it is not known if it is harmful to the newborn.

Side Effects

The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhydrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension [FDA Savella prescribing information]. Milnacipran can have a significant impact on sexual functions, including both a decrease in sexual desire and ability. Milnacipran can cause pain of the testicles in men. The incidence of cardiovascular and anticholinergic side effects was significantly lower compared to TCAs as a controlled study with over 3,300 patients revealed. Elevation of liver enzymes without signs of symptomatic liver disease has been infrequent. Mood swing to mania has also been seen and dictates termination of treatment. In psychotic patients emergence of delirium has been noticed. Milnacipran has a low incidence of sedation but improves sleep (both duration and quality) in depressed patients. In agitated patients or those with suicidal thoughts additive sedative/anxiolytic treatment is usually indicated. However, several studies found that there seems to be no “activation syndrome” and no increased risk of suicidality in milnacipran therapy; instead it is said to reduce suicidality along with depressive symptoms.

Interactions

  • MAOIs — hyperserotonergia (serotonin syndrome), potentially lethal hypertensive crisis.
  • 5-HT1 receptor agonists — coronary vasoconstriction with risk of angina pectoris and myocardial infarction.
  • Epinephrine, norepinephrine (also in local anaesthesia) — hypertensive crisis and/or possible cardiac arrhythmia.
  • Clonidine — antihypertensive action of clonidine may be antagonised
  • Digitalis — haemodynamic actions increased.
  • Triptans — there have been rare postmarketing reports of hyperserotonergia (serotonin syndrome). If concomitant treatment of milnacipran with a triptan is clinically warranted, careful observation of patient is advised when starting or increasing dosages.
  • Alcohol — no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended; the FDA advises against the concomitant use of alcohol and milnacipran.

Pharmacology

Pharmacodynamics

Milnacipran inhibits the reuptake of serotonin and norepinephrine in an approximately 2:1 ratio, respectively. Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors, nor on benzodiazepine and opioid binding sites.

Recently, levomilnacipran, the levorotatory enantiomer of milnacipran, has been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment of Alzheimer’s disease. Other BACE-1 inhibitors, such as CTS-21166 (ASP1720), MK-8931, and AZD3293 were in clinical trials for the treatment of Alzheimer’s disease, but in both cases clinical trials were halted due to a lack of positive evidence of a favourable benefit to risk ratio and both were considered unlikely to return satisfactory results.

Pharmacokinetics

Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%. Meals do not have an influence on the rapidity and extent of absorption. Peak plasma concentrations are reached 2 hours after oral dosing. The elimination half-life of 8 hours is not increased by liver impairment and old age, but by significant renal disease. Milnacipran is conjugated to the inactive glucuronide and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found.

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

Published on by Andrew MarshallLeave a comment

Introduction

Lubazodone (developmental code names YM-992, YM-35995) is an experimental antidepressant which was under development by Yamanouchi for the treatment for major depressive disorder in the late 1990s and early 2000s but was never marketed.

Outline

It acts as a serotonin reuptake inhibitor (Ki for SERTTooltip serotonin transporter = 21 nM) and 5-HT2A receptor antagonist (Ki = 86 nM), and hence has the profile of a serotonin antagonist and reuptake inhibitor (SARI). The drug has good selectivity against a range of other monoamine receptors, with its next highest affinities being for the α1-adrenergic receptor (Ki = 200 nM) and the 5-HT2C receptor (Ki = 680 nM).

Lubazodone is structurally related to trazodone and nefazodone, but is a stronger serotonin reuptake inhibitor and weaker as a 5-HT2A receptor antagonist in comparison to them and is more balanced in its actions as a SARI. It reached phase II clinical trials for depression, but development was discontinued in 2001 reportedly due to the “erosion of the SSRITooltip selective serotonin reuptake inhibitor market in the United States”.

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

Published on by Andrew Marshall2 Comments

Introduction

Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally.

Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion). Gepirone acts as a partial agonist of the serotonin 5-HT1A receptor. An active metabolite of gepirone, 1-(2-pyrimidinyl)piperazine, is an α2-adrenergic receptor antagonist. Gepirone is a member of the azapirone group of compounds.

Gepirone was synthesized by Bristol-Myers Squibb in 1986 and was developed and marketed by Fabre-Kramer Pharmaceuticals. It was approved for the treatment of major depressive disorder in the United States in September 2023. This came after the drug had been rejected by the US Food and Drug Administration (FDA) three times over two decades due to insufficient evidence of effectiveness.

Brief History

Gepirone was developed by Bristol-Myers Squibb in 1986, but was out-licensed to Fabre-Kramer in 1993. The FDA rejected approval for gepirone in 2002 and 2004. It was submitted for the preregistration (NDA) phase again in May 2007 after adding additional information from clinical trials as the FDA required in 2009. However, in 2012 it once again failed to convince the FDA of its qualities for treating anxiety and depression. In December 2015, the FDA once again gave gepirone a negative review for depression due to concerns of efficacy. However, in March 2016, the FDA reversed its decision and gave gepirone ER a positive review. Gepirone ER was finally approved for the treatment of major depressive disorder in the United States in September 2023.

Medical Uses

Gepirone is indicated for the treatment of major depressive disorder in adults. Of 15 clinical trials of gepirone for major depressive disorder submitted to the FDA, three were excluded for methodological reasons, three were deemed “failed” and “uninformative”, seven were deemed negative and did not demonstrate effectiveness, and two were deemed positive and did show effectiveness. Two positive trials are needed for FDA drug approval, with this being the case regardless of the number of negative trials. In the two positive trials of gepirone for depression, the drug significantly outperformed placebo in terms of depressive symptom reduction and showed effect sizes similar to those of other approved antidepressants. In both trials, gepirone reduced depressive symptoms by about 2.5 points more than placebo on the 52-point Hamilton Depression Rating Scale (17-item version or HAMD-17). The baseline depression scores in the trials ranged from 22.7 to 24.2 in the different patient groups.

Available Forms

Gepirone comes in the form of extended-release tablets of the hydrochloride salt, gepirone hydrochloride, in the strengths 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg.

Side Effects

Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion).

Interactions

The CYP3A4 inhibitors ketoconazole and verapamil strongly increase exposure to gepirone, whereas lithium, paroxetine, and warfarin have no effect on exposure to gepirone. The CYP3A4 inducer rifampin profoundly decreases exposure to gepirone.

Pharmacology

Pharmacodynamics

Gepirone acts as a selective partial agonist of the 5-HT1A receptor. Unlike its relative buspirone, however, gepirone has greater efficacy in activating the 5-HT1A and has negligible affinity for the D2 receptor (30- to 50-fold lower in comparison to buspirone). However, similarly to buspirone, gepirone metabolises into 1-(2-pyrimidinyl)piperazine (1-PP), which is known to act as a potent antagonist of the α2-adrenergic receptor.

Pharmacokinetics

Absorption

The absolute bioavailability of gepirone is 14 to 17%. The time to peak concentrations of gepirone with the extended-release formulation is 6 hours. When taken with a high-fat meal, the time to peak levels decreases to 3 hours. A high-fat meal increases exposure to gepirone, with the effect increasing dependent on the amount of fat in the meal. Peak concentrations were increased by 27% with a low-fat meal, 55% with a medium-fat meal, and 62% with a high-fat meal, while area-under-the-curve levels of gepirone were increased by 14% with a low-fat meal, 22% with a medium-fat meal, and 32 to 37% with a high-fat meal. The effect was similar for the metabolites of gepirone, 1-PP and 3′-hydroxygepirone (3′-OH-gepirone).

Distribution

The apparent volume of distribution of gepirone is approximately 94.5 L. The plasma protein binding of gepirone in vitro is 72% and is independent of concentration. The plasma protein binding of 3′-OH-gepirone is 59% and of 1-PP is 42%.

Metabolism

Gepirone is metabolised primarily by CYP3A4. Its major metabolites are 1-PP and 3′-OH-gepirone, both of which are pharmacologically active. These metabolites are present in the circulation at higher concentrations than gepirone.

Elimination

With a single oral dose of radiolabeled gepirone, 81% is recovered in urine and 13% is recovered in faeces as metabolites. About 60% of the gepirone is eliminated in urine within 24 hours.

The terminal half-life of gepirone as the extended-release form is approximately 5 hours.

Chemistry

Gepirone is a member of the azapirone group of compounds and is structurally related to buspirone, tandospirone, and other azapirones.

Society and Culture

Names

The brand name of gepirone is Exxua. Former tentative brand names which were never used included Ariza, Variza, and Travivo.

Research

Gepirone is under development for the treatment of decreased libido and generalized anxiety disorder. As of October 2023, it is in phase 3 clinical trials for these indications. The pro-sexual effects of gepirone appear to be independent of its antidepressant and anxiolytic effects.

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

Published on by Andrew MarshallLeave a comment

Introduction

Brexpiprazole, sold under the brand name Rexulti among others, is a medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease. It is an atypical antipsychotic.

The most common side effects include akathisia (a constant urge to move) and weight gain. The most common side effects among people with agitation associated with dementia due to Alzheimer’s disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia).

Brexpiprazole was developed by Otsuka and Lundbeck, and is considered to be a successor to aripiprazole (Abilify). It was approved for medical use in the United States in July 2015. A generic version was approved in August 2022. Brexpiprazole is the first treatment approved by the US Food and Drug Administration (FDA) for agitation associated with dementia due to Alzheimer’s disease.

Medical Uses

In the United States and Canada, brexpiprazole is indicated as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. In May 2023, the indication for brexpiprazole was expanded in the US to include the treatment of agitation associated with dementia due to Alzheimer’s disease.

In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.

In 2020, it was approved in Brazil only as an adjunctive to the treatment of major depressive disorder.

Side Effects

The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%). Brexpiprazole can cause impulse control disorders.

Pharmacology

Pharmacodynamics

Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors. Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor, aripiprazole, which may decrease its risk for agitation and restlessness. Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D2 receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, while brexpiprazole has the inverse effect because a partial agonist competes with dopamine. Brexpiprazole has a high affinity for the 5-HT1A receptor, acting as a potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole. In vivo characterisation of brexpiprazole shows that it may act as a near-full agonist of the 5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT1A receptor agonism. It is also an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the α1A-, α1B-, α1D-, and α2C-adrenergic receptors. The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects. Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.

Brief History

Clinical Trials

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease.

Major Depressive Disorder

Phase II

The phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.

Phase III

A phase III study was in the recruiting stage: “Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)”. Its goal is “to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with major depressive disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT”. Estimated enrolment was 1,250 volunteers.

Adult Attention Deficit Hyperactivity Disorder

  • Attention Deficit/Hyperactivity Disorder (STEP-A)

Schizophrenia

Phase I

  • Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder

Phase II

  • A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia

Phase III

  • Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)
  • Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)
  • A Long-term Trial of OPC-34712 in Patients With Schizophrenia

Agitation Associated with Dementia due to Alzheimer’s Disease

The effectiveness of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer’s disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies. In these studies, participants were required to have a probable diagnosis of Alzheimer’s dementia; have a score between 5 and 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviours that require medication. Trial participants ranged between 51 and 90 years of age.

Society and Culture

Legal Status

In January 2018, it was approved for the treatment of schizophrenia in Japan.

Economics

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance. Lundbeck gave Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.

Patents

  • US Patent 8,071,600
  • WIPO PCT/JP2006/317704
  • Canadian patent: 2620688

Research

Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication. It reached phase II clinical trials for this use prior to discontinuation.

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

Published on by Andrew Marshall4 Comments

Introduction

Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally.

Common side-effects include dry mouth, feeling faint, vomiting, and headache. More serious side effects may include suicide, mania, irregular heart rate, and pathologically prolonged erections. It is unclear if use during pregnancy or breastfeeding is safe. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. Trazodone also has sedating effects.

Trazodone was approved for medical use in the United States in 1981. It is available as a generic medication. In 2020, it was the 21st most commonly prescribed medication in the United States, with more than 26 million prescriptions.

Brief History

Trazodone was developed in Italy, in the 1960s, by Angelini Research Laboratories as a second-generation antidepressant. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold. In sharp contrast to most other antidepressants available at the time of its development, trazodone showed minimal effects on muscarinic cholinergic receptors. Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration (FDA) in 1981 and was the first non-tricyclic or MAOI antidepressant approved in the US.

Medical Uses

Depression

The primary use of trazodone is the treatment of unipolar major depression with or without anxiety. Data from open and double-blind trials suggest the antidepressant efficacy of trazodone is comparable to that of amitriptyline, doxepin, and mianserin. Also, trazodone showed anxiolytic properties, low cardiotoxicity, and relatively mild side effects.

Because trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for geriatric patients with depression when it first became available. Three double-blind studies reported trazodone has antidepressant efficacy similar to that of other antidepressants in geriatric patients. However, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients; thus, this side effect, along with sedation, often makes trazodone less acceptable for this population, compared with newer compounds that share its lack of anticholinergic activity but not the rest of its side-effect profile. Still, trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia.

Trazodone is usually used at a dosage of 150 to 300 mg/day for the treatment of depression. Lower doses have also been used to augment other antidepressants, or when initiating therapy. Higher doses up to 600 mg/day have been used in more severe cases of depression, for instance in hospitalised patients. Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective.

Insomnia

Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication. It may also be used to treat antidepressant-related insomnia. Trazodone was the second-most prescribed agent for insomnia in the early 2000s, though most studies of trazodone for treatment of sleep disturbances have been in depressed individuals.

Systematic reviews and meta-analyses published in the late 2010s, including a Cochrane review, found low-dose trazodone to be an effective medication for short-term treatment of insomnia both in depressed and non-depressed people. Trazodone slightly improves subjective sleep quality (SMD = –0.34 to –0.41) and reduces number of nighttime awakenings (MD = –0.31, SMD = –0.51). Conversely, it does not appear to affect sleep onset, total sleep time, time awake after sleep onset, or sleep efficiency. It appears to increase deep sleep, in contrast to certain other hypnotics. The quality of evidence of trazodone for short-term treatment of insomnia was rated as low to moderate. There is no evidence available at present to inform long-term use of trazodone in the treatment of insomnia.

The benefits of trazodone for insomnia must be weighed against potential adverse effects such as morning grogginess, daytime sleepiness, cognitive and motor impairment, and postural hypotension, among others. Quality safety data on use of trazodone as a sleep aid are currently lacking.

Trazodone is used at low doses in the range of 25 to 150 mg/day for insomnia. Higher doses of 200 to 600 mg/day have also been studied.

The American Academy of Sleep Medicine’s 2017 clinical practice guidelines recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits.

Other Disorders

Trazodone is often used in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), and obsessive–compulsive disorder (OCD). However, use of trazodone in anxiety disorders is off-label and evidence of its effectiveness for these indications is variable and limited. Benefits for OCD appear to be mild. Besides anxiety, trazodone has been used to treat sleep disturbances and nightmares in PTSD. Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders.

Combination with Other Antidepressants

Trazodone is often used in combination with other antidepressants such as selective serotonin reuptake inhibitors (SSRI) in order to augment their antidepressant and anxiolytic effects and to reduce side effects such as sexual dysfunction, anxiety, and insomnia.

Available Forms

Trazodone is provided as the hydrochloride salt and is available in the form of 50 mg, 100 mg, 150 mg, and 300 mg oral tablets.

An extended-release oral tablet formulation at doses of 150 mg and 300 mg is also available.

Side Effects

Because of its lack of anticholinergic side effects, trazodone is especially useful in situations in which antimuscarinic effects are particularly problematic (e.g. in patients with benign prostatic hyperplasia, closed-angle glaucoma, or severe constipation). Trazodone’s propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable psychomotor retardation and feelings of low energy, therapeutic doses of trazodone may not be tolerable because of sedation. Trazodone elicits orthostatic hypotension in some people, probably as a consequence of α1-adrenergic receptor blockade. The unmasking of bipolar disorder may occur with trazodone and other antidepressants.

Precautions for trazodone include known hypersensitivity to trazodone and under 18 years and combined with other antidepressant medications, it may increase the possibility of suicidal thoughts or actions.

While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly. Care must, therefore, be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.

Suicide

Antidepressants may increase the risk of suicidal thoughts and behaviours in children and young adults. Close monitoring for emergence of suicidal thoughts and behaviours is thus recommended.

Sedation

Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired. Compared to the reversible MAOI antidepressant drug moclobemide, more impairment of vigilance occurs with trazodone. Trazodone has been found to impair driving ability.

Cardiac

Case reports have noted cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with pre-existing mitral valve prolapse and in patients with negative personal and family histories of cardiac disease.

QT prolongation has been reported with trazodone therapy. Arrhythmia identified include isolated PVCs, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. Several post-marketing reports have been made of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

Priapism

A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors. More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. <150 mg/day). Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment. Spontaneous orgasms have also been reported with trazodone in men.

Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms.

Others

Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.

Elevated prolactin concentrations have been observed in people taking trazodone. They appear to be increased by around 1.5- to 2-fold.

Studies on trazodone and cognitive function are mixed, with some finding improvement, others finding no change, and some finding impairment.

Trazodone does not seem to worsen periodic limb movements during sleep.

Trazodone is associated with increased risk of falls in older adults. It has also been associated with increased risk of hip fractures in older adults.

Pregnancy and Lactation

Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.

Overdose

There are reported cases of high doses of trazodone precipitating serotonin syndrome. There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome.

Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200 mg. In one report, 9 of 294 cases of overdose were fatal, and all nine patients had also taken other central nervous system (CNS) depressants. When trazodone overdoses occur, clinicians should carefully monitor for low blood pressure, a potentially serious toxic effect. In a report of a fatal trazodone overdose, torsades de pointes and complete atrioventricular block developed, along with subsequent multiple organ failure, with a trazodone plasma concentration of 25.4 mg/L on admission.

Interactions

Trazodone is metabolised by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2. Its active metabolite meta-chlorophenylpiperazine (mCPP) is known to be formed by CYP3A4 and metabolized by CYP2D6. Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations. The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may interact with these substances. Potent CYP3A4 inhibitors such as clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ketoconazole, and ritonavir may lead to increased concentrations of trazodone and decreased concentrations of mCPP, while CYP3A4 inducers like carbamazepine, enzalutamide, phenytoin, phenobarbital, and St. John’s wort may result in decreased trazodone concentrations and increased mCPP concentrations. CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP while CYP2D6 inducers may decrease their concentrations. Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. CYP1A2 inhibitors may increase trazodone concentrations while CYP1A2 inducers may decrease trazodone concentrations. Examples of potent CYP1A2 inhibitors include ethinylestradiol (found in hormonal birth control), fluoroquinolones (e.g. ciprofloxacin), fluvoxamine, and St. John’s wort, while potent CYP1A2 inducers include phenytoin, rifampin, ritonavir, and tobacco.

A study found that ritonavir, a strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased trazodone peak levels by 1.34-fold, increased area-under-the-curve levels by 2.4-fold, and decreased the clearance of trazodone by 50%. This was associated with adverse effects such as nausea, hypotension, and syncope. Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of trazodone by 60 to 74%. The strong CYP2D6 inhibitor thioridazine has been reported to increase concentrations of trazodone by 1.36-fold and concentrations of mCPP by 1.54-fold. On the other hand, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although it did correlate with side effects like dizziness and prolonged corrected QT interval.

Combination of trazodone with SSRIs, tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors has a theoretical risk of serotonin syndrome. However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context. On the other hand, cases of excessive sedation and serotonin syndrome have been reported with the combinations of trazodone and fluoxetine or paroxetine. This may be due to combined potentiation of the serotonin system. However, it may also be related to the fact that fluoxetine and paroxetine are strong inhibitors of CYP2D6 and fluoxetine is additionally a weak or moderate inhibitor of CYP3A4. Accordingly, fluoxetine has been reported to result in increased levels of trazodone and mCPP by 1.31- to 1.65-fold and by 2.97- to 3.39-fold, respectively.

Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone. Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.29-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers. Smoking is known to induce CYP1A2, and this may be involved in these findings.

Pharmacology

Pharmacodynamics

Trazodone is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H1 receptor antagonist, and weak serotonin reuptake inhibitor. More specifically, it is an antagonist of 5-HT2A and 5-HT2B receptors, a partial agonist of the 5-HT1A receptor, and an antagonist of the α1- and α2-adrenergic receptors.It is also a ligand of the 5-HT2C receptor with lower affinity than for the 5-HT2A receptor. However, it is unknown whether trazodone acts as a full agonist, partial agonist, or antagonist of the 5-HT2C receptor. Trazodone is a 5-HT1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity. A range of weak affinities (Ki) have been reported for trazodone at the human histamine H1 receptor, including 220 nM, 350 nM, 500 nM, and 1,100 nM.

Trazodone has a minor active metabolite known as meta-chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of trazodone. In contrast to trazodone, mCPP is an agonist of various serotonin receptors. It has relatively low affinity for α1-adrenergic receptors unlike trazodone, but does high affinity for α2-adrenergic receptors and weak affinity for the H1 receptor. In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA. In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic neurotoxicity).

Trazodone’s 5-HT2A receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) type.

Target Occupancy Studies

Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question. Roughly half of brain 5-HT2A receptors are blocked by 1 mg of trazodone and essentially all 5-HT2A receptors are saturated at 10 mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100 mg range. The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100 mg/day and 90% at 150 mg/day. Trazodone may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150 mg/day. Significant occupancy of a number of other sites may also occur. However, another study estimated much lower occupancy of the SERT and 5-HT2A receptors by trazodone.

Correspondence to Clinical Effects

Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression. Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak. In relation to these properties, trazodone does not have similar properties to SSRIs and is not particularly associated with increased appetite and weight gain – unlike other 5-HT2C antagonists like mirtazapine. Moderate 5-HT1A partial agonism may contribute to trazodone’s antidepressant and anxiolytic actions to some extent as well.

The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone. Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia. Low doses exploit trazodone’s potent actions as a 5-HT2A receptor antagonist, and its properties as an antagonist of H1 and α1-adrenergic receptors, but do not adequately exploit its SERT or 5-HT2C inhibition properties, which are weaker. Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic is often necessary for patients with a major depressive episode. Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to improvement of other symptoms such as loss of energy and depressed mood. Thus, the ability of low doses of trazodone to improve sleep in depressed patients may be an important mechanism whereby trazodone can augment the efficacy of other antidepressants.

Trazodone’s potent α1-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation. Conversely, along with 5-HT2A and H1 receptor antagonism, it may contribute to its efficacy as a hypnotic. Trazodone lacks any affinity for the muscarinic acetylcholine receptors, so does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor modulator and serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits. However, research has not supported this hypothesis and mCPP might actually antagonise the efficacy of trazodone as well as produce additional side effects.

Pharmacokinetics

Absorption

Trazodone is well-absorbed after oral administration. Its bioavailability is 65 to 80%. Peak blood levels of trazodone occur 1 to 2 hours after ingestion and peak levels of the metabolite mCPP occur after 2 to 4 hours. Absorption is somewhat delayed and enhanced by food.

Distribution

Trazodone is not sequestered into any tissue. The medication is 89 to 95% protein-bound. The volume of distribution of trazodone is 0.8 to 1.5 L/kg. Trazodone is highly lipophilic.

Metabolism

The metabolic pathways involved in the metabolism are not well-characterized. In any case, the cytochrome P450 enzymes CYP3A4, CYP2D6, and CYP1A2 may all be involved to varying extents. Trazodone is known to be extensively metabolized by the liver via hydroxylation, N-oxidation, and N-dealkylation. Several metabolites of trazodone have been identified, including a dihydrodiol metabolite (via hydroxylation), a metabolite hydroxylated at the para position of the meta-chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via N-dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen. CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of trazodone or mCPP. In any case, there are large interindividual variations in the metabolism of trazodone. In addition, poor metabolisers of dextromethorphan, a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than do extensive metabolizers.

mCPP is formed from trazodone by CYP3A4 and is metabolised via hydroxylation by CYP2D6 (to a para-hydroxylated metabolite). It may contribute to the pharmacological actions of trazodone. mCPP levels are only 10% of those of trazodone during therapy with trazodone, but is nonetheless present at concentrations known to produce psychic and physical effects in humans when mCPP has been administered alone. In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP. As a consequence of the production of mCPP as a metabolite, patients administered trazodone may test positive on EMIT II urine tests for the presence of MDMA (“ecstasy”).

Elimination

The elimination of trazodone is biphasic: the first phase’s half-life (distribution) is 3 to 6 hours, and the following phase’s half-life (elimination) is 4.1 to 14.6 hours. The elimination half-life of extended-release trazodone is 9.1 to 13.2 hours. The elimination half-life of mCPP is 2.6 to 16.0 hours and is longer than that of trazodone. Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours. The remaining drug and its metabolites are excreted in the faeces via biliary elimination. Less than 1% of the drug is excreted in its unchanged form. After an oral dose of trazodone, it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP. mCPP is glucuronidated and sulfated similarly to other trazodone metabolites.

Chemistry

Trazodone is a triazolopyridine derivative and a phenylpiperazine that is structurally related to nefazodone and etoperidone, each of which are derivatives of it. Flibanserin is an analogue of trazodone.

Society and Culture

Generic Names

Trazodone is the generic name of the drug and its INN, BAN, and DCF, while trazodone hydrochloride is its USAN, USP, BANM, and JAN.

Brand Names

Trazodone has been marketed under a large number of brand names throughout the world. Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide).

Research

Trazodone may be effective in the treatment of sexual dysfunction, for instance female sexual dysfunction and erectile dysfunction. A 2003 systematic review and meta-analysis found some indication that trazodone may be useful in the treatment of erectile dysfunction. Besides trazodone alone, a combination of trazodone and bupropion (developmental code names and tentative brand names S1P-104, S1P-205, Lorexys, and Orexa) is under development for the treatment of erectile dysfunction and female sexual dysfunction. As of September 2021, it is in phase 2 clinical trials for these indications. It has been in this stage of clinical development since at least February 2015.

Trazodone may be useful in the treatment of certain symptoms like sleep disturbances in alcohol withdrawal and recovery. However, reviews have recommended against use of trazodone for alcohol withdrawal due to inadequate evidence. Very limited evidence suggests that trazodone might be useful in the treatment of certain symptoms in cocaine use disorder. Trazodone has been reported to be effective in the treatment of sleep apnoea. Cochrane reviews found that trazodone was not effective in the treatment of agitation in dementia. Another Cochrane review found that trazodone might be useful in the treatment of sleep disturbances in dementia. Further systematic reviews have found that trazodone may be effective for behavioural and psychological symptoms in dementias such as frontotemporal dementia and Alzheimer’s disease.

Trazodone has been studied as an adjunctive therapy in the treatment of schizophrenia. It has been reported to decrease negative symptoms without worsening positive symptoms although improvement in negative symptoms was modest. Trazodone has also been reported to be effective in treating antipsychotic-related extrapyramidal symptoms such as akathisia. Trazodone has been studied and reported to be effective in the treatment of bulimia, but there is limited evidence to support this use. It might be useful in the treatment of night eating disorder as well. Trazodone might be effective in the treatment of adjustment disorder. It may also be effective in the treatment of bruxism in children and adolescents.

Trazodone may be useful in the treatment of certain chronic pain disorders. There is limited but conflicting evidence to support the use of trazodone in the treatment of headaches and migraines in children. Trazodone may be useful in the treatment of fibromyalgia as well as diabetic neuropathy. It may also be useful in the treatment of burning mouth syndrome. A 2004 narrative review claimed that trazodone could be used in the treatment of complex regional pain syndrome. Trazodone may also be effective in the treatment of functional gastrointestinal disorders. It may be effective in the treatment of non-cardiac chest pain as well.

Trazodone may be useful in promoting motor recovery after stroke.

Veterinary Use

Trazodone has been used to reduce anxiety and stress, to improve sleep, and to produce sedation in dogs and cats in veterinary medicine.

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

Published on by Andrew Marshall3 Comments

Introduction

Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.

Common side effects include sleepiness, dry mouth, constipation, nausea, and blurry vision. Serious side effects may include increased risk of suicide in those under the age of 25, mania, and urinary retention. A withdrawal syndrome may occur if the dose is rapidly decreased. Use during pregnancy and breastfeeding is not generally recommended. Although how it works for treating depression remains an area of active inquiry, it may involve increasing the levels of norepinephrine, along with blocking histamine, acetylcholine, and serotonin.

Doxepin was approved for medical use in the United States in 1969. It is available as a generic medication. In 2020, it was the 252nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.

Brief History

Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969. It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.

Medical Uses

Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia). As a cream it is used for short-term treatment of itchiness caused by atopic dermatitis or lichen simplex chronicus.

Insomnia

Doxepin is used in the treatment of insomnia. In 2016, the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioural therapy and behavioural changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence. The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar. A 2015 Agency for Healthcare Research and Quality review of treatments for insomnia had similar findings.

A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxepin had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.30 (95% CI –0.05 to 0.64). The certainty of evidence was rated as very low, and no data were available for longer-term treatment (3 months). For comparison, the other sedating antihistamines assessed, trimipramine and doxylamine, had effect sizes (SMD) at 4 weeks of 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence) and 0.47 (95% CI 0.06 to 0.89) (moderate certainty evidence), respectively. Benzodiazepines and Z-drugs generally showed larger effect sizes (e.g. SMDs of 0.45 to 0.83) than doxepin, whereas the effect sizes of orexin receptor antagonists, such as suvorexant, were more similar (SMDs of 0.23 to 0.44).

Doses of doxepin used for sleep normally range from 3 to 6 mg, but high doses of up to 25 to 50 mg may be used as well.

Other Uses

A 2010 review found that topical doxepin is useful to treat itchiness.

A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second-line treatment.

Contraindications

Known contraindications include:

  • Hypersensitivities to doxepin, other TCAs, or any of the excipients inside the product used
  • Glaucoma
  • A predisposition to developing urinary retention such as in benign prostatic hyperplasia
  • Use of monoamine oxidase inhibitors in last 14 days

Pregnancy and Lactation

Its use in pregnant and lactating women is advised against, although the available evidence suggests it is unlikely to cause negative effects on foetal development. The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the foetus and it is known to cross the placenta. Doxepin is secreted in breast milk and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.

Side Effects

Doxepin’s side effects profile may differ from the list below in some countries where it is licensed to be used in much smaller doses (viz., 3 mg and 6 mg).

  • Central nervous system: fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, difficulty sleeping, seizures (infrequently), temporary confusion (delirium), rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side effects (rarely), abuse in patients with polytoxicomania (rarely), ringing in the ears (tinnitus)
  • Anticholinergic: dry mouth, constipation, even ileus (rarely), difficulties in urinating, sweating, precipitation of glaucoma
  • Antiadrenergic: Low blood pressure, (if patient arises too fast from the lying/sitting position to standing—known as orthostatic hypotension), abnormal heart rhythms (e.g. sinus tachycardia, bradycardia, and atrioventricular block)
  • Allergic/toxic: skin rash, photosensitivity, liver damage of the cholestatic type (rarely), hepatitis (extremely rare), leuko- or thrombocytopenia (rarely), agranulocytosis (very rarely), hypoplastic anaemia (rarely)
  • Others: frequently increased appetite and weight gain, rarely nausea, rarely high blood pressure. May increase or decrease liver enzyme levels in the blood of some people.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Like other TCAs, doxepin is highly toxic in cases of overdose. Mild symptoms include drowsiness, stupor, blurred vision, and excessive dryness of mouth. More serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia. Urinary retention, decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils, and hyperactive reflexes are other possible symptoms of doxepin overdose. Management of overdose is mostly supportive and symptomatic, and can include the administration of a gastric lavage so as to reduce absorption of the doxepin. Supportive measures to prevent respiratory aspiration is also advisable. Antiarrhythmic agents may be an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose. Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects. Haemodialysis is not recommended due to the high degree of protein binding with doxepin. ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.

Interactions

Doxepin should not be used within 14 days of using a monoamine oxidase inhibitor (MAOI) such as phenelzine due to the potential for hypertensive crisis or serotonin syndrome to develop. Its use in those taking potent CYP2D6 inhibitors such as fluoxetine, paroxetine, sertraline, duloxetine, bupropion, and quinidine is recommended against owing to the potential for its accumulation in the absence of full CYP2D6 catalytic activity. Hepatic enzyme inducers such as carbamazepine, phenytoin, and barbiturates are advised against in patients receiving TCAs like doxepin owing to the potential for problematically rapid metabolism of doxepin to occur in these individuals. Sympathomimetic agents may have their effects potentiated by TCAs like doxepin. Doxepin also may potentiate the adverse effects of anticholinergic agents such as benztropine, atropine and hyoscine (scopolamine). Tolazamide, when used in conjunction with doxepin has been associated with a case of severe hypoglycaemia in a type II diabetic individual. Cimetidine may influence the absorption of doxepin. Alcohol may potentiate some of the CNS depressant effects of doxepin. Antihypertensive agents may have their effects mitigated by doxepin. Cotreatment with CNS depressants such as the benzodiazepines can cause additive CNS depression. Co-treatment with thyroid hormones may also increase the potential for adverse reactions.

Pharmacology

Doxepin is a tricyclic antidepressant (TCA). It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) (a reuptake inhibitor of serotonin and norepinephrine), with additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.

Pharmacodynamics

Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a SNRI, and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities. It is specifically an antagonist of the histamine H1 and H2 receptors, the serotonin 5-HT2A and 5-HT2C receptors, the α1-adrenergic receptor, and the muscarinic acetylcholine receptors (M1–M5). Similarly to other TCAs, doxepin is often prescribed as an effective alternative to SSRI medications. Doxepin is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose and its effectiveness as an analgesic (including in the treatment of neuropathic pain, and as a local anaesthetic). The potencies of doxepin in terms of its receptor antagonism specifically are as follows:

  • Extremely strong: Histamine H1 receptor
  • Strong: α1-adrenergic receptor, 5-HT2A and muscarinic acetylcholine receptors
  • Moderate: 5-HT2C and 5-HT1A receptors
  • Weak: α2-adrenergic and D2 receptors

Based on its IC50 values for monoamine reuptake inhibition, doxepin is relatively selective for the inhibition of norepinephrine reuptake, with a much weaker effect on the serotonin transporter. Although there is a significant effect that takes place at one of the specific serotonergic binding sites, the 5-HT2A serotonin receptor subtype. There is negligible influence on dopamine reuptake.

The major metabolite of doxepin, nordoxepin (desmethyldoxepin), is pharmacologically active similarly, but relative to doxepin, is much more selective as a norepinephrine reuptake inhibitor. In general, the demethylated variants of tertiary amine TCAs like nordoxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.

Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day. Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg, although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia. At low doses, below 25 mg, doxepin is a pure antihistamine and has more of a sedative effect. At antidepressant doses of above 75 mg, doxepin is more stimulating with antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.

Doxepin is a mixture of (E) and (Z) stereoisomers with an approximate ratio of 85:15. When doxepin was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio. (Z)-Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than (E)-doxepin. The selectivity of doxepin for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of (E)-doxepin in the mixture. Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit E-Z isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake.

As a Hypnotic

Doxepin is a highly potent antihistamine, with this being its strongest activity. In fact, doxepin has been said to be the most or one of the most potent H1 receptor antagonists available, with one study finding an in vitro Ki of 0.17 nM. It is the most potent and selective H1 receptor antagonist of the TCAs (although the tetracyclic antidepressant (TeCA) mirtazapine is slightly more potent), and other sedating antihistamines, for instance the over-the-counter diphenhydramine (Ki = 16 nM) and doxylamine (Ki = 42 nM), show far lower affinities for this receptor in comparison. The affinity of doxepin for the H1 receptor is far greater than its affinity for other sites, and 10- to 100-fold higher doses are needed for antidepressant effects. In accordance, although it is often described as a “dirty drug” due to its highly promiscuous binding profile, doxepin acts as a highly selective antagonist of the H1 receptor at very low doses (less than 10 mg; typically 3 to 6 mg). At these doses, it notably has no clinically relevant anticholinergic effects such as dry mouth or cognitive/memory impairment, unlike most other sedating antihistamines, and similarly has no effect on other receptors such as adrenergic and serotonin receptors.

The H1 receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses. The incidence of side effects with doxepin and its safety at these doses was similar to that of placebo in clinical trials; the most frequent side effects were headache and somnolence/sedation, both with an incidence of less than 5%. Other side effects sometimes associated with antihistamines, including daytime sedation, increased appetite, and weight gain, all were not observed. Clinical evidence of H1 receptor antagonists and TCAs for the treatment insomnia shows mixed effectiveness and is limited in its quality due to weaknesses like small sample sizes and poor generalisability. However, doxepin is a unique and notable exception; it has been well-studied in the treatment of insomnia and shows consistent benefits with excellent tolerability and safety. Aside from diphenhydramine and doxylamine, which have historical approval as hypnotics, doxepin is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States.

The effect sizes of very low-dose doxepin in the treatment of insomnia range from small to medium. These include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency. Conversely, very low-dose doxepin shows relatively weak effects on sleep initiation and does not significantly separate from placebo on this measure. This is in contrast to benzodiazepines and nonbenzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep onset latency. However, it is also in contrast to higher doses of doxepin (50 to 300 mg/day), which have been found to significantly reduce latency to sleep onset. A positive dose–response relationship on sleep measures was observed for doses of doxepin between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and older adults. However, the incidence of adverse effects appeared to increase with longer treatment duration. A dose of doxepin as low as 1 mg/day was found to significantly improve most of the assessed sleep measures, but unlike the 3 and 6 mg/day doses, was not able to improve wake time during sleep. This, along with greater effect sizes with the higher doses, was likely the basis for the approval of the 3 and 6 mg doses of doxepin for insomnia and not the 1 mg dose.

At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia. Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration. This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness. It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e. 1 week). It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H1 receptor of the latter or may have to do with the use of optimal doses. Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion. This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65. Anticholinergic activity notably may interfere with the sleep-promoting effects of H1 receptor blockade.

Antagonism of the H1, 5-HT2A, 5-HT2C, and α1-adrenergic receptors is thought to have sleep-promoting effects and to be responsible for the sedative effects of TCAs including those of doxepin. Although doxepin is selective for the H1 receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses. However, in contrast to very low doses of doxepin, rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses (25 to 50 mg/day) of the drug. In addition, one study found that although such doses of doxepin improved sleep measures initially, most of the benefits were lost with chronic treatment (by 4 weeks). Due to limited data however, more research on potential tolerance and withdrawal effects of moderate doses of doxepin is needed. At these doses of doxepin, dry mouth, an anticholinergic effect, was common (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also frequently observed, although these adverse effects were notably not significantly more frequent than with placebo in the study in question. In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects as well as apparent loss of hypnotic effectiveness with chronic treatment.

Doxepin at a dose of 25 mg/day for 3 weeks has been found to decrease cortisol levels by 16% in adults with chronic insomnia and to increase melatonin production by 26% in healthy volunteers. In individuals with neuroendocrine dysregulation in the form of nocturnal melatonin deficiency presumably due to chronic insomnia, very-low-dose doxepin was found to restore melatonin levels to near-normal values after 3 weeks of treatment. These findings suggest that normalization of the hypothalamic–pituitary–adrenal axis and the circadian sleep–wake cycle may be involved in the beneficial effects of doxepin on sleep and insomnia.

CYP2D6 Inhibition

Doxepin has been identified as an inhibitor of CYP2D6 in vivo in a study of human patients being treated with 75 to 250 mg/day for depression. While it significantly altered metabolic ratios for sparteine and its metabolites, doxepin did not convert any of the patients to a different metabolizer phenotype (e.g. extensive to intermediate or poor). Nonetheless, inhibition of CYP2D6 by doxepin could be of clinical importance.

Pharmacokinetics

Absorption

Doxepin is well-absorbed from the gastrointestinal tract but between 55 and 87% undergoes first-pass metabolism in the liver, resulting in a mean oral bioavailability of approximately 29%. Following a single very low dose of 6 mg, peak plasma levels of doxepin are 0.854 ng/mL (3.06 nmol/L) at 3 hours without food and 0.951 ng/mL (3.40 nmol/L) at 6 hours with food. Plasma concentrations of doxepin with antidepressant doses are far greater, ranging between 50 and 250 ng/mL (180 to 900 nmol/L). Area-under-curve levels of the drug are increased significantly when it is taken with food.

Distribution

Doxepin is widely distributed throughout the body and is approximately 80% plasma protein-bound, specifically to albumin and α1-acid glycoprotein.

Metabolism

Doxepin is extensively metabolized by the liver via oxidation and N-demethylation. Its metabolism is highly stereoselective. Based on in vitro research, the major enzymes involved in the metabolism of doxepin are the cytochrome P450 enzymes CYP2D6 and CYP2C19, with CYP1A2, CYP2C9, and CYP3A4 also involved to a lesser extent. The major active metabolite of doxepin, nordoxepin, is formed mainly by CYP2C19 (>50% contribution), while CYP1A2 and CYP2C9 are involved to a lesser extent, and CYP2D6 and CYP3A4 are not involved. Both doxepin and nordoxepin are hydroxylated mainly by CYP2D6, and both doxepin and nordoxepin are also transformed into glucuronide conjugates. The elimination half-life of doxepin is about 15–18 hours, whereas that of nordoxepin is around 28–31 hours. Up to 10% of Caucasian individuals show substantially reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal.

Nordoxepin is a mixture of (E) and (Z) stereoisomers similarly to doxepin. Whereas pharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of (E)- and (Z)-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the (E)- and (Z)-stereoisomers of nordoxepin, due to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1.

Elimination

Doxepin is excreted primarily in the urine and predominantly in the form of glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin.

Pharmacogenetics

Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug’s efficacy.

Individuals can be categorized into different types of cytochrome P450 metabolisers depending on which genetic variations they carry. These metaboliser types include poor, intermediate, extensive, and ultrarapid metabolisers. Most people are extensive metabolisers, and have “normal” metabolism of doxepin. Poor and intermediate metabolisers have reduced metabolism of the drug as compared to extensive metabolisers; patients with these metaboliser types may have an increased probability of experiencing side effects. Ultrarapid metabolisers break down doxepin much faster than extensive metabolisers; patients with this metaboliser type may have a greater chance of experiencing pharmacological failure.

A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 enzymes. In CYP2D6 extensive, intermediate, and poor metabolizers, the mean clearance rates of (E)-doxepin were 406, 247, and 127 L/hour, respectively (~3-fold difference between extensive and poor). In addition, the bioavailability of (E)-doxepin was about 2-fold lower in extensive relative to poor CYP2D6 metabolizers, indicating a significant role of CYP2D6 in the first-pass metabolism of (E)-doxepin. The clearance of (E)-doxepin in CYP2C9 slow metabolizers was also significantly reduced at 238 L/hour. CYP2C19 was involved in the metabolism of (Z)-doxepin, with clearance rates of 191 L/hour in CYP2C19 extensive metabolisers and 73 L/hour in poor metabolisers (~2.5-fold difference). Area-under-the-curve (0–48 hour) levels of nordoxepin were dependent on the genotype of CYP2D6 with median values of 1.28, 1.35, and 5.28 nM•L/hour in CYP2D6 extensive, intermediate, and poor metabolisers, respectively (~4-fold difference between extensive and poor). Taken together, doxepin metabolism appears to be highly stereoselective, and CYP2D6 genotype has a major influence on the pharmacokinetics of (E)-doxepin. Moreover, CYP2D6 poor metabolisers, as well as patients taking potent CYP2D6 inhibitors (which can potentially convert a CYP2D6 extensive metaboliser into a poor metaboliser), may be at an increased risk for adverse effects of doxepin due to their slower clearance of the drug.

Another study assessed doxepin and nordoxepin metabolism in CYP2D6 ultra-rapid, extensive, and poor metabolisers following a single 75 mg oral dose. They found up to more than 10-fold variation in total exposure to doxepin and nordoxepin between the different groups. The researchers suggested that in order to achieve equivalent exposure, based on an average dose of 100%, the dosage of doxepin might be adjusted to 250% in ultra-rapid metabolisers, 150% in extensive metabolisers, 50% in intermediate metabolisers, and 30% in poor metabolisers.

Chemistry

Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together with a side chain attached in its chemical structure. It is the only TCA with a dibenzoxepin ring system to have been marketed. Doxepin is a tertiary amine TCA, with its side chain-demethylated metabolite nordoxepin being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and trimipramine. Doxepin is a mixture of (E) and (Z) stereoisomers (the latter being known as cidoxepin or cis-doxepin) and is used commercially in a ratio of approximately 85:15. The chemical name of doxepin is (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H21NO with a molecular weight of 279.376 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.

Society and Culture

Generic Names

Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.

The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN.

Brand Names

It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.

Doxepin is marketed under many brand names worldwide, including: Adnor, Anten, Antidoxe, Colian, Deptran, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinquan, and Zonalon. It is also marketed as a combination drug with levomenthol under the brand name Doxure.

Approvals

The oral formulations of doxepin are US Food and Drug Administration (FDA)-approved for the treatment of depression and sleep-maintenance insomnia, and its topical formulations are FDA-approved the short-term management for some itchy skin conditions. In Australia and the United Kingdom, the only licensed indications are in the treatment of major depression and pruritus in eczema.

Research

Antihistamine

Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives). As of 2017, it is in phase II clinical trials for this indication. The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.

Headache

Doxepin was under development by Winston Pharmaceuticals in an intranasal formulation for the treatment of headache. As of August 2015, it was in phase II clinical trials for this indication.

Neuropathic Pain

As of 2017, there was no good evidence that topical doxepin was useful to treat localised neuropathic pain.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Doxepin >; 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 Social Support Questionnaire?

Published on by Andrew Marshall1 Comment

Introduction

The Social Support Questionnaire (SSQ) is a quantitative, psychometrically sound survey questionnaire intended to measure social support and satisfaction with said social support from the perspective of the interviewee.

Degree of social support has been shown to influence the onset and course of certain psychiatric disorders such as clinical depression or schizophrenia. The SSQ was approved for public release in 1981 by Irwin Sarason, Henry Levine, Robert Basham and Barbara Sarason under the University of Washington Department of Psychology and consists of 27 questions. Overall, the SSQ has good test-retest reliability and convergent internal construct validity.

Refer to Peer Support.

Overview

The questionnaire is designed so that each question has a two-part answer. The first part asks the interviewee to list up to nine people available to provide support that meet the criteria stated in the question. These support individuals are specified using their initials in addition to the relationship to the interviewee. Example questions from the first part includes questions such as “Whom could you count on to help if you had just been fired from your job or expelled from school?” and “Whom do you feel would help if a family member very close to you died?”.

The second part asks the interviewee to specify how satisfied they are with each of the people stated in the first part. The SSQ respondents use a 6 -point Likert scale to indicate their degree of satisfaction with the support from the above people ranging from “1 – very dissatisfied” to “6 – very satisfied”.

The Social Support Questionnaire has multiple short forms such as the SSQ3 and the SSQ6.

Brief History

The SSQ is based on 4 original studies. The first study set out to determine whether the SSQ had the desired psychometric properties. The second study tried to relate SSQ and a diversity of personality measures such as anxiety, depression and hostility in connection with the Multiple Affect Adjective Checklist. The third study considered the relationship between social support, the prior year’s negative and positive life events, internal-external locus of control and self- esteem in conjunction with the Life Experiences Survey. The fourth study tested the idea that social support could serve as a buffer when faced with difficult life situations via trying to solve a maze and subsequently completing the Cognitive Interference Questionnaire.

Scoring

The overall support score (SSQN) is calculated by taking an average of the individual scores across the 27 items. A high score on the SSQ indicates more optimism about life than a low score. Respondents with low SSQ scores have a higher prevalence of negative life events and illness. Scoring is as follows:

  1. Add the total number of people for all 27 items (questions). (Max. is 243). Divide by 27 for average item score. This gives you SSQ Number Score, or SSQN.
  2. Add the total satisfaction scores for all 27 items (questions). (Max is 162). Divide by 27 for average item score. This gives you SSQ Satisfaction score or SSQS.
  3. Finally, you can average the above for the total number of people that are family members – this results in the SSQ family score.

Reliability

According to Sarason, the SSQ takes between fifteen and eighteen minutes to properly administer and has “good” test-retest reliability.

Validity

The SSQ was compared with the depression scale and validity tests show significant negative correlation ranging from -0.22 to -0.43. The SSQ and the optimism scale have a correlation of 0.57. The SSQ and the satisfaction score have a correlation of 0.34. The SSQ has high internal consistency among items.

Linkages

The SSQ has been used to show that higher levels of social support correlated with less suicide ideation in Military Medical University Soldiers in Iran in 2015. A low level of social support is an important risk factor in women for dysmenorrhea or menstrual cramps. Low Social Support is the strongest predictor of dysmenorrhea when compared to affect, personality and alexithymia.

Related Surveys

SSQ3

The SSQ3 is a short form of the SSQ and has only three questions. The SSQ3 has acceptable test-test reliability and correlation with personality variables as compared to the long form of the Social Support Questionnaire. The internal reliability was borderline but this low level of internal reliability is as expected since there are only three questions.

SSQ6

The SSQ6 is a short form of the SSQ. The SSQ6 has been shown to have high correlation with: the SSQ, SSQ personality variables and internal reliability. In the development of the SSQ6, the research suggests that professed social support in adults may be a connected to “early attachment experience.” The SSQ6 consists of the below 6 questions:

  1. Whom can you really count on to be dependable when you need help?
  2. Whom can you really count on to help you feel more relaxed when you are under pressure or tense?
  3. Who accepts you totally, including both your worst and your best points?
  4. Whom can you really count on to care about you, regardless of what is happening to you?
  5. Whom can you really count on to help you feel better when you are feeling generally down-in-the-dumps?
  6. Whom can you count on to console you when you are very upset?

Interpersonal Support Evaluation List (ISEL)

The Interpersonal Support Evaluation List includes 40 items (questions) with four sub-scales in the areas of Tangible Support, Belonging Support, Self-Esteem Support and Appraisal Support. The interviewee rates each item based on how true or false they feel the item is for themselves. The four total response options are “Definitely True”, “Probably True”, “Probably False”, and “Definitely False”.

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