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What is Duloxetine?

Published on by Andrew Marshall4 Comments

Introduction

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalised anxiety disorder, fibromyalgia, and neuropathic pain. It is taken by mouth.

Common side effects include dry mouth, nausea, feeling tired, dizziness, agitation, sexual problems, and increased sweating. Severe side effects include an increased risk of suicide, serotonin syndrome, mania, and liver problems. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. It is a serotonin-norepinephrine reuptake inhibitor (SNRI). How it works is not entirely clear.

Duloxetine was approved for medical use in the United States and in the European Union in 2004. It is available as a generic medication. In 2018, it was the 36th most commonly prescribed medication in the United States, with more than 21 million prescriptions.

Brief History

Duloxetine was created by Eli Lilly and Company researchers. David Robertson; David Wong, a co-discoverer of fluoxetine; and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990. The first publication on the discovery of the racemic form of duloxetine known as LY227942, was made in 1988. The (+)-enantiomer, assigned LY248686, was chosen for further studies, because it inhibited serotonin reuptake in rat synaptosomes to twice the degree of the (–)-enantiomer. This molecule was subsequently named duloxetine.

In 2001, Lilly filed a New Drug Application (NDA) for duloxetine with the US Food and Drug Administration (FDA). In 2003, however, the FDA “recommended this application as not approvable from the manufacturing and control standpoint” because of “significant cGMP (current Good Manufacturing Practice) violations at the finished product manufacturing facility” of Eli Lilly in Indianapolis. Additionally, “potential liver toxicity” and QTc interval prolongation appeared as a concern. The FDA experts concluded that “duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver.” The FDA also recommended “routine blood pressure monitoring” at the new highest recommended dose of 120 mg, “where 24% patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients.”

After the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause QTc interval prolongation, duloxetine was approved by the FDA for depression and diabetic neuropathy in 2004. In 2007, Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain.

Duloxetine was approved for use of stress urinary incontinence (SUI) in the EU in 2004. In 2005, Lilly withdrew the duloxetine application for stress urinary incontinence (SUI) in the US, stating that discussions with the FDA indicated “the agency is not prepared at this time to grant approval … based on the data package submitted.” A year later Lilly abandoned the pursuit of this indication in the US market.

The FDA approved duloxetine for the treatment of generalised anxiety disorder in February 2007.

Cymbalta generated sales of nearly US$5 billion in 2012, with United States of that in the US, but its patent protection terminated 01 January 2014. Lilly received a six-month extension beyond 30 June 2013, after testing for the treatment of depression in adolescents, which may produce US$1.5 billion in added sales.

The first generic duloxetine was marketed by Dr. Reddy.

Medical Uses

The main uses of duloxetine are in major depressive disorder, generalised anxiety disorder, neuropathic pain, chronic musculoskeletal pain, and fibromyalgia.

Duloxetine is recommended as a first-line agent for the treatment of chemotherapy-induced neuropathy by the American Society of Clinical Oncology, as a first-line therapy for fibromyalgia in the presence of mood disorders by the German Interdisciplinary Association for Pain Therapy, as a Grade B recommendation for the treatment of diabetic neuropathy by the American Association for Neurology and as a level A recommendation in certain neuropathic states by the European Federation of Neurological Societies.

A 2014 Cochrane review concluded that duloxetine is beneficial in the treatment of diabetic neuropathy and fibromyalgia but that more comparative studies with other medicines are needed. The French medical journal Prescrire concluded that duloxetine is no better than other available agents and has a greater risk of side effects.

Major Depressive Disorder

Duloxetine was approved for the treatment of major depression in 2004. While duloxetine has demonstrated improvement in depression-related symptoms compared to placebo, comparisons of duloxetine to other antidepressant medications have been less successful. A 2012 Cochrane Review did not find greater efficacy of duloxetine compared to SSRIs and newer antidepressants. Additionally, the review found evidence that duloxetine has increased side effects and reduced tolerability compared to other antidepressants. It thus did not recommend duloxetine as a first line treatment for major depressive disorder, given the (then) high cost of duloxetine compared to inexpensive off-patent antidepressants and lack of increased efficacy. Duloxetine appears less tolerable than some other antidepressants. Generic duloxetine became available in 2013.

Generalised Anxiety Disorder

Duloxetine is more effective than placebo in the treatment of generalised anxiety disorder (GAD). A review from the Annals of Internal Medicine lists duloxetine among the first line drug treatments, however, along with citalopram, escitalopram, sertraline, paroxetine, and venlafaxine.

Diabetic Neuropathy

Duloxetine was approved for the pain associated with diabetic peripheral neuropathy (DPN), based on the positive results of two clinical trials. The average daily pain was measured using an 11-point scale, and duloxetine treatment resulted in an additional 1-1.7 points decrease of pain as compared with placebo. At least 50% pain relief was achieved in 40-45% of the duloxetine patients vs. 20-22% of placebo patients. Pain decreased by more than 90%, in 9-14% of duloxetine patients vs. 2-4% of placebo patients. Most of the response was achieved in the first two weeks on the medication. Duloxetine slightly increased the fasting serum glucose; this effect was deemed to be of “minimal clinical significance”, however.

The comparative efficacy of duloxetine and established pain-relief medications for DPN is unclear. A systematic review noted that tricyclic antidepressants (imipramine and amitriptyline), traditional anticonvulsants and opioids have better efficacy than duloxetine. Duloxetine, tricyclic antidepressants and anticonvulsants have similar tolerability while the opioids caused more side effects. Another review in Prescrire International considered the moderate pain relief achieved with duloxetine to be clinically insignificant and the results of the clinical trials unconvincing. The reviewer saw no reason to prescribe duloxetine in practice. The comparative data collected by reviewers in BMC Neurology indicated that amitriptyline, other tricyclic antidepressants and venlafaxine may be more effective. The authors noted that the evidence in favour of duloxetine is much more solid, however. A Cochrane review concluded that the evidence in support of duloxetine’s efficacy in treating painful diabetic neuropathy was adequate, and that further trials should focus on comparisons with other medications.

Fibromyalgia and Chronic Pain

A review of duloxetine found that it reduced pain and fatigue, and improved physical and mental performance compared to placebo.

The FDA approved the drug for the treatment of fibromyalgia in June 2008.

It may be useful for chronic pain from osteoarthritis.

On 04 November 2010, the FDA approved duloxetine to treat chronic musculoskeletal pain, including discomfort from osteoarthritis and chronic lower back pain.

Stress Urinary Incontinence

Duloxetine failed to receive US approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; it was approved for this use in the UK, however, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.

The safety and utility of duloxetine in the treatment of incontinence has been evaluated in a series of meta analyses and practice guidelines.

  • A 2017 meta-analysis found that harms are at least as great if not greater than the benefits.
  • A 2013 meta-analysis concluded that duloxetine decreased incontinence episodes more than placebo with people about 56% more likely than placebo to experience a 50% decrease in episodes. Adverse effects were experienced by 83% of duloxetine-treated subjects and by 45% of placebo-treated subjects.
  • A 2012 review and practice guideline published by the European Association of Urology concluded that the clinical trial data provides Grade 1a evidence that duloxetine improves but does not cure urinary incontinence, and that it causes a high rate of gastrointestinal side effects (mainly nausea and vomiting) leading to a high rate of treatment discontinuation.
  • The National Institute for Clinical and Health Excellence recommends (as of September 2013) that duloxetine not be routinely offered as first line treatment, and that it only be offered as second line therapy in women wishing to avoid therapy. The guideline further states that women should be counselled regarding the drug’s side effects.

Contraindications

The following contraindications are listed by the manufacturer:

  • Hypersensitivity: duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
  • Monoamine oxidase inhibitors (MAOIs): concomitant use in patients taking MAOIs is contraindicated.
  • Uncontrolled narrow-angle glaucoma: in clinical trials, Cymbalta use was associated with an increased risk of mydriasis (dilation of the pupil); therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma, in which mydriasis can cause sudden worsening.
  • Central nervous system (CNS) acting drugs: given the primary CNS effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.
  • Duloxetine and thioridazine should not be co-administered.
  • In addition, the FDA has reported on life-threatening drug interactions that may be possible when co-administered with triptans and other drugs acting on serotonin pathways leading to increased risk for serotonin syndrome.

Adverse Effects

Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% of patients.

In a trial for major depressive disorder (MDD), the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group. In a long-term study of fibromyalgia patients receiving duloxetine, frequency and type of adverse effects was similar to that reported in the MDD trial above. Side effects tended to be mild-to-moderate, and tended to decrease in intensity over time.

In four clinical trials of duloxetine for the treatment of MDD, sexual dysfunction occurred significantly more frequently in patients treated with duloxetine than those treated with placebo, and this difference occurred only in men. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Loss of or decreased response to sexual stimuli and ejaculatory anhedonia are also reported. Frequency of treatment-emergent sexual dysfunction were similar for duloxetine and SSRIs when compared in a 6-month observational study in depressed patients. Rates of sexual dysfunction in MDD patients treated with duloxetine vs escitalopram did not differ significantly at 4, 8, and 12 weeks of treatment, although the trend favoured duloxetine (33.3% of duloxetine patients experienced sexual side effects compared to 43.6% of those receiving escitalopram and 25% of those receiving placebo).

Discontinuation Syndrome

During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paraesthesia’s such as brain zap electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. The withdrawal syndrome from duloxetine resembles the SSRI discontinuation syndrome.

When discontinuing treatment with duloxetine, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

In placebo-controlled clinical trials of up to nine weeks’ duration of patients with MDD, a systematic evaluation of discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paraesthesia, vomiting, irritability, and nightmare.

Suicidality

In the United States all antidepressants, including duloxetine carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behaviour in children and adolescents, and 1.5-fold increase of suicidality in the 18-24 age group. To obtain statistically significant results the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation and behaviour in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance.

In 2005, the United States FDA released a public health advisory noting that there had been eleven reports of suicide attempts and three reports of suicidality within the mostly middle-aged women participating in the open label extension trials of duloxetine for the treatment of stress urinary incontinence (SUI). The FDA described the potential role of confounding social stressors “unclear”. The suicide attempt rate in the SUI study population (based on 9,400 patients) was calculated to be 400 per 100,000 person years. This rate is greater than the suicide attempt rate among middle-aged US women that has been reported in published studies, i.e. 150 to 160 per 100,000 person years. In addition, one death from suicide was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer without SUI. No increase in suicidality was reported in controlled trials of Cymbalta for depression or diabetic neuropathic pain.

Post-Marketing Reports

Reported adverse events that were temporally correlated to duloxetine therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatotoxicity, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens-Johnson syndrome, syncope (especially at initiation of treatment), and urticaria.

Pharmacology

Mechanism of Action

Duloxetine inhibits the reuptake of serotonin and norepinephrine (NE) in the central nervous system. Duloxetine increases dopamine (DA) specifically in the prefrontal cortex, where there are few DA reuptake pumps, via the inhibition of NE reuptake pumps (NET), which is believed to mediate reuptake of DA and NE. Duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, glutamate, and GABA reuptake transporters, however, and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NE transporters. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.

In vitro binding studies using synaptosomal preparations isolated from rat cerebral cortex indicated that duloxetine was approximately 3 fold more potent at inhibiting serotonin uptake than norepinephrine uptake.

Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system. Antidepressants including ones with a similar mechanism of action as duloxetine, i.e. serotonin metabolism inhibition, cause a decrease in proinflammatory cytokine activity and an increase in anti-inflammatory cytokines; this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is lacking.

The analgesic properties of duloxetine in the treatment of diabetic neuropathy and central pain syndromes such as fibromyalgia are believed to be due to sodium ion channel blockade.

Pharmacokinetics

  • Absorption: Duloxetine is acid labile, and is formulated with enteric coating to prevent degradation in the stomach. Duloxetine has good oral bioavailability, averaging 50% after one 60 mg dose. There is an average 2-hour lag until absorption begins with maximum plasma concentrations occurring about 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours.
  • Distribution: Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. Volume of distribution is 1640L.
  • Metabolism: Duloxetine undergoes predominately hepatic metabolism via two cytochrome P450 isozymes, CYP2D6 and CYP1A2. Circulating metabolites are pharmacologically inactive. Duloxetine is a moderate CYP2D6 inhibitor.
  • Elimination: Administered in healthy young male subjects at doses between 20-40 mg twice a day, had a half-life of 12.5 hours and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state is usually achieved after 3 days. Only trace amounts (<1%) of unchanged duloxetine are present in the urine and most of the dose (approx. 70%) appears in the urine as metabolites of duloxetine with about 20% excreted in the faeces.

Smoking is associated with a decrease in duloxetine concentration.

On This Day … 05 July

Published on by Andrew MarshallLeave a comment

People (Births)

  • 1929 – Jovan Rašković, Serbian psychiatrist, academic, and politician (d. 1992).

Jovan Raskovic

Jovan Rašković (05 July 1929 to 28 July 1992) was a Croatian Serb psychiatrist, academic and politician.

During World War II, after an Ustasha pogrom which resulted in the deaths of his relatives, he was exiled to Kistanje in Italian-occupied Dalmatia. He passed his secondary school exams in Šibenik, and graduated in Zagreb. He then studied electrical engineering and medicine at the University of Zagreb, where he obtained his diploma and a PhD from the university’s medical school.

In the 1960s, he served as director of Šibenik city hospital and later director of the medical centre. He was one of the founders of the Medical Research Institute of Neurophysiology in Ljubljana. Rašković was a member of the Serbian Academy of Sciences and Arts, the Academy of Medical Sciences of Croatia and a number of psychiatry associations in the United States, Czechoslovakia and Italy. He was a university professor in Zagreb and Ljubljana and a visiting professor at the Universities of Pavia, Rome, Houston and London.

In February 1990, Rašković went into politics and founded and led the Serbian Democratic Party (SDS), which took part in the first Croatian democratic elections. He noticed that there was no equivalent party in Bosnia and Herzegovina so he contacted Radovan Karadžić, a colleague, to suggest for him to establish one.

Although the SDS won relatively few seats in the 1990 elections, it quickly began to increase its power, and Rašković was soon perceived as a leader of Serbs by Franjo Tuđman and his new government. That led to direct negotiations between the two about the future of Serbs in Croatia. During one meeting, Rašković remarked, “Serbs were crazy people”. Tuđman’s chief political advisor, Slaven Letica, had the words secretly taped and leaked the transcript to Croatian media to discredit Rašković among his people and then replace him with someone more acceptable to Croatian government. That backfired, as instead of rejecting Rašković, many Serbs lost any trust in Croatian government and embraced extremism and then armed conflict.

Later in 1990, Rašković was removed from power by “more radical, hard-line Serb nationalists”, who went on to create the Republic of Serbian Krajina. Rašković retired from politics in 1991, after the Plitvice Lakes incident.

Rašković died in Belgrade from a heart attack on 28 July 1992 at the age of 63. He is interred in the Alley of Distinguished Citizens in the Belgrade New Cemetery.

Streets in Trebinje, Prijedor, Banja Luka and Novi Banovci are named in his honour.

What is Escitalopram?

Published on by Andrew Marshall11 Comments

Introduction

Escitalopram, sold under the brand names Cipralex and Lexapro, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder (MDD) or generalised anxiety disorder (GAD). It is taken by mouth.

Common side effects include trouble sleeping, nausea, sexual problems, and feeling tired. More serious side effects may include suicide in people under the age of 25. It is unclear if use during pregnancy or breastfeeding is safe. Escitalopram is the (S)-stereoisomer (left-handed version) of citalopram (which exists as a racemate), hence the name escitalopram. In other words, escitalopram is a chiral switch of citalopram.

Escitalopram was approved for medical use in the United States in 2002. Escitalopram is sometimes replaced by twice the dose of citalopram. In 2018, it was the 22nd most commonly prescribed medication in the United States with more than 25 million prescriptions.

Brief History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.

The FDA issued the approval of escitalopram for major depression in August 2002 and for GAD in December 2003. On 23 May 2006, the FDA approved a generic version of escitalopram by Teva. On 14 July of that year, however, the US District Court of Delaware decided in favour of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiration date from 07 December 2009, to 14 September 2011. Together with the 6-month paediatric exclusivity, the final expiration date was 14 March 2012.

Medical Uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults. In European countries and the United Kingdom, it is approved for depression (MDD) and anxiety disorders, these include: GAD, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia. In Australia it is approved for major depressive disorder.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo-controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.

Controversy existed regarding the effectiveness of escitalopram compared with its predecessor, citalopram. The importance of this issue followed from the greater cost of escitalopram relative to the generic mixture of isomers of citalopram, prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. As of 2012, reviews had concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.

A 2011 review concluded that second-generation antidepressants appear equally effective, although they may differ in onset and side effects. Treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

Anxiety Disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram at 20% rather than placebo at 50%.

Escitalopram appears effective in treating social anxiety disorder.

Other

Escitalopram is effective in reducing the symptoms of premenstrual syndrome, whether taken continuously or in the luteal phase only. There are no good data available for escitalopram as treatment for seasonal affective disorder as of 2021.

Side Effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, and anorgasmia.

There is also evidence that SSRIs may cause an increase in suicidal ideation. An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses at 20 mg for adults and 10 mg for those older than 65 years or with liver impairment. There are concerns of higher rates of QT prolongation and torsades de pointes compared with other SSRIs. The US Food and Drug Administration (FDA) and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.

Very Common Effects

Very common effects (>10% incidence) include:

  • Headache (24%).
  • Nausea (18%).
  • Ejaculation disorder (9-14%).
  • Somnolence (4-13%).
  • Insomnia (7-12%).

Common Effects

Common effects (1-10% incidence) include:

  • Insomnia.
  • Somnolence (sleepiness).
  • Dizziness.
  • Paraesthesia.
  • Tremor.
  • Decreased or increased appetite.
  • Anxiety.
  • Restlessness.
  • Abnormal dreams.
  • Libido decreased.
  • Anorgasmia.
  • Sinusitis (nasal congestion).
  • Yawning.
  • Diarrhoea.
  • Constipation.
  • Vomiting.
  • Dry mouth.
  • Excessive sweating.
  • Arthralgia (joint pain).
  • Myalgia (muscular aches and pains).
  • Fatigue.
  • Pyrexia (fever).
  • Impotence (erectile dysfunction).

Psychomotor Effects

The most common effect is fatigue or somnolence, particularly in older adults, although patients with pre-existing daytime sleepiness and fatigue may experience paradoxical improvement of these symptoms. Escitalopram has not been shown to affect serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance.

Discontinuation Symptoms

Refer to Antidepressant Discontinuation Syndrome.

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as anhedonia (83%), “electric shock” sensations, colloquially called “brain shivers” or “brain zaps” by sufferers. Frequent symptoms in one study were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Very slow tapering was recommended. There have been spontaneous reports of discontinuation of Lexapro and other SSRIs and SNRIs, especially when abrupt, leading to dysphoric mood, irritability, agitation, anxiety, headache, lethargy, emotional lability, insomnia, and hypomania. Other symptoms such as panic attacks, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), mania, worsening of depression, and suicidal ideation can emerge when the dose is adjusted down.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as post-SSRI sexual dysfunction (PSSD). Common symptoms include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including escitalopram) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. There is a tentative association of SSRI use during pregnancy with heart problems in the baby. The advantages of their use during pregnancy may thus outweigh the possible negative effects on the baby.

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects, such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Therapeutic blood levels of escitalopram are usually in the range of 20-80 μg/L but may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolisers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.

Pharmacology

Mechanism of Action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.

Interactions

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected. Escitalopram should be taken with caution when using St. John’s wort. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern. Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmics, antipsychotics, tricyclic antidepressants, some antihistamines (astemizole, mizolastine) and some antiretrovirals (ritonavir, saquinavir, lopinavir). As an SSRI, escitalopram should generally not be given concurrently with MAOIs.

Chemistry

Escitalopram is the (S)-stereoisomer (left-handed version) of the racemate citalopram, which is responsible for its name: escitalopram. The (R)-stereoisomer (R-citalopram, the right-handed version) is not thought to have useful effects for treating depression.

Society and Culture

Allegations of Illegal Marketing

In 2004, separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers: a physician named Joseph Piacentile and a Forest salesman named Christopher Gobble. In February 2009, the suits were joined. Eleven states and the District of Columbia filed notices of intent to intervene as plaintiffs in the action.

The suits alleged that Forest illegally engaged in off-label promotion of Lexapro for use in children; hid the results of a study showing lack of effectiveness in children; paid kickbacks to physicians to induce them to prescribe Lexapro to children; and conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors. Forest denied the allegations but ultimately agreed to settle with the plaintiffs for over $313 million.

Brand Names

Escitalopram is sold under many brand names worldwide such as Cipralex, Lexapro, Mozarin, Aciprex, Depralin, Ecytara, Elicea, Nexpram, Pramatis, and Betesda.

What is Fluvoxamine?

Published on by Andrew Marshall17 Comments

Introduction

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class which is used primarily for the treatment of depression disorder and obsessive-compulsive disorder (OCD). It is also used to treat anxiety disorders, such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.

Fluvoxamine’s side-effect profile is very similar to other SSRIs: constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects). The tolerance profile also appears to be quite superior than other SSRIs, despite its age.

Anti-inflammatory effects of fluvoxamine are being researched to determine if it can be used to treat COVID-19. It is not approved by the US Federal Drug Administration (FDA) for treatment of any infection.

Brief History

Fluvoxamine was developed by Kali-Duphar, part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983. It was approved by the FDA in 1994, and introduced as Luvox in the US. In India, it is available, among several other brands, as Uvox by Abbott. It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression. It was the first SSRI, a non-TCA drug, approved by the FDA specifically for the treatment of OCD. At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine. Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997. In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999 and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder. Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.

Medical Uses

In many countries (e.g. Australia, the UK, and Russia) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for OCD, and social anxiety disorder. In Japan it is also approved to treat OCD, social anxiety disorder (SAD) and major depressive disorder (MDD). Fluvoxamine is indicated for children and adolescents with OCD. The drug works long-term, and retains its therapeutic efficacy for at least one year. It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.

There is tentative evidence that fluvoxamine is effective for social phobia in adults. Fluvoxamine is also effective for generalised anxiety disorder (GAD), SAD, panic disorder and separation anxiety disorder in children and adolescents. There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.

Adverse Effects

Gastrointestinal side effects are more common in those receiving fluvoxamine than with other SSRIs. Otherwise, fluvoxamine’s side-effect profile is very similar to other SSRIs.

Common (1-10% Incidence) Adverse Effects

  • Nausea.
  • Vomiting.
  • Weight loss.
  • Yawning.
  • Loss of appetite.
  • Agitation.
  • Nervousness.
  • Anxiety.
  • Insomnia.
  • Somnolence (drowsiness).
  • Tremor.
  • Restlessness.
  • Headache.
  • Dizziness.
  • Palpitations.
  • Tachycardia (high heart rate).
  • Abdominal pain.
  • Dyspepsia (indigestion).
  • Diarrhoea.
  • Constipation.
  • Hyperhidrosis (excess sweating).
  • Asthenia (weakness).
  • Malaise.
  • Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.).
  • Xerostomia (dry mouth).

Uncommon (0.1-1% Incidence) Adverse Effects

  • Arthralgia.
  • Hallucination.
  • Confusional state.
  • Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.).
  • Orthostatic hypotension.
  • Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus).

Rare (0.01-0.1% Incidence) Adverse Effects

  • Mania.
  • Seizures.
  • Abnormal hepatic (liver) function.
  • Photosensitivity (being abnormally sensitive to light).
  • Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding).

Unknown Frequency Adverse Effects

  • Hyperprolactinaemia (elevated plasma prolactin levels leading to galactorrhoea, amenorrhoea [cessation of menstrual cycles], etc.).
  • Bone fractures.
  • Glaucoma.
  • Mydriasis.
  • Urinary incontinence.
  • Urinary retention.
  • Bed-wetting.
  • Serotonin syndrome: A potentially fatal condition characterised by abrupt onset muscle rigidity, hyperthermia (elevated body temperature), rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.
  • Neuroleptic malignant syndrome – practically identical presentation to serotonin syndrome except with a more prolonged onset.
  • Akathisia – a sense of inner restlessness that presents itself with the inability to stay still.
  • Paraesthesia.
  • Dysgeusia.
  • Haemorrhage.
  • Withdrawal symptoms.
  • Weight changes.
  • Suicidal ideation and behaviour.
  • Violence towards others.
  • Hyponatraemia.
  • Syndrome of inappropriate antidiuretic hormone secretion.
  • Ecchymoses.

Interactions

Fluvoxamine inhibits the following cytochrome P450 enzymes:

  • CYP1A2 (strongly) which metabolises agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
  • CYP3A4 (moderately) which metabolises alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.
  • CYP2D6 (weakly) which metabolises aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.[43]
  • CYP2C9 (moderately) which metabolises nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
  • CYP2C19 (strongly) which metabolises clonazepam, diazepam, phenytoin, etc.
  • CYP2B6 (weakly) which metabolises bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.

The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, midazolam, alprazolam and diazepam) are likely to be increased when co-administered with fluvoxamine. However the clearance of benzodiazepines metabolised by glucuronidation (e.g. lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. It appears that benzodiazepines metabolised by nitro-reduction (clonazepam, nitrazepam) are unlikely to be affected by fluvoxamine. Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations. If alprazolam is co-administered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.

Fluvoxamine and ramelteon co-administration is not indicated.

Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolised by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans. Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.

Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Fluvoxamine’s interaction with St John’s wort can lead to increased serotonin levels and potentially lead to serotonin syndrome.

Pharmacology

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor. It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression. Unlike some other SSRI, fluvoxamine’s metabolites are pharmacologically neutral.

Society and Culture

Manufacturers include BayPharma, Synthon, and Teva, among others. Luvox was notably used by Eric Harris, one of the Columbine shooters.

What is Fluoxetine?

Published on by Andrew Marshall42 Comments

Introduction

Fluoxetine, sold under the brand names Prozac and Sarafem among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over. It has also been used to treat premature ejaculation. Fluoxetine is taken by mouth.

Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, dry mouth, and rash. Serious side effects include serotonin syndrome, mania, seizures, an increased risk of suicidal behaviour in people under 25 years old, and an increased risk of bleeding. Discontinuation syndrome is less likely to occur with fluoxetine than with other antidepressants, but it still happens in many cases. Fluoxetine taken during pregnancy is associated with significant increase in congenital heart defects in the newborns. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective. Its mechanism of action is unknown, but some hypothesize that it is related to serotonin activity in the brain.

Fluoxetine was discovered by Eli Lilly and Company in 1972, and entered medical use in 1986. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2018, it was the 23rd most commonly prescribed medication in the United States, with more than 25 million prescriptions. Lilly also markets fluoxetine in a fixed-dose combination with olanzapine as olanzapine/fluoxetine (Symbyax).

Brief History

The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized a series of dozens of its derivatives. Hoping to find a derivative inhibiting only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. Wong published the first article about fluoxetine in 1974. A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the trade name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly & Company, filed an Investigational New Drug application to the US Food and Drug Administration (FDA) for fluoxetine.

Fluoxetine appeared on the Belgian market in 1986. In the US, the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the US reached $350 million within a year. Worldwide sales eventually reached a peak of $2.6 billion a year.

Lilly tried several product line extension strategies, including extended release formulations and paying for clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric disorder and rebranding fluoxetine for that indication as “Sarafem” after it was approved by the FDA in 2000, following the recommendation of an advisory committee in 1999. The invention of using fluoxetine to treat PMDD was made by Richard Wurtman at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.

To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-dollar battle in court with the generic company Barr Pharmaceuticals to protect its patents on fluoxetine, and lost the cases for its line-extension patents, other than those for Sarafem, opening fluoxetine to generic manufacturers starting in 2001. When Lilly’s patent expired in August 2001, generic drug competition decreased Lilly’s sales of fluoxetine by 70% within two months.

In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year. Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets connected with the drug for $295M to Galen Holdings, a small Irish pharmaceutical company specializing in dermatology and women’s health that had a sales force tasked to gynaecologists’ offices; analysts found the deal sensible since the annual sales of Sarafem made a material financial difference to Galen, but not to Lilly.

Bringing Sarafem to market harmed Lilly’s reputation in some quarters. The diagnostic category of PMDD was controversial since it was first proposed in 1987, and Lilly’s role in retaining it in the appendix of the DSM-IV-TR, the discussions for which got under way in 1998, has been criticised. Lilly was criticised for inventing a disease in order to make money, and for not innovating but rather just seeking ways to continue making money from existing drugs. It was also criticised by the FDA and groups concerned with women’s health for marketing Sarafem too aggressively when it was first launched; the campaign included a television commercial featuring a harried woman at the grocery store who asks herself if she has PMDD.

Medical Uses

Fluoxetine is frequently used to treat major depressive disorder, OCD, post-traumatic stress disorder (PTSD), bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and trichotillomania. It has also been used for cataplexy, obesity, and alcohol dependence, as well as binge eating disorder. Fluoxetine seems to be ineffective for social anxiety disorder. Studies do not support a benefit in children with autism, though there is but tentative evidence for its benefit in adult autism.

Depression

Efficacy of fluoxetine for acute and maintenance treatment of major depressive disorder in adults as well as children and adolescents (8 to 18 years) was established in multiple clinical trials. In addition to being effective for depression in 6-week long double-blind controlled trials, fluoxetine was better than placebo for the prevention of depression recurrence, when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as paediatric depression was also demonstrated in placebo-controlled trials.

Fluoxetine is as effective as tricyclic antidepressants but is better tolerated. It is less effective than sertraline, mirtazapine, and venlafaxine. According to a network analysis of clinical trials, fluoxetine may belong to the group of less effective antidepressants; however, its acceptability is higher than any other antidepressant, except agomelatine.

Obsessive-Compulsive Disorder

The efficacy of fluoxetine in the treatment of OCD was demonstrated in two randomised multicentre phase III clinical trials. The pooled results of these trials demonstrated that 47% of completers treated with the highest dose were “much improved” or “very much improved” after 13 weeks of treatment, compared to 11% in the placebo arm of the trial. The American Academy of Child and Adolescent Psychiatry state that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioural therapy (CBT), for the treatment of moderate to severe OCD.

Panic Disorder

The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomised multicentre phase III clinical trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm.

Bulimia Nervosa

A 2011 systematic review discussed seven trials which compared fluoxetine to a placebo in the treatment of bulimia nervosa, six of which found a statistically significant reduction in symptoms such as vomiting and binge eating. However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone.

Premenstrual Dysphoric Disorder

Fluoxetine is used to treat premenstrual dysphoric disorder, a condition where individuals have affective and somatic symptoms monthly during the luteal phase of menstruation. Taking fluoxetine 20 mg/d can be effective in treating PMDD, though doses of 10mg/d have also been prescribed effectively.

Impulsive Aggression

Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity. Fluoxetine reduced low intensity aggressive behaviour in patients in intermittent aggressive disorder and borderline personality disorder. Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behaviour.

Special Populations

In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favouring its efficacy and tolerability. In pregnancy, fluoxetine is considered a category C drug by the US Food and Drug Administration (FDA). Evidence supporting an increased risk of major foetal malformations resulting from fluoxetine exposure is limited, although the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has warned prescribers and patients of the potential for fluoxetine exposure in the first trimester (during organogenesis, formation of the foetal organs) to cause a slight increase in the risk of congenital cardiac malformations in the newborn. Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor foetal malformations was observed in one study.

However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada – concluded:

“the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations.”

Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester. A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, “Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation.” Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal foetal exposure observed and its safety profile while breastfeeding.

Adverse Effects

Side effects observed in fluoxetine-treated persons in clinical trials with an incidence >5% and at least twice as common in fluoxetine-treated persons compared to those who received a placebo pill include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhoea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilation, and yawning. Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation). It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.).

Sexual Dysfunction

Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, are some of the most commonly encountered adverse effects of treatment with fluoxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is >70%. On the 11th of June 2019 the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that there is a possible causal association between SSRI use and long-lasting sexual dysfunction that persists despite discontinuation of SSRI, including fluoxetine, and that the labels of these drugs should be updated to include a warning.

Discontinuation Syndrome

Fluoxetine’s longer half-life makes it less common to develop discontinuation syndrome following cessation of therapy, especially when compared to antidepressants with shorter half-lives such as paroxetine. Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine.

Pregnancy

Antidepressant exposure (including fluoxetine) is associated with shorter average duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). There is 30-36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy, with fluoxetine use in the first trimester associated with 38-65% increase in septal heart defects.

Suicide

In 2007 the FDA required all antidepressants to carry a black box warning stating that antidepressants increase the risk of suicide in people younger than 25. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 2-fold increase of the suicidal ideation and behaviour in children and adolescents, and 1.5-fold increase of suicidality in the 18-24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group. This analysis was criticized by Donald Klein, who noted that suicidality, that is suicidal ideation and behaviour, is not necessarily a good surrogate marker for completed suicide, and it is still possible, while unproven, that antidepressants may prevent actual suicide while increasing suicidality.

There is less data on fluoxetine than on antidepressants as a whole. For the above analysis on the antidepressant level, the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%, and in adults decreased the odds of suicidality by approximately 30%. Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.

QT Prolongation

Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents Ito and IKs that repolarise the cardiac action potential. Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an electrocardiogram reflecting how long it takes for the heart to electrically recharge after each heartbeat. When fluoxetine is taken alongside other drugs that prolong the QT interval, or by those with a susceptibility to long QT syndrome, there is a small risk of potentially lethal abnormal heart rhythms such as Torsades de Pointes. As of 2019, the drug reference site CredibleMeds lists Fluoxetine as leading to a conditional risk of arrhythmias.

Overdose

In overdose, most frequent adverse effects include:

  • Nervous system effects:
    • Anxiety.
    • Nervousness.
    • Insomnia.
    • Drowsiness.
    • Fatigue or asthenia.
    • Tremor.
    • Dizziness or lightheadedness.
  • Gastrointestinal effects:
    • Anorexia (symptom).
    • Nausea.
    • Diarrhoea.
    • Vasodilation.
    • Dry mouth.
    • Abnormal vision.
  • Other effects:
    • Abnormal ejaculation.
    • Rash.
    • Sweating.
    • Decreased libido.

Interactions

Contraindications include prior treatment (within the past 5-6 weeks, depending on the dose) with MAOIs such as phenelzine and tranylcypromine, due to the potential for serotonin syndrome. Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used. Its use in those concurrently receiving pimozide or thioridazine is also advised against.

In some cases, use of dextromethorphan-containing cold and cough medications with fluoxetine is advised against, due to fluoxetine increasing serotonin levels, as well as the fact that fluoxetine is a cytochrome P450 2D6 inhibitor, which causes dextromethorphan to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome and other potential side effects of dextromethorphan.

Patients who are taking anticoagulants or NSAIDS must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.

Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that are involved in drug metabolism. Both are potent inhibitors of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9. In vivo, fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and CYP3A4. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates such as loperamide may have their central effects potentiated. This extensive effect on the body’s pathways for drug metabolism creates the potential for interactions with many commonly used drugs.

Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, amphetamine, MDMA, triptans, buspirone, serotonin–norepinephrine reuptake inhibitors and other SSRIs due to the potential for serotonin syndrome to develop as a result.

There is also the potential for interaction with highly protein-bound drugs due to the potential for fluoxetine to displace said drugs from the plasma or vice versa hence increasing serum concentrations of either fluoxetine or the offending agent.

Pharmacology

Pharmacodynamics

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine. Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60-80 mg). This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine.

Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain. Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically-relevant.

In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear. Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel. A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be inhibited at similar concentrations.

Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.

Mechanism of Action

Fluoxetine elicits antidepressant effect by inhibiting serotonin re-uptake in the synapse by binding to the re-uptake pump on the neuronal membrane to increase serotonin availability and enhance neurotransmission. Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin re-uptake inhibitors, increasing the duration of action of the drug.

Pharmacokinetics

The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6-8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein. Fluoxetine is metabolised in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, norfluoxetine. Both drugs are also potent inhibitors of CYP2D6.

The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life increases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. The full benefit of the current dose a patient receives is not realised for at least a month following ingestion. For example, in one 6-week study, the median time to achieving consistent response was 29 days. Likewise, complete excretion of the drug may take several weeks. During the first week after treatment discontinuation, the brain concentration of fluoxetine decreases by only 50%, The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood.

Measurement in Body Fluids

Fluoxetine and norfluoxetine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in a hospitalised person or assist in a medicolegal death investigation. Blood or plasma fluoxetine concentrations are usually in a range of 50-500 μg/L in persons taking the drug for its antidepressant effects, 900-3000 μg/L in survivors of acute overdosage and 1000-7000 μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy, but may be substantially less following acute overdosage, since it requires at least 1-2 weeks for the metabolite to achieve equilibrium.

Usage

In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States, making it the third-most prescribed antidepressant after sertraline and citalopram. In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.

Society and Culture

American Airline Pilots

Beginning 05 April 2010, fluoxetine became one of four antidepressant drugs that the US Federal Aviation Authority (FAA) permitted for pilots with authorisation from an aviation medical examiner. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). These four remain the only antidepressants permitted by FAA as of 02 December 2016.

Sertraline, citalopram and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019.

Environmental Effects

Fluoxetine has been detected in aquatic ecosystems, especially in North America. There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.

In 2003, one of the first studies addressed in detail the potential effects of fluoxetine on aquatic wildlife; this research concluded that exposure at environmental concentrations was of little risk to aquatic systems if a hazard quotient approach was applied to risk assessment. However, they also stated the need for further research addressing sub-lethal consequences of fluoxetine, specifically focusing on study species’ sensitivity, behavioural responses, and endpoints modulated by the serotonin system.

Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour, reproduction, and foraging at or below field-detected concentrations. However, a 2014 review on the ecotoxicology of fluoxetine concluded that, at that time, a consensus on the ability of environmentally realistic dosages to affect the behaviour of wildlife could not be reached.

Politics

During the 1990 campaign for Governor of Florida, it was disclosed that one of the candidates, Lawton Chiles, had depression and had resumed taking fluoxetine, leading his political opponents to question his fitness to serve as Governor.

On This Day … 02 July

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People (Deaths)

  • 1926 – Émile Coué, French psychologist and pharmacist (b. 1857).

Emile Coue

Émile Coué de la Châtaigneraie (26 February 1857 to 02 July 1926) was a French psychologist and pharmacist who introduced a popular method of psychotherapy and self-improvement based on optimistic autosuggestion. Considered by Charles Baudouin to represent a second Nancy School, Coué treated many patients in groups and free of charge.

On This Day … 01 July

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People (Births)

  • 1818 – Karl von Vierordt, German physician, psychologist and academic (d. 1884).
  • 1917 – Humphry Osmond, English-American lieutenant and psychiatrist (d. 2004)

Karl von Vierordt

Karl von Vierordt (01 July 1818 to 22 November 1884) was a German physiologist.

Vierordt was born in Lahr, Baden. He studied at the universities of Berlin, Göttingen, Vienna, and Heidelberg, and began a practice in Karlsruhe in 1842. In 1849 he became a professor of theoretical medicine at the University of Tübingen, and in 1853 a professor of physiology.

Vierordt developed techniques and tools for the monitoring of blood circulation. He is credited with the construction of an early “hemotachometer”, an apparatus for monitoring the velocity of blood flow. In 1854, he created a device called a sphygmograph, a mechanism consisting of weights and levers used to estimate blood pressure, and considered to be a forerunner of the modern sphygmomanometer. One of his better known written works was a treatise on the arterial pulse, titled Die Lehre vom Arterienpuls in gesunden und kranken Zuständen.

Vierordt also made substantial contributions to the psychology of time perception, via his book (published in 1868) Der Zeitsinn nach Versuchen, “The experimental study of the time sense”. This reported a large number of experiments on the perception of duration, with the time sense being considered a “general sense” along with the perception of space, in contrast to the “special senses” such as vision and hearing. Included in this book is discussion of, and evidence for, what has come to be known as Vierordt’s Law: roughly the proposition that short durations tend to be overestimated, while long durations tend to be underestimated.

Between these two extremes is a “point of indifference” where the “time sensation”, in Vierordt’s terminology, corresponds exactly to physical time. However, the 1868 book does much more than report this “law” and contains extensive discussions of different methods used to measure duration perception, as well as different sorts of errors that can occur.

Although Vierordt was not the first person to carry out experiments on time perception, his 1868 book involved much more extensive experimentation and discussion than had been carried out until then.

He died in Tübingen, aged 66.

Humphrey Osmond

Humphry Fortescue Osmond (01 July 1917 to 06 February 2004) was an English psychiatrist who expatriated to Canada, then moved to work in the United States. He is known for inventing the word psychedelic and for his research into interesting and useful applications for psychedelic drugs. Osmond also explored aspects of the psychology of social environments, in particular how they influenced welfare or recovery in mental institutions.

As a young man, he worked for an architect and attended Guy’s Hospital Medical School at King’s College London. While active as a surgeon-lieutenant in the Navy during World War II, Osmond trained to become a psychiatrist.

Work with Psychedelics

After the war, Osmond joined the psychiatric unit at St George’s Hospital, London where he rose to become senior registrar. His time at the hospital was to prove pivotal in three respects: firstly it was where he met his wife Amy “Jane” Roffey who was working there as a nurse, secondly he met Dr John Smythies who was to become one of his major collaborators, and thirdly he first encountered the drugs that would become associated with his name (and his with theirs): LSD and mescaline. While researching the drugs at St George’s, Osmond noticed that they produced similar effects to schizophrenia and he became convinced that the disease was caused by a chemical imbalance in the brain. These ideas were not well received amongst the psychiatric community in London at the time. In 1951, Osmond and Smythies moved to Saskatchewan, Canada to join the staff of the Weyburn Mental Hospital in the southeastern city of Weyburn, Saskatchewan.

At Weyburn, Osmond recruited a group of research psychologists to turn the hospital into a design-research laboratory. There, he conducted a wide variety of patient studies and observations using hallucinogenic drugs, collaborating with Abram Hoffer and others. In 1952, Osmond related the similarity of mescaline to adrenaline molecules, in a theory which implied that schizophrenia might be a form of self-intoxication caused by one’s own body. He collected the biographies of recovered schizophrenics, and he held that psychiatrists can only understand the schizophrenic by understanding the rational way the mind makes sense of distorted perceptions. He pursued this idea with passion, exploring all avenues to gain insight into the shattered perceptions of schizophrenia, holding that the illness arises primarily from distortions of perception. Yet during the same period, Osmond became aware of the potential of psychedelics to foster mind-expanding and mystical experiences.

In 1953, English-born Aldous Huxley was long-since a renowned poet and playwright who, in his twenties, had gone on to achieve success and acclaim as a novelist and widely published essayist. He had lived in the US for well over a decade and gained some experience screenwriting for Hollywood films. Huxley had initiated a correspondence with Osmond. In one letter, Huxley lamented that contemporary education seemed typically to have the unintended consequence of constricting the minds of the educated – close the minds of students, that is, to inspiration and to many things other than material success and consumerism. In their exchange of letters, Huxley asked Osmond if he would be kind enough to supply a dose of mescaline.

In May of that year, Osmond travelled to the Los Angeles area for a conference and, while there, provided Huxley with the requested dose of mescaline and supervised the ensuing experience in the author’s home neighbourhood. As a result of his experience, Huxley produced an enthusiastic book called The Doors of Perception, describing the look of the Hollywood Hills and his responses to artwork while under the influence. Osmond’s name appears in four footnotes in the early pages of the book (in references to articles Osmond had written regarding medicinal use of hallucinogenic drugs).

Osmond was respected and trusted enough that in 1955 he was approached by Christopher Mayhew (later, Baron Mayhew), an English politician, and guided Mayhew through a mescaline trip that was filmed for broadcast by the BBC.

Osmond and Abram Hoffer were taught a way to “maximize the LSD experience” by the influential layman Al Hubbard, who came to Weyburn. Thereafter they adopted some of Hubbard’s methods.

Humphry Osmond first proposed the term “psychedelic” at a meeting of the New York Academy of Sciences in 1956. He said the word meant “mind manifesting” (from “mind”, ψυχή (psyche), and “manifest”, δήλος (delos)) and called it “clear, euphonious and uncontaminated by other associations.” Huxley had sent Osmond a rhyme containing his own suggested invented word: “To make this trivial world sublime, take half a gram of phanerothyme” (θυμός (thymos) meaning ‘spiritedness’ in Ancient Greek.) Osmond countered with “To fathom Hell or soar angelic, just take a pinch of psychedelic” (Alternative version: To fall in Hell or soar angelic / You’ll need a pinch of psychedelic).

Osmond is also known for a study in the late 1950s in which he attempted to cure alcoholics with LSD. He claimed to have achieved a fifty-percent success rate. Osmond noticed that some drinkers were only able to give up drinking after an episode of delirium tremens and tried to replicate this state in patients through giving them high doses of the drug. This came to be known as the psychedelic treatment model, contrasted to the psycholytic model that used low doses to help release repressed material from the mind which it was hoped would help the psychotherapeutic process. One of Osmond’s patients during this time was Bill W., co-founder of Alcoholics Anonymous. However, what with the growing reputation for psychedelics’ potential for enabling spiritual insight, rather than a delirium tremens type of experience, Bill W. hoped to recapture a mystical state of consciousness that he had experienced, years earlier, without a drug.

On This Day … 30 June

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People (Births)

  • 1791 – Félix Savart, French physicist and psychologist (d. 1841).

Felix Savart

Félix Savart (30 June 1791 to 16 March 1841) was a physicist and mathematician who is primarily known for the Biot-Savart law of electromagnetism, which he discovered together with his colleague Jean-Baptiste Biot. His main interest was in acoustics and the study of vibrating bodies. A particular interest in the violin led him to create an experimental trapezoidal model. He gave his name to the savart, a unit of measurement for musical intervals, and to Savart’s wheel – a device he used while investigating the range of human hearing.

Biography

He was the son of Gérard Savart, an engineer at the military school of Metz. His brother, Nicolas, who was a student at the École Polytechnique and an officer in the engineering corps, did work on vibration. At the military hospital at Metz, Savart studied medicine and later he went on to continue his studies at the University of Strasbourg, where he received his medical degree in 1816. Savart became a professor at Collège de France in 1820 and was the co-originator of the Biot-Savart law, along with Jean-Baptiste Biot. Together, they worked on the theory of magnetism and electrical currents. Their law was developed and published in 1820. The Biot-Savart law relates magnetic fields to the currents which are their sources.

Savart also studied acoustics. He developed the Savart wheel which produces sound at specific graduated frequencies using rotating discs.

Félix Savart is the namesake of a unit of measurement for musical intervals, the savart, though it was actually invented by Joseph Sauveur (Stigler’s law of eponymy).

What is Dysthymia?

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Introduction

Dysthymia, also known as persistent depressive disorder (PDD), is a mental and behavioural disorder, specifically a disorder primarily of mood, consisting of the same cognitive and physical problems as depression, but with longer-lasting symptoms.

The concept was coined by Robert Spitzer as a replacement for the term “depressive personality” in the late 1970s.

In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), dysthymia is a serious state of chronic depression, which persists for at least two years (one year for children and adolescents). Dysthymia is less acute than major depressive disorder, but not necessarily less severe.

As dysthymia is a chronic disorder, sufferers may experience symptoms for many years before it is diagnosed, if diagnosis occurs at all. As a result, they may believe that depression is a part of their character, so they may not even discuss their symptoms with doctors, family members or friends. In the DSM-5, dysthymia is replaced by persistent depressive disorder. This new condition includes both chronic major depressive disorder and the previous dysthymic disorder. The reason for this change is that there was no evidence for meaningful differences between these two conditions.

Epidemiology

Globally dysthymia occurs in about 105 million people a year (1.5% of the population). It is 38% more common in women (1.8% of women) than in men (1.3% of men). The lifetime prevalence rate of dysthymia in community settings appears to range from 3 to 6% in the United States. However, in primary care settings the rate is higher ranging from 5 to 15 percent. United States prevalence rates tend to be somewhat higher than rates in other countries.

Signs and Symptoms

Dysthymia characteristics include an extended period of depressed mood combined with at least two other symptoms which may include insomnia or hypersomnia, fatigue or low energy, eating changes (more or less), low self-esteem, or feelings of hopelessness. Poor concentration or difficulty making decisions are treated as another possible symptom. Irritability is one of the more common symptoms in children and adolescents.

Mild degrees of dysthymia may result in people withdrawing from stress and avoiding opportunities for failure. In more severe cases of dysthymia, people may withdraw from daily activities. They will usually find little pleasure in usual activities and pastimes.

Diagnosis of dysthymia can be difficult because of the subtle nature of the symptoms and patients can often hide them in social situations, making it challenging for others to detect symptoms. Additionally, dysthymia often occurs at the same time as other psychological disorders, which adds a level of complexity in determining the presence of dysthymia, particularly because there is often an overlap in the symptoms of disorders.

There is a high incidence of comorbid illness in those with dysthymia. Suicidal behaviour is also a particular problem with those with dysthymia. It is vital to look for signs of major depression, panic disorder, generalised anxiety disorder, alcohol and substance use disorders, and personality disorder.

Causes

There are no known biological causes that apply consistently to all cases of dysthymia, which suggests diverse origin of the disorder. However, there are some indications that there is a genetic predisposition to dysthymia: “The rate of depression in the families of people with dysthymia is as high as fifty percent for the early-onset form of the disorder”. Other factors linked with dysthymia include stress, social isolation, and lack of social support.

In a study using identical and fraternal twins, results indicated that there is a stronger likelihood of identical twins both having depression than fraternal twins. This provides support for the idea that dysthymia is in part caused by heredity.

Co-Occurring Conditions

Dysthymia often co-occurs with other mental disorders. A “double depression” is the occurrence of episodes of major depression in addition to dysthymia. Switching between periods of dysthymic moods and periods of hypomanic moods is indicative of cyclothymia, which is a mild variant of bipolar disorder.

“At least three-quarters of patients with dysthymia also have a chronic physical illness or another psychiatric disorder such as one of the anxiety disorders, cyclothymia, drug addiction, or alcoholism”. Common co-occurring conditions include major depression (up to 75%), anxiety disorders (up to 50%), personality disorders (up to 40%), somatoform disorders (up to 45%) and substance use disorders (up to 50%). People with dysthymia have a higher-than-average chance of developing major depression. A 10-year follow-up study found that 95% of dysthymia patients had an episode of major depression. When an intense episode of depression occurs on top of dysthymia, the state is called “double depression.”

Double Depression

Double depression occurs when a person experiences a major depressive episode on top of the already-existing condition of dysthymia. It is difficult to treat, as sufferers accept these major depressive symptoms as a natural part of their personality or as a part of their life that is outside of their control. The fact that people with dysthymia may accept these worsening symptoms as inevitable can delay treatment. When and if such people seek out treatment, the treatment may not be very effective if only the symptoms of the major depression are addressed, but not the dysthymic symptoms. Patients with double depression tend to report significantly higher levels of hopelessness than is normal. This can be a useful symptom for mental health services providers to focus on when working with patients to treat the condition. Additionally, cognitive therapies can be effective for working with people with double depression in order to help change negative thinking patterns and give individuals a new way of seeing themselves and their environment.

It has been suggested that the best way to prevent double depression is by treating the dysthymia. A combination of antidepressants and cognitive therapies can be helpful in preventing major depressive symptoms from occurring. Additionally, exercise and good sleep hygiene (e.g. improving sleep patterns) are thought to have an additive effect on treating dysthymic symptoms and preventing them from worsening.

Pathophysiology

There is evidence that there may be neurological indicators of early onset dysthymia. There are several brain structures (corpus callosum and frontal lobe) that are different in women with dysthymia than in those without dysthymia. This may indicate that there is a developmental difference between these two groups.

Another study, which used fMRI techniques to assess the differences between individuals with dysthymia and other people, found additional support for neurological indicators of the disorder. This study found several areas of the brain that function differently. The amygdala (associated with processing emotions such as fear) was more activated in dysthymia patients. The study also observed increased activity in the insula (which is associated with sad emotions). Finally, there was increased activity in the cingulate gyrus (which serves as the bridge between attention and emotion).

A study comparing healthy individuals to people with dysthymia indicates there are other biological indicators of the disorder. An anticipated result appeared as healthy individuals expected fewer negative adjectives to apply to them, whereas people with dysthymia expected fewer positive adjectives to apply to them in the future. Biologically these groups are also differentiated in that healthy individuals showed greater neurological anticipation for all types of events (positive, neutral, or negative) than those with dysthymia. This provides neurological evidence of the dulling of emotion that individuals with dysthymia have learned to use to protect themselves from overly strong negative feelings, compared to healthy people.

There is some evidence of a genetic basis for all types of depression, including dysthymia. A study using identical and fraternal twins indicated that there is a stronger likelihood of identical twins both having depression than fraternal twins. This provides support for the idea that dysthymia is caused in part by heredity.

A new model has recently surfaced in the literature regarding the HPA axis (structures in the brain that get activated in response to stress) and its involvement with dysthymia (e.g. phenotypic variations of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), and down-regulation of adrenal functioning) as well as forebrain serotonergic mechanisms. Since this model is highly provisional, further research is still needed.

Diagnosis

The Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), published by the American Psychiatric Association, characterises dysthymic disorder. The essential symptom involves the individual feeling depressed for the majority of days, and parts of the day, for at least two years. Low energy, disturbances in sleep or in appetite, and low self-esteem typically contribute to the clinical picture as well. Sufferers have often experienced dysthymia for many years before it is diagnosed. People around them often describe the sufferer in words similar to “just a moody person”. Note the following diagnostic criteria:

  1. During a majority of days for two years or more, the adult patient reports depressed mood, or appears depressed to others for most of the day.
  2. When depressed, the patient has two or more of:
    1. decreased or increased appetite
    2. decreased or increased sleep (insomnia or hypersomnia)
    3. Fatigue or low energy
    4. Reduced self-esteem
    5. Decreased concentration or problems making decisions
    6. Feelings of hopelessness or pessimism
  3. During this two-year period, the above symptoms are never absent longer than two consecutive months.
  4. During the duration of the two-year period, the patient may have had a perpetual major depressive episode.
  5. The patient has not had any manic, hypomanic, or mixed episodes.
  6. The patient has never fulfilled criteria for cyclothymic disorder.
  7. The depression does not exist only as part of a chronic psychosis (such as schizophrenia or delusional disorder).
  8. The symptoms are often not directly caused by a medical illness or by substances, including substance use or other medications.
  9. The symptoms may cause significant problems or distress in social, work, academic, or other major areas of life functioning.

In children and adolescents, mood can be irritable, and duration must be at least one year, in contrast to two years needed for diagnosis in adults.

Early onset (diagnosis before age 21) is associated with more frequent relapses, psychiatric hospitalisations, and more co-occurring conditions. For younger adults with dysthymia, there is a higher co-occurrence in personality abnormalities and the symptoms are likely chronic. However, in older adults suffering from dysthymia, the psychological symptoms are associated with medical conditions and/or stressful life events and losses.

Dysthymia can be contrasted with major depressive disorder by assessing the acute nature of the symptoms. Dysthymia is far more chronic (long lasting) than major depressive disorder, in which symptoms may be present for as little as 2 weeks. Also Dysthymia often presents itself at an earlier age than Major Depressive Disorder.

Prevention

Though there is no clear-cut way to prevent dysthymia from occurring, some suggestions have been made. Since dysthymia will often first occur in childhood, it is important to identify children who may be at risk. It may be beneficial to work with children in helping to control their stress, increase resilience, boost self-esteem, and provide strong networks of social support. These tactics may be helpful in warding off or delaying dysthymic symptoms.

Treatment

Persistent depressive disorder can be treated with psychotherapy and pharmacotherapy. The overall rate and degree of treatment success is somewhat lower than for non-chronic depression, and a combination of psychotherapy and pharmacotherapy shows best results.

Therapy

Psychotherapy can be effective in treating dysthymia. In a meta-analytic study from 2010, psychotherapy had a small but significant effect when compared to control groups. However, psychotherapy is significantly less effective than pharmacotherapy in direct comparisons.

There are many different types of therapy, and some are more effective than others.

  • The empirically most studied type of treatment is cognitive-behavioural therapy.
    • This type of therapy is very effective for non-chronic depression, and it appears to be also effective for chronic depression.
  • Cognitive behavioural analysis system of psychotherapy (CBASP) has been designed specifically to treat PDD.
    • Empirical results on this form of therapy are inconclusive: While one study showed remarkably high treatment success rates, a later, even larger study showed no significant benefit of adding CBASP to treatment with antidepressants.
  • Schema therapy and psychodynamic psychotherapy have been used for PDD, though good empirical results are lacking.
  • Interpersonal psychotherapy has also been said to be effective in treating the disorder, though it only shows marginal benefit when added to treatment with antidepressants.

Medications

In a 2010 meta-analysis, the benefit of pharmacotherapy was limited to selective serotonin reuptake inhibitors (SSRIs) rather than tricyclic antidepressants (TCA).

According to a 2014 meta-analysis, antidepressants are at least as effective for persistent depressive disorder as for major depressive disorder. The first line of pharmacotherapy is usually SSRIs due to their purported more tolerable nature and reduced side effects compared to the irreversible monoamine oxidase inhibitors or tricyclic antidepressants. Studies have found that the mean response to antidepressant medications for people with dysthymia is 55%, compared with a 31% response rate to a placebo. The most commonly prescribed antidepressants/SSRIs for dysthymia are escitalopram, citalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine. It often takes an average of 6-8 weeks before the patient begins to feel these medications’ therapeutic effects. Additionally, STAR*D, a multi-clinic governmental study, found that people with overall depression will generally need to try different brands of medication before finding one that works specifically for them. Research shows that 1 in 4 of those who switch medications get better results regardless of whether the second medication is an SSRI or some other type of antidepressant.

In a meta-analytic study from 2005, it was found that SSRIs and TCAs are equally effective in treating dysthymia. They also found that MAOIs have a slight advantage over the use of other medication in treating this disorder. However, the author of this study cautions that MAOIs should not necessarily be the first line of defence in the treatment of dysthymia, as they are often less tolerable than their counterparts, such as SSRIs.

Tentative evidence supports the use of amisulpride to treat dysthymia but with increased side effects.

Combination Treatment

When pharmacotherapy alone is compared with combined treatment with pharmacotherapy plus psychotherapy, there is a strong trend in favour of combined treatment. Working with a psychotherapist to address the causes and effects of the disorder, in addition to taking antidepressants to help eliminate the symptoms, can be extremely beneficial. This combination is often the preferred method of treatment for those who have dysthymia. Looking at various studies involving treatment for dysthymia, 75% of people responded positively to a combination of cognitive behavioural therapy and pharmacotherapy, whereas only 48% of people responded positively to just CBT or medication alone.

A 2019 Cochrane review of 10 studies involving 840 participants could not conclude with certainty that continued pharmacotherapy with antidepressants (those used in the studies) was effective in preventing relapse or recurrence of persistent depressive disorder. The body of evidence was too small for any greater certainty although the study acknowledges that continued psychotherapy may be beneficial when compared to no treatment.

Resistance

Because of dysthymia’s chronic nature, treatment resistance is somewhat common. In such a case, augmentation is often recommended. Such treatment augmentations can include lithium pharmacology, thyroid hormone augmentation, amisulpride, buspirone, bupropion, stimulants, and mirtazapine. Additionally, if the person also suffers from seasonal affective disorder, light therapy can be useful in helping augment therapeutic effects.

What is Cognitive Analytic Therapy?

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Introduction

Cognitive analytic therapy (CAT) is a form of psychological therapy initially developed in the United Kingdom by Anthony Ryle.

This time-limited therapy was developed in the context of the UK’s National Health Service (NHS) with the aim of providing effective and affordable psychological treatment which could be realistically provided in a resource constrained public health system. It is distinctive due to its intensive use of reformulation, its integration of cognitive and analytic practice and its collaborative nature, involving the patient very actively in their treatment.

The CAT practitioner aims to work with the patient to identify procedural sequences; chains of events, thoughts, emotions and motivations that explain how a target problem (for example self-harm) is established and maintained. In addition to the procedural sequence model, a second distinguishing feature of CAT is the use of reciprocal roles (RRs). These identify problems as occurring between people and not within the patient. RRs may be set up in early life and then be replayed in later life; for example someone who as a child felt neglected by parents perceived as abandoning might be vulnerable to feelings of abandonment in later life (or indeed neglect themselves).

Background

As the name implies, CAT evolved as an integrative therapy based on ideas from cognitive and analytic therapies. CAT was also influenced in part by George Kelly’s constructivism. Kelly had developed personal construct theory and the repertory grid method, and Kelly’s approach to therapy “offered a model of nonauthoritarian practice” that psychotherapist Anthony Ryle found appealing.

Ryle, a general practitioner and analytically trained psychotherapist, was undertaking research into psychotherapy practice using repertory grids in the 1970s. He found that the themes eventually addressed in analytic work were in fact present in transcripts from the very first sessions. However the slow, exploratory nature of traditional analytic therapy meant that these were not always addressed early and assertively, with the result that therapy, while effective, took a long time to produce results. In a 1979 paper, he proposed a shorter, more active form of therapy which integrated elements from cognitive therapy practice (such as goal setting and Socratic questioning) into analytic practice. This would include explicitly formulating the problems experienced by the patient, and sharing this formulation with the patient to engage them in psychotherapy as a co-operative enterprise.

Subsequently CAT has been influenced by ideas from the work of Soviet psychologist Lev Vygotsky and Russian philosopher Mikhail Bakhtin. From Vygotsky come concepts such as the zone of proximal development (ZPD) and scaffolding. The ZPD implies that new tasks set for the patient (for example, tolerating anxiety about social situations) should extend what they do beyond their current capabilities, but only by a small and achievable amount. Scaffolding involves the therapist providing support for the patient’s efforts to change, but varying this level of support as the patient’s needs change.

Bakhtin provided concepts such as dialogism from which come techniques such as Dialogical Sequence Analysis. This is a structured attempt to identify and visually display sequences of behaviour, thinking, and emotions so that the patient becomes more aware of these and can start to modify them.

In Practice

The model emphasises collaborative work with the client, and focuses on the understanding of the patterns of maladaptive behaviours. The aim of the therapy is to enable the client to recognise these patterns, understand their origins, and subsequently to learn alternative strategies in order to cope better.

The approach is always time-limited, typically taking place over 8-24 weekly sessions (the precise number being agreed at the start of therapy). Sixteen sessions is probably the most common length. In the first quarter of the therapy (the Reformulation phase) the therapist collects all the relevant information, asking the patient about present day problems and also earlier life experiences. At that point the therapist writes a reformulation letter to the client. This letter summarises the therapist’s understanding of the client’s problems. Particular attention is given to understanding the connection between childhood patterns of behaviour and their impact on adult life. The letter is agreed between patient and therapist and forms the basis for the rest of the work.

After the reformulation letter the patient may be asked to complete diaries or rating sheets to record the occurrence of problems and their context. During this period (known as the Recognition phase) patient and therapist construct a diagrammatic formulation to illustrate the unhelpful procedures which maintain problems for the patient. The aim of this phase is to enable the patient to recognise when and how problems occur.

In the second half of the therapy work moves into the Revision phase, where patient and therapist identify and practice “exits” from the procedural diagram established in the previous phase. For example, a problematic procedure might move a patient from feeling angry to taking an overdose. An exit might involve expressing the anger in some way as an alternative to self-injuring behaviour.

At the end of the therapy, patient and therapist each write “goodbye letters” which they exchange, summarising what has been achieved in the therapy and what remains to be done. After the end of the agreed number of weekly sessions, planned follow-up sessions take place to monitor and support the changes that have been made. Typically, a 16-session CAT might be followed up by a single session one month after the end of therapy, and a final one three months later.

Evidence Base

CAT has been the subject of a number of research studies published in peer-reviewed journals. These include randomised controlled trials (RCTs) and other kinds of study. The approach is too new for any systematic reviews of RCTs to have been conducted, and therefore is not yet explicitly recommended by name by the UK National Institute for Health and Clinical Excellence (NICE). However NICE has recommended that there should be further research of CAT, for example in borderline personality disorder. A review of CAT research evidence published in 2014 reported that although there were five randomised controlled trials published, research evidence into the approach was dominated by small-scale, practice-based studies. These tended to be with complex and severe clinical groups; 44% of studies reviewed involved personality disorder. A review of CAT looking back over the 30 years to its beginnings contains a meta-analysis of 11 outcome studies of CAT. The overall number of patients treated in the studies was 324 and the average effect size across all studies was 0.83 (95% confidence interval 0.66-1.00). This is a large effect and suggests that CAT is efficacious in treating mental health problems.

Evidence from Randomised Controlled Trials

CAT has been shown to lead to subjective improvement in people with anorexia nervosa. It has also been shown to produce significant improvements in adolescents with a diagnosis of borderline personality disorder. A different trial suggested that CAT for adult patients with personality disorders also showed improvements in symptoms and interpersonal functioning, as against controls who deteriorated on these measures. CAT has also been shown to improve patients’ management of diabetes. An RCT of the use of a CAT-informed assessment for young people who had self-harmed suggested that it was effective in increasing rates of attendance at community follow-up.

Evidence from Other Methodologies

Comparative studies have suggested CAT to be at least as effective as other forms of brief psychotherapy, person-centred therapy and cognitive behavioural therapy, and interpersonal psychotherapy.

Case series and single case studies have also been published describing the use of CAT in:

  • Depression.
  • Dissociative psychosis.
  • The treatment of offenders.
  • Brain injury.
  • Deliberate self-harm.
  • Dissociative identity disorder.
  • Histrionic personality disorder.
  • Panic disorder.
  • Psychological problems in multiple sclerosis.
  • With carers of people with dementia.
  • Morbid jealousy.
  • Borderline personality disorder.
  • Paranoid personality disorder.
  • Survivors of child sexual abuse.