Author: Andrew Marshall

Founder & Editor of the BootCampMilitaryFitnessInstitute.com, MilitaryGogglebox.com, and Mental-Health-Matters.org.

What is Aripiprazole?

Published on by Andrew Marshall6 Comments

Introduction

Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressive disorder (MDD), tic disorders and irritability associated with autism. It is taken by mouth or injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.

Common side effects include vomiting, constipation, sleepiness, dizziness, weight gain and movement disorders. Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia and anaphylaxis. It is not recommended for older people with dementia-related psychosis due to an increased risk of death. In pregnancy, there is evidence of possible harm to the baby. It is not recommended in women who are breastfeeding. It has not been very well studied in people less than 18 years old. The exact mode of action is not entirely clear but may involve effects on dopamine and serotonin.

Aripiprazole was approved for medical use in the United States in 2002. It is available as a generic medication. In 2019, it was the 101st most commonly prescribed medication in the United States, with more than 6 million prescriptions. Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical.

Refer to Aripiprazole Lauroxil.

Brief History

Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.

It was approved by the US Food and Drug Administration (FDA) for schizophrenia in November 2002, and the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 01 October 2004; as an adjunct for major depressive disorder on 20 November 2007; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.

Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.

In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS’s off-label marketing of aripiprazole for children and older people with dementia.

In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.

As of 2013, Abilify had annual sales of US$7 billion. In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.

Otsuka’s US patent on aripiprazole expired on 20 October 2014, but due to a paediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the US District Court in New Jersey.

Otsuka’s European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014. The UK Intellectual Property Office decided on 04 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.

From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.

In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.

In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.

In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.

Medical Uses

Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.

Schizophrenia

The 2016 NICE guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second line treatment after risperidone for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia. A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second generation antipsychotics for people who have trouble taking medication as directed or who prefer it.

A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor. A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behaviour, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse. A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia. Accordingly, part of its methodology on quality of evidence is based on quantity of qualified studies.

A 2013 review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.

In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.

The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic, and that such treatment should continue for at least 1-2 years, as “There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period”. The guideline further notes that “Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)”.

The British Association for Psychopharmacology and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person’s preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics

Bipolar Disorder

Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents. Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression. Thus, it is often used in combination with an additional mood stabiliser; however, co-administration with a mood stabiliser increases the risk of extrapyramidal side effects.

Major Depression

Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning. Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram, and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.

Autism

Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours. Adverse effects include weight gain, sleepiness, drooling and tremors. It is suggested that children and adolescents need to be monitored regularly while taking this medication, to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long term use.

Tic Disorders

Aripiprazole is approved for the treatment of Tourette’s syndrome. It is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses

Obsessive-Compulsive Disorder

A 2014 systematic review and meta-analysis concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with selective serotonin reuptake inhibitors (SSRIs) alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms. Risperidone, another second-generation antipsychotic, appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines. However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD. Aripiprazole is not currently approved for the treatment of OCD and is instead used off-label for this indication.

Adverse Effects

In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.

Uncontrolled movement such as restlessness, tremors, and muscle stiffness may occur.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Overdose

Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3-4 fold over normal therapeutic levels; as of 2008 no deaths had been recorded.

Interactions

Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.

Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.

Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid attention-deficit hyperactivity disorder (ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.

Pharmacology

Pharmacodynamics

Aripiprazole’s mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D2). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors, D3, and partially D4 and is a partial activator of serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7). It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.

As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D2 partial agonist (with an intrinsic activity of ~25%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, in vitro, to bind to and/or induce receptor conformations (i.e. facilitate receptor shapes) in such a way as to not only prevent receptor internalisation (and, thus, lower receptor density) but even to lower the rate of receptor internalisation below that of neurons not in the presence of agonists (including dopamine) or antagonists. It is often the nature of partial agonists, including aripiprazole, to display a stabilising effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole’s partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D2 receptor occupancy (approximately 32%, 53%, 72%, 80%, and 97% at daily dosages of 0.5 mg, 1 mg, 2 mg, 10 mg, and 40 mg respectively) as well as balanced selectivity for pre- and postsynaptic receptors (as suggested by its equal affinity for both D2S and D2L receptor forms). Aripiprazole has been characterised as possessing predominantly antagonistic activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors; however, while this explanation intuitively explains the drug’s efficacy as an antipsychotic, as degree of agonism is a function of more than a drug’s inherent properties as well as in vitro demonstration of aripiprazole’s partial agonism in cells expressing postsynaptic (D2L) receptors, it was noted that “It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D2 receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5-1 pmol/mg). Instead, the current data are most parsimoniously explained by the ‘functional selectivity’ hypothesis of Lawler et al (1999)”. Aripiprazole is also a partial agonist of the D3 receptor. In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.

Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%). Casting doubt on the significance of aripiprazole’s agonism of 5-HT1A receptors, a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT1A receptor occupancy to be only 16% compared to ~90% for D2. It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%), and like other atypical antipsychotics, displays a functional antagonist profile at this receptor. The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor. At the 5-HT2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, “Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC50 of 11 nM”. Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity; this property may underlie the minimal weight gain seen in the course of therapy. At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.

Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions. The ‘functional-selectivity’ hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially ‘sensed’ by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.

Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an anti-obsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as anti-obsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favourable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have anti-obsessional and anorectic actions in humans.

Wood and Reavill’s (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor. It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.

Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduce.

Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3-5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via faeces and urine.

Chemistry

Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs.

Society and Culture

Classification

Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.

Research

Attention Deficit Hyperactivity Disorder

Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all 6 non-controlled open-label studies in the review reported effectiveness, two small randomised controlled trials found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.

Substance Dependence

Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.

Other Uses

Aripiprazole is under development for the treatment of agitation and pervasive child development disorders. As of May 2021, it is in phase 3 clinical trials for these indications.

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On This Day … 22 September [2022]

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People (Deaths)

  • 1988 – Rais Amrohvi, Pakistani psychoanalyst, scholar, and poet (b. 1914).
  • 2012 – Jan Hendrik van den Berg, Dutch psychiatrist and academic (b. 1914).

Rais Amrohvi

Rais Amrohvi (Urdu: رئیس امروہوی), whose real name was Syed Muhammad Mehdi (1914-1988) was a Pakistani scholar, Urdu poet, paranormal investigator, and psychoanalyst and elder brother of Jaun Elia. He was known for his style of qatanigari (quatrain writing). He wrote quatrains for Pakistani newspaper Jang for several decade. He promoted the Urdu language and supported the Urdu-speaking people of Pakistan. His family is regarded as family of poets.

The Sindh Assembly passed The Sind Teaching, Promotion and Use of Sindhi Language Bill, 1972 that created conflict and language violence in the regime of Prime Minister Zulfikar Ali Bhutto, he wrote his famous poem Urdu ka janaza hai zara dhoom say niklay (It is the funeral of Urdu, carry it out with fanfare). He also intended to translate the Bhagavad Gita into standard Urdu.

Jan Hendrik van den Berg

Jan Hendrik van den Berg (11 June 1914 to 22 September 2012) was a Dutch psychiatrist notable for his work in phenomenological psychotherapy (cf. phenomenology) and metabletics, or “psychology of historical change.” He is the author of numerous articles and books, including A different existence and The changing nature of man.

On This Day … 21 September [2022]

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People (Births)

  • 1946 – Mart Siimann, Estonian psychologist and politician, 12th Prime Minister of Estonia.

Mart Siimann

Mart Siimann (born 21 September 1946) was the Prime Minister of Estonia from 1997 to 1999, representing the liberal/centrist Estonian Coalition Party. He was the president of the Estonian Olympic Committee from 2001 to 2012.

Born at Kilingi-Nõmme, Siimann studied at the University of Tartu from 1965 to 1971. In 1971, he graduated as a philologist-psychologist. From 1989 to 1992, he was the director of the Estonian Television and from 1992 to 1995, Managing Director of Advertising Television Co. He was a member of the Estonian Parliament from 1995 to 1997 and from 1999 to 2003, elected as a Coalition Party member (but since 2001 served as the chairman of the centre-left/social democratic association “Mõistuse ja Südamega” (“With Reason and Heart”).

On This Day … 20 September [2022]

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People (Births)

  • 1847 – Susanna Rubinstein, Austrian psychologist (d. 1914).

Susanna Rubinstein

Susanna or Susanne Rubinstein (20 September 1847 to 29 March 1914) was an Austrian psychologist and the first woman to earn a doctorate from the University of Bern in Switzerland.

Rubinstein was born in Czernowitz (then part of Austria-Hungary, now Chernivtsi, Ukraine) into the Jewish family of the banker and parliamentarian Isak Rubinstein (c. 1804-1878). Her mother died when she was young.

She and her three siblings were greatly encouraged to pursue their education, even though this was a time when girls were often denied that opportunity. (A high school for girls was eventually opened in Czernowitz in1898 and a girls’ grammar school was established only during the years just before the First World War).

At first, her father arranged for Rubinstein to take private lessons but, when it came time to finish high school, she was unable to take the necessary examinations from tutors, so she did so before an academic committee from a boys’ high school.

Rubinstein went on to study psychology and German literature at the University of Prague, in the spring of 1870, and then at the Leipzig University three years later. After being denied admission to the doctoral program in Basel, Switzerland, she enrolled at the University of Bern and there she gained a Ph.D. in 1874 in psychology and German literature. By doing so, she became the first woman to receive a doctorate in Bern. Her thesis was “Uber die sensoriellen und sensitiven Sinne” (“About the sensory and sensitive senses”).

With the completion of her doctorate, Rubinstein spent a year in Germany visiting Leipzig, Heidelberg and Munich.

Her 1878 work “Psychologisch-Asthetische Essays” (“Psychological-Aesthetic Essays”) has been described as “a major contribution to the study of human emotions”. It was reprinted in 2012 (Nabu Press, ISBN 978-1277814729).

Susanna Rubinstein died 29 March 1914 in Würzburg, Germany.

What is Amoxapine?

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Introduction

Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCAs). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1992 (approximately 30 to 40 years after most of the other TCAs were introduced in the United States).

Medical Uses

Moxapine is used in the treatment of major depressive disorder (MDD). Compared to other antidepressants it is believed to have a faster onset of action, with therapeutic effects seen within four to seven days. In excess of 80% of patients that do respond to amoxapine are reported to respond within two weeks of the beginning of treatment. It also has properties similar to those of the atypical antipsychotics, and may behave as one and may be used in the treatment of schizophrenia off-label. Despite its apparent lack of extrapyramidal side effects in patients with schizophrenia it has been found to exacerbate motor symptoms in patients with Parkinson’s disease and psychosis.

Contraindications

As with all US Food and Drug Administration (FDA)-approved antidepressants it carries a black-box warning about the potential of an increase in suicidal thoughts or behaviour in children, adolescents and young adults under the age of 25. Its use is also advised against in individuals with known hypersensitivities to either amoxapine or other ingredients in its oral formulations. Its use is also recommended against in the following disease states:

  • Severe cardiovascular disorders (potential of cardiotoxic adverse effects such as QT interval prolongation).
  • Uncorrected narrow angle glaucoma.
  • Acute recovery post-myocardial infarction.

Its use is also advised against in individuals concurrently on monoamine oxidase inhibitors or if they have been on one in the past 14 days and in individuals on drugs that are known to prolong the QT interval (e.g. ondansetron, citalopram, pimozide, sertindole, ziprasidone, haloperidol, chlorpromazine, thioridazine, etc.).

Lactation

Its use in breastfeeding mothers not recommended as it is excreted in breast milk and the concentration found in breast milk is approximately a quarter that of the maternal serum level.

Side Effects

Very Common (>10% Incidence) Adverse Effects Include:

  • Constipation.
  • Dry mouth.
  • Sedation.

Common (1–10% Incidence) Adverse Effects Include:

  • Anxiety.
  • Ataxia.
  • Blurred vision.
  • Confusion.
  • Dizziness.
  • Headache.
  • Fatigue.
  • Nausea.
  • Nervousness/restlessness.
  • Excessive appetite.
  • Rash.
  • Increased perspiration (sweating).
  • Tremor.
  • Palpitations.
  • Nightmares.
  • Excitement.
  • Weakness.
  • ECG changes.
  • Oedema.
    • An abnormal accumulation of fluids in the tissues of the body leading to swelling.
  • Prolactin levels increased.
    • Prolactin is a hormone that regulates the generation of breast milk.
    • Prolactin elevation is not as significant as with risperidone or haloperidol.

Uncommon/Rare (<1% Incidence) Adverse Effects Include:

  • Diarrhoea.
  • Flatulence.
  • Hypertension (high blood pressure).
  • Hypotension (low blood pressure).
  • Syncope (fainting).
  • Tachycardia (high heart rate).
  • Menstrual irregularity.
  • Disturbance of accommodation.
  • Mydriasis (pupil dilation).
  • Orthostatic hypotension (a drop in blood pressure that occurs upon standing up).
  • Seizure.
  • Urinary retention (being unable to pass urine).
  • Urticaria (hives).
  • Vomiting.
  • Nasal congestion.
  • Photosensitisation
  • Hypomania (a dangerously elated/irritable mood).
  • Tingling.
  • Paresthaesias of the extremities.
  • Tinnitus.
  • Disorientation.
  • Numbness.
  • Incoordination.
  • Disturbed concentration.
  • Epigastric distress.
  • Peculiar taste in the mouth.
  • Increased or decreased libido.
  • Impotence (difficulty achieving an erection).
  • Painful ejaculation.
  • Lacrimation (crying without an emotional cause).
  • Weight gain.
  • Altered liver function.
  • Breast enlargement.
  • Drug fever.
  • Pruritus (itchiness).
  • Vasculitis a disorder where blood vessels are destroyed by inflammation.
    • Can be life-threatening if it affects the right blood vessels.
  • Galactorrhoea:
    • Lactation that is not associated with pregnancy or breast feeding.
  • Delayed micturition:
    • That is, delays in urination from when a conscious effort to urinate is made.
  • Hyperthermia:
    • Elevation of body temperature; its seriousness depends on the extent of the hyperthermia.
  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) this is basically when the body’s level of the hormone, antidiuretic hormone, which regulates the conservation of water and the restriction of blood vessels, is elevated.
    • This is potentially fatal as it can cause electrolyte abnormalities including hyponatraemia (low blood sodium), hypokalaemia (low blood potassium) and hypocalcaemia (low blood calcium) which can be life-threatening.
  • Agranulocytosis a drop in white blood cell counts.
    • The white blood cells are the cells of the immune system that fight off foreign invaders.
    • Hence agranulocytosis leaves an individual open to life-threatening infections.
  • Leukopaenia the same as agranulocytosis but less severe.
  • Neuroleptic malignant syndrome (a potentially fatal reaction to antidopaminergic agents, most often antipsychotics.
    • It is characterised by hyperthermia, diarrhoea, tachycardia, mental status changes [e.g. confusion], rigidity, extrapyramidal side effects)
  • Tardive dyskinesia a most often irreversible neurologic reaction to antidopaminergic treatment, characterised by involuntary movements of facial muscles, tongue, lips, and other muscles.
    • It develops most often only after prolonged (months, years or even decades) exposure to antidopaminergics.
  • Extrapyramidal side effects.
    • Motor symptoms such as tremor, parkinsonism, involuntary movements, reduced ability to move one’s voluntary muscles, etc.

Unknown Incidence or Relationship to Drug Treatment Adverse Effects Include:

  • Paralytic ileus (paralysed bowel).
  • Atrial arrhythmias including atrial fibrillation.
  • Myocardial infarction (heart attack).
  • Stroke.
  • Heart block.
  • Hallucinations.
  • Purpura.
  • Petechiae.
  • Parotid swelling.
  • Changes in blood glucose levels.
  • Pancreatitis swelling of the pancreas.
  • Hepatitis swelling of the liver.
  • Urinary frequency.
  • Testicular swelling.
  • Anorexia (weight loss).
  • Alopecia (hair loss).
  • Thrombocytopenia:
    • A significant drop in platelet count that leaves one open to life-threatening bleeds.
  • Eosinophilia an elevated level of the eosinophils of the body.
    • Eosinophils are the type of immune cell that’s job is to fight off parasitic invaders.
  • Jaundice:
    • yellowing of the skin, eyes and mucous membranes due to an impaired ability of the body to clear the by product of haem breakdown, bilirubin, most often the result of liver damage as it is the liver’s responsibility to clear bilirubin.

It tends to produce less anticholinergic effects, sedation and weight gain than some of the earlier TCAs (e.g. amitriptyline, clomipramine, doxepin, imipramine, trimipramine). It may also be less cardiotoxic than its predecessors.

Overdose

Refer to Tricyclic Antidepressant Overdose.

It is considered particularly toxic in overdose, with a high rate of renal failure (which usually takes 2-5 days), rhabdomyolysis, coma, seizures and even status epilepticus. Some believe it to be less cardiotoxic than other TCAs in overdose, although reports of cardiotoxic overdoses have been made.

Pharmacology

Pharmacodynamics

Amoxapine possesses a wide array of pharmacological effects. It is a moderate and strong reuptake inhibitor of serotonin and norepinephrine, respectively, and binds to the 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D2, α1-adrenergic, D3, D4, and H1 receptors with varying but significant affinity, where it acts as an antagonist (or inverse agonist depending on the receptor in question) at all sites. It has weak but negligible affinity for the dopamine transporter and the 5-HT1A, 5-HT1B, D1, α2-adrenergic, H4, mACh, and GABAA receptors, and no affinity for the β-adrenergic receptors or the allosteric benzodiazepine site on the GABAA receptor. Amoxapine is also a weak GlyT2 blocker, as well as a weak (Ki = 2.5 μM, EC50 = 0.98 μM) δ-opioid receptor partial agonist.

7-Hydroxyamoxapine, a major active metabolite of amoxapine, is a more potent dopamine receptor antagonist and contributes to its neuroleptic efficacy, whereas 8-hydroxyamoxapine is a norepinephrine reuptake inhibitor but a stronger serotonin reuptake inhibitor and helps to balance amoxapine’s ratio of serotonin to norepinephrine transporter blockade

Pharmacokinetics

Amoxapine is metabolised into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine.

Society and Culture

Brand Names

Brand names for amoxapine include (where † denotes discontinued brands):

  • Adisen (KR).
  • Amolife (IN).
  • Amoxan (JP).
  • Asendin† (previously marketed in CA, NZ, US).
  • Asendis† (previously marketed in IE, UK).
  • Défanyl (FR).
  • Demolox (DK†, IN, ES†).
  • Oxamine (IN).
  • Oxcap.

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

On This Day … 19 September [2022]

Published on by Andrew MarshallLeave a comment

People (Births)

  • 1913 – Frances Farmer, American actress (d. 1970).
  • 1954 – Adam Phillips, Welsh psychotherapist and author.

Frances Farmer

Frances Elena Farmer (19 September 1913 to 01 August 1970) was an American actress and television hostess. She appeared in over a dozen feature films over the course of her career, though she garnered notoriety for the various sensationalised accounts of her life, especially her involuntary commitment to psychiatric hospitals and subsequent mental health struggles.

A native of Seattle, Washington, Farmer began acting in stage productions while a student at the University of Washington. After graduating, she began performing in stock theatre before signing a film contract with Paramount Pictures on her 22nd birthday in September 1935. She made her film debut in the B film Too Many Parents (1936), followed by another B picture, Border Flight, before being given the lead role opposite Bing Crosby in the musical Western Rhythm on the Range (1936). Unhappy with the opportunities the studio gave her, Farmer returned to stock theatre in 1937 before being cast in the original Broadway production of Clifford Odets’s Golden Boy, staged by New York City’s Group Theatre. She followed this with two Broadway productions directed by Elia Kazan in 1939, but a battle with depression and binge drinking caused her to drop out of a subsequent Ernest Hemingway stage adaptation.

Farmer returned to Los Angeles, earning supporting roles in the comedy World Premiere (1941) and the film noir Among the Living (1941). In 1942, publicity of her reportedly erratic behaviour began to surface and, after several arrests and committals to psychiatric institutions, Farmer was diagnosed with paranoid schizophrenia. At the request of her family, particularly her mother, she was committed to an institution in her home state of Washington, where she remained a patient until 1950. Farmer attempted an acting comeback, mainly appearing as a television host in Indianapolis on her own series, Frances Farmer Presents. Her final film role was in the 1958 drama The Party Crashers, after which she spent the majority of the 1960s occasionally performing in local theatre productions staged by Purdue University. In the spring of 1970, she was diagnosed with oesophageal cancer, from which she died on 01 August 1970, aged 56.

Farmer has been the subject of various works, including two feature films and several books, many of which focus on her time spent institutionalised, during which she claimed to have been subject to various systemic abuses. Her posthumously released, ghostwritten, and widely discredited autobiography, Will There Really Be a Morning? (1972), details these claims, but has been exposed as a largely fictional work by a friend of Farmer’s to clear debts. Another discredited 1978 biography of her life, Shadowland, alleged that Farmer underwent a transorbital lobotomy during her institutionalisation, but the author has since stated in court that he fabricated this incident and several other aspects of the book. A 1982 biographical film based on this book depicted these events as true, resulting in renewed interest in her life and career.

Adam Phillips

Adam Phillips (born 19 September 1954) is a British psychoanalytic psychotherapist and essayist.

Since 2003 he has been the general editor of the new Penguin Modern Classics translations of Sigmund Freud. He is also a regular contributor to the London Review of Books.

Joan Acocella, writing in The New Yorker, described Phillips as “Britain’s foremost psychoanalytic writer”,[2] an opinion echoed by historian Élisabeth Roudinesco in Le Monde.

On This Day … 18 September [2022]

Published on by Andrew MarshallLeave a comment

People (Births)

  • 1888 – Toni Wolff, Swiss psychologist and author (d. 1953).
  • 1954 – Steven Pinker, Canadian-American psychologist, linguist, and author.

Toni Wolff

Toni Anna Wolff (18 September 1888 to 21 March 1953) was a Swiss Jungian analyst and a close collaborator of Carl Jung. During her analytic career Wolff published relatively little under her own name, but she helped Jung identify, define, and name some of his best-known concepts, including anima, animus, and persona, as well as the theory of the psychological types. Her best-known paper is an essay on four “types” or aspects of the feminine psyche: the Amazon, the Mother, the Hetaira, and the Medial (or mediumistic) Woman.

Steven Pinker

Steven Arthur Pinker (born 18 September 1954) is a Canadian-American cognitive psychologist, psycholinguist, popular science author and public intellectual. He is an advocate of evolutionary psychology and the computational theory of mind.

On This Day … 16 September [2022]

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People (Deaths)

  • 1980 – Jean Piaget, Swiss psychologist and philosopher (b. 1896).

Jean Piaget

Jean William Fritz Piaget (09 August 1896 to 16 September 1980) was a Swiss psychologist known for his work on child development. Piaget’s theory of cognitive development and epistemological view are together called “genetic epistemology”.

Piaget placed great importance on the education of children. As the Director of the International Bureau of Education, he declared in 1934 that “only education is capable of saving our societies from possible collapse, whether violent, or gradual”. His theory of child development is studied in pre-service education programs. Educators continue to incorporate constructivist-based strategies.

Piaget created the International Centre for Genetic Epistemology in Geneva in 1955 while on the faculty of the University of Geneva, and directed the centre until his death in 1980. The number of collaborations that its founding made possible, and their impact, ultimately led to the Centre being referred to in the scholarly literature as “Piaget’s factory”.

According to Ernst von Glasersfeld, Piaget was “the great pioneer of the constructivist theory of knowing”. However, his ideas did not become widely popularised until the 1960s. This then led to the emergence of the study of development as a major sub-discipline in psychology. By the end of the 20th century, Piaget was second only to B.F. Skinner as the most-cited psychologist of that era.

On This Day … 15 September [2022]

Published on by Andrew MarshallLeave a comment

People (Deaths)

Jurg Schubiger

Jürg Schubiger (14 October 1936 to 15 September 2014) was a Swiss psychotherapist and writer of children’s books. He won the Deutscher Jugendliteraturpreis (German Youth Literature Award) in 1996 for Als die Welt noch jung war.

For his “lasting contribution” as a children’s writer Schubiger received the biennial Hans Christian Andersen Medal in 2008. The award conferred by the International Board on Books for Young People is the highest recognition available to a writer or illustrator of children’s books.

A Brief Overview of Advocacy in Fife (Scotland)?

Published on by Andrew Marshall1 Comment

Introduction

This short article aims to introduce key concepts about advocacy in Fife, Scotland, including:

  • The importance of advocacy;
  • The principles and standards;
  • Types of advocacy; and
  • The services available for children, younger people, adults and older people in Fife.

Read in conjunction with What is Advocacy?.

What is Advocacy?

Advocacy IS:

  • Supporting people to speak about issues important to them;
  • A safeguarding role;
  • Supporting people to make their own choices and decisions;
  • Supporting people to have their views heard and increase their self-confidence; and
  • Representing the views of people when they are unable to do so for themselves.

Advocacy IS NOT:

  • Counselling;
  • Mediation;
  • Care/support;
  • Telling somebody what to do; or
  • Befriending.

What are the Two Types of Advocate?

  • Citizen Advocates:
    • Are volunteers from all walks of life who want to help others in their community.
    • They are a friend, an ally and a spokesperson and they take time out of their busy lives to support people who may not otherwise be able to put their own interests forward.
    • Advocates may help their partner with practical support and advice, or just be someone to turn to for moral support.
  • Advocacy Partners:
    • Are vulnerable adults looking for support and someone to speak up for them.
    • Partners are generally people with learning disabilities or other issues that mean they may risk isolation, social exclusion or unfair treatment.
    • Partners may also have a mental health need, physical disability or long-term (chronic) health condition that means they are at risk of being unable to safeguard their rights.
    • Partners may be people living independently, in long-term care or in supported housing.

What is an Advocacy Relationship?

  • An advocacy relationship is a mutual partnership in which the advocate’s sole loyalty is to their partner.
  • It is not a service provided to the person with a disability but a relationship of friendship and support between two individuals.

What is the Importance of Advocacy?

Independent advocacy services are critical to safeguarding and empowering those people who are most vulnerable and at risk be enabling them to express their views and to have their voice heard.

Advocacy has to main themes:

  • Safeguarding people who are in situations where they are vulnerable; and
  • Speaking up for and with people who are not being heard, helping them to express their views and make their own decisions and contributions.

What are the Principles and Standards of Independent Advocacy?

Independent advocacy should be provided by an organisation whose sole role is independent advocacy, or whose other tasks either compliment or do not conflict with the provision of independent advocacy. If the service or advocate has a conflict of interest, they should withdraw from acting for the person.

  • Listening:
    • Ensures people are listened to and their views are taken into account.
    • Recognises and safeguards everyone’s right to be heard.
    • Reduces the barriers people face in having their voice head because of communication, capacity, the political, social, economic and personal interests.
  • Loyalty:
    • Is loyal to the people it supports, and stands by their views and wishes.
    • Provides no others services, has no other interests, ties or links other than delivery, promotion, support and defence of independent advocacy.
    • Must be able to evidence and demonstrate its structural, financial, and psychological independence from others.
    • Follows the agenda of the people supported, regardless of the views, interest and agendas of others.
  • Upholding Rights:
    • Stands up to injustice, discrimination and disempowerment.
    • Enables people to have greater control and influence.
    • Challenges discrimination and promotes equality and human rights.
    • Recognises power imbalances, or the barriers people face, and takes steps to address these.

What are the Types of Independent Advocacy?

Below are some of the most common types of independent advocacy services:

  • Individual Advocacy:
    • Professional, or issue-based advocacy, involves a professional advocate providing expert and specialist knowledge to help resolve a particular issue. The relationship is normally short-term.
    • Citizen advocacy is a person-based service that usually, but not always, takes place on a longer-term basis The advocate is usually an unpaid volunteer, who builds a trusting relationship with a person, and supports them to resolve any issues they have. This ensures that individuals have an active life within the community.
  • Non-Instructed Advocacy:
    • Can be provided by professional or citizen advocates. It happens when a person cannot tell an advocate what they want. This may be because the person has complex needs, and/or limited communication, which prevent them from clearly stating their wished and desires.
    • The advocate observes the person, tries different ways of communicating with them, and will speak to significant others in the person’s life.
  • Group Advocacy:
    • Group advocacy, or collective self-advocacy, is designed to allow people with the same concerns, issues or experiences to provide support to each other and highlight issues or campaign for improvement. The groups are run by members, for members, and are supported by a development worker.
  • Peer Advocacy:
    • This is provided by an individual who has gone through similar experiences. This arrangement can help to reassure the person, who is be advocated for, that the individual providing the advocacy understands them and their situation.
  • Children’s Rights Services:
    • The nature of Children’s Right Services is very similar to professional advocacy. It aims to ensure that a child’s rights are fully taken into account when decisions are made about them. Generally, this service is focussed on providing support for children and young people who have been in the care system, or who are subject to a child protection case conference.
    • The service supports the child or young person at reviews and other complex meetings, helping them to express their views and wishes in all decisions affecting them. This advocacy allows children and young people to contribute to statutory child’s plans.

What are the Adult Eligibility Criteria?

Within Fife, Scotland, the eligibility criteria for adults and older people includes:

  • People in Fife aged 16 or over;
  • People affected by disability;
  • People affected by chronic illness;
  • People with dementia or mental disorder (including mental illness, learning disability or personality disorder); and
  • Individuals who are unable to safeguard their own well-being, rights, care, or other interests.

What are the Professional Advocacy Services for Available for Adults and Older People in Fife?

  • Fife Women’s Aid (FWA):
  • Fife Forum:
    • A voluntary sector advice and information agency.
    • Established in 1990 as the Fife Elderly Forum Executive.
    • Provides advocacy for people over 65 who are in community hospitals, residential homes, or nursing care homes.
    • http://www.fifeforum.org.uk.
  • Fife Carers Centre:
  • Kindred:
  • Circles Network:
  • Fife Advocacy Forum (FVA):
    • Provides professional advocacy to children subject to compulsory measures under the Mental Health (Care and Treatment) (Scotland) Act 2003.
    • http://www.fifeadvocacyforum.org.uk.

What are the Citizen Advocacy Services for Adults and Older People in Fife?

  • Citizen advocates are unpaid and independent of service providers and families.
  • They are members of the local community.
  • Fife has three (3) citizen advocacy organisations who provide support on a longer term basis for people aged 16-65.
  • Shorter term advocacy is also available when someone would benefit from a citizen advocacy relationship to resolve a specific issue.

Organisations include:

What are the Group/Peer Advocacy Services for Adults and Older People in Fife?

  • People First (Scotland) work to support people with learning difficulties to have more choice and control over their lives.
  • Peer advocacy refers to one-to-one support provided by advocates with a similar disability or experience to a person using the service(s).
  • Trained and supported volunteers often provide peer advocacy as part of a coordinated project.
  • They facilitate seventeen (17) local advocacy groups in Fife, including two (2) women only groups and two (2) men only groups.
  • People First workers will support individuals to find a suitable local group for their needs.
  • http://peoplefirstscotland.org/.

What are the Advocacy Services for Children and Young People in Fife?

  • Who Cares? Scotland:
    • Provides professional advocacy for young people up to the age of 25.
    • These young people will either have been, or will be, resident in Fife’s residential homes.
    • http://www.whocaresscotland.org/.
  • Kindred:
  • Fife Young Carers:
  • Circles Network:
    • Provides professional advocacy to children subject to compulsory measures under the Mental Health (Care and Treatment) Act 2003.
    • http://circlesnetwork.org.uk/.
  • Believe in Children (Barnardo’s):
    • Provides a children’s rights and advocacy service to children and young people in secure or purchased residential placements.
    • Children looked after at home, in kinship care, foster care, or children and young people who are subject to multi-agency statutory child’s plans can also access advocacy through Barnardo’s.
    • http://www.barnardos.org.uk/fifeservices/.

Further Reading

  • Fife Advocacy Strategy 2018-2021.
  • Carers Strategy for Fife 2018-2021.
  • Advocacy in Fife (Information Leaflet).
  • Fife Adult Support and Protection (webpage).
  • Fife Health and Social Care Strategic Plan 2016-2019.