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On This Day … 09 August

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People (Births)

  • 1890 – Eino Kaila, Finnish philosopher and psychologist, attendant of the Vienna circle (d. 1958).
  • 1896 – Jean Piaget, Swiss psychologist and philosopher (d. 1980).
  • 1949 – Jonathan Kellerman, American psychologist and author.

People (Deaths)

  • 1949 – Edward Thorndike, American psychologist and academic (b. 1874).

Eino Kaila

Eino Sakari Kaila (August 9, 1890 – July 31, 1958[1]) was a Finnish philosopher, critic and teacher. He worked in numerous fields including psychology (sometimes considered to be the founder of Finnish psychology), physics and theater, and attempted to find unifying principles behind various branches of human and natural sciences.

Life

Eino Kaila was born in Alajärvi, Finland. Kaila’s father, Erkki Kaila was a Protestant minister and later archbishop. He graduated from the University of Helsinki in 1910. In the 1920s he worked in the field of literary criticism and psychology as a professor at the University of Turku and is said to have been the first to introduce gestalt psychology to Finland. He was a part of the cultural circles of the time with the likes of Jean Sibelius and Frans Eemil Sillanpää. In 1916 he married the painter Anna Lovisa Snellman, who was granddaughter of Johan Vilhelm Snellman. He had University positions as lecturer in Helsinki and professor in Turku, and in 1930 he was appointed professor of theoretical philosophy at the University of Helsinki. In the 1930s, Kaila was closely associated with the Vienna Circle.

During World War II, Kaila lectured in Germany. In 1948 Kaila became a member of the Finnish Academy. He died in Kirkkonummi on 31 July 1958.

Ideas

Despite being greatly influenced by the logical positivists and critical of unempirical speculation, an aspect common to all of Kaila’s work was in strive for a holistic, almost pantheistic understanding of things. He also maintained a more naturalist approach to psychology. His book Persoonallisuus (1934, Personality) was a psychological study with philosophical dimensions, in which emphasized the biological nature of psychological phenomena. During the last years of his life he attempted to construct a theory of everything in Terminalkausalität Als Die Grundlage Eines Unitarischen Naturbegriffs, but this, what was meant to be the first installment in a more extensive study, was not met with much enthusiasm outside of Finland.

Though he withdrew his support of the National Socialists before the end of the Second World War, he wrote about the differences between “western” and “eastern” thought and claimed that the homogeneity of the people was a necessity for a functioning democracy. After the war his close friendships with Edwin Linkomies and Veikko Antero Koskenniemi put a political shadow even over Kaila.

Influence

Kaila’s most famous pupil was Georg Henrik von Wright, who was the successor of Ludwig Wittgenstein at the University of Cambridge. The tradition of highly German-influenced analytical-idealist philosophy which Kaila championed remained unchallenged in Finnish philosophy until the appearance of continental influences in the 1980s.

Kaila founded the psychological laboratory at the University of Helsinki, and educated the next generation of psychologists. He contributed to founding professorship in psychology, and to establishment of the Faculty of Political Science together with Edwin Linkomies.

Jean Piaget

Jean 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, Jean 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.

Jonathan Kellerman

Jonathan Seth Kellerman (born 09 August 1949) is an American novelist, psychologist, and Edgar- and Anthony Award–winning author best known for his popular mystery novels featuring the character Alex Delaware, a child psychologist who consults for the Los Angeles Police Department.

Born on the Lower East Side of New York City, his family relocated to Los Angeles when Jonathan was nine years old.

Kellerman graduated from the University of Southern California (USC) with a doctor of philosophy degree in psychology in 1974, and began working as a staff psychologist at the USC School of Medicine, where he eventually became a full clinical professor of paediatrics. He opened a private practice in the early 1980s while writing novels in his garage at night.

His first published novel, When the Bough Breaks, appeared in 1985, many years after writing and having works rejected. He then wrote five best-selling novels while still a practicing psychologist. In 1990, he quit his private practice to write full-time. He has written more than 40 crime novels, as well as nonfiction works and children’s books.

Edward Thorndike

Edward Lee Thorndike (31 August 1874 to 09 August 1949) was an American psychologist who spent nearly his entire career at Teachers College, Columbia University. His work on comparative psychology and the learning process led to the theory of connectionism and helped lay the scientific foundation for educational psychology. He also worked on solving industrial problems, such as employee exams and testing. He was a member of the board of the Psychological Corporation and served as president of the American Psychological Association in 1912.

A Review of General Psychology survey, published in 2002, ranked Thorndike as the ninth-most cited psychologist of the 20th century. Edward Thorndike had a powerful impact on reinforcement theory and behaviour analysis, providing the basic framework for empirical laws in behaviour psychology with his law of effect. Through his contributions to the behavioural psychology field came his major impacts on education, where the law of effect has great influence in the classroom.

On This Day … 08 August

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People (Births)

  • 1879 – Bob Smith, American physician and surgeon, co-founded Alcoholics Anonymous (d. 1950).

Bob Smith

Robert Holbrook Smith (08 August 1879 to 16 November 1950), also known as Dr. Bob, was an American physician and surgeon who founded Alcoholics Anonymous with Bill Wilson (more commonly known as Bill W.).

Smith began drinking at college attending Dartmouth College in Hanover, New Hampshire. Early on he noticed that he could recover from drinking bouts quicker and easier than his classmates and that he never had headaches, which caused him to believe he was an alcoholic from the time he began drinking. Smith was a member of Kappa Kappa Kappa fraternity at Dartmouth. After graduation in 1902, he worked for three years selling hardware in Boston, Chicago, and Montreal and continued drinking heavily. He then returned to school to study medicine at the University of Michigan. By this time drinking had begun to affect him to the point where he began missing classes. His drinking caused him to leave school, but he returned and passed his examinations for his sophomore year. He transferred to Rush Medical College, but his alcoholism worsened to the point that his father was summoned to try to halt his downward trajectory. But his drinking increased and after a dismal showing during final examinations, the university required that he remain for two extra quarters and remain sober during that time as a condition of graduating.

After graduation, Smith became a hospital intern, and for two years he was able to stay busy enough to refrain from heavy drinking. He married Anne Robinson Ripley on 25 January 1915, and opened up his own office in Akron, Ohio, specialising in colorectal surgery and returned to heavy drinking. Recognising his problem, he checked himself into more than a dozen hospitals and sanitariums in an effort to stop his drinking. He was encouraged by the passage of Prohibition in 1919, but soon discovered that the exemption for medicinal alcohol, and bootleggers, could supply more than enough to continue his excessive drinking. For the next 17 years his life revolved around how to subvert his wife’s efforts to stop his drinking and obtain the alcohol he craved while trying to hold together a medical practice in order to support his family and his drinking.

Meeting Bill Wilson

In January 1933, Anne Smith attended a lecture by Frank Buchman, the founder of the Oxford Group. For the next two years he and Smith attended local meetings of the group in an effort to solve his alcoholism, but recovery eluded him until he met Bill Wilson on 12 May 1935. Wilson was an alcoholic who had learned how to stay sober, thus far only for some limited amounts of time, through the Oxford Group in New York, and was close to discovering long-term sobriety by helping other alcoholics. Wilson was in Akron on business that had proven unsuccessful and he was in fear of relapsing. Recognising the danger, he made inquiries about any local alcoholics he could talk to and was referred to Smith by Henrietta Seiberling, one of the leaders of the Akron Oxford Group. After talking to Wilson, Smith stopped drinking and invited Wilson to stay at his home. He relapsed almost a month later while attending a professional convention in Atlantic City. Returning to Akron on 09 June, he was given a few drinks by Wilson to avoid delirium tremens. He drank one beer the next morning to settle his nerves so he could perform an operation, which proved to be the last alcoholic drink he would ever have. The date, 10 June 1935, is celebrated as the anniversary of the founding of Alcoholics Anonymous.

Final Years

Smith was called the “Prince of Twelfth Steppers” by Wilson because he helped more than 5000 alcoholics before his death. He was able to stay sober from 10 June 1935, until his death in 1950 from colon cancer. He is buried at the Mount Peace Cemetery in Akron, Ohio.

What is Imipramine?

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Introduction

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression.

It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. Imipramine is taken by mouth.

Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes. Overdose of the medication can result in death. Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergic receptors.

Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which have fewer side effects and are safer in overdose.

Brief History

The parent compound of imipramine, 10,11-dihydro-5H-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.

In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as “depressive psychosis”. The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalised patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. Such powerful antidepressant properties have made it favourable in the treatment of treatment-resistant depression.

Before the advent of SSRIs, its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since the 1990s, it has no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In paediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Medical Uses

Imipramine is used in the treatment of depression and certain anxiety disorders. It is similar in efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150-250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.

Available Forms

Imipramine is available in the form of oral tablets and capsules.

Contraindications

Combining it with alcohol consumption causes excessive drowsiness. It may be unsafe during pregnancy.

Side Effects

Those listed in italics below denote common side effects.

  • Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paraesthesia.
  • Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias
  • Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis.
  • Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change.
  • Genitourinary: urinary retention.
  • Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia.
  • Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Pharmacology

Pharmacodynamics

Imipramine affects numerous neurotransmitter systems known to be involved in the aetiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of imipramine’s actions include, but are not limited to, effects on:

  • Serotonin: very strong reuptake inhibition.
  • Norepinephrine: strong reuptake inhibition.
    • Desipramine has more affinity to norepinephrine transporter than imipramine.
  • Dopamine:
    • Imipramine blocks D2 receptors.
    • Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).
  • Acetylcholine:
    • Imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors.
    • Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the “dementing” effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population.
  • Epinephrine:
    • Imipramine antagonises adrenergic receptors, thus sometimes causing orthostatic hypotension.
  • Sigma receptor:
    • Activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM).
  • Histamine:
    • Imipramine is an antagonist of the histamine H1 receptors.
  • BDNF:
    • BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis.
    • It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours.
    • Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.

Pharmacokinetics

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H24N2 with a molecular weight of 280.407 g/mol. The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used. The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8.

Society and Culture

Generic Names

Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum. The embonate salt is known as imipramine pamoate.

Brand Names

Imipramine is marketed throughout the world mainly under the brand name Tofranil. Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.

Availability

Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, Brazil, South Africa, Australia, and New Zealand.

What is Inhibitory Control?

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Introduction

Inhibitory control, also known as response inhibition, is a cognitive process – and more specifically an executive function – that permits an individual to inhibit their impulses and natural, habitual, or dominant behavioural responses to stimuli (e.g. prepotent responses) in order to select a more appropriate behaviour that is consistent with completing their goals.

Self-control is an important aspect of inhibitory control. For example, successfully suppressing the natural behavioural response to eat cake when one is craving it while dieting requires the use of inhibitory control.

The prefrontal cortex, caudate nucleus, and subthalamic nucleus are known to regulate inhibitory control cognition. Inhibitory control is impaired in both addiction and attention deficit hyperactivity disorder. In healthy adults and ADHD individuals, inhibitory control improves over the short term with low (therapeutic) doses of methylphenidate or amphetamine. Inhibitory control may also be improved over the long-term via consistent aerobic exercise.

Tests

An inhibitory control test is a neuropsychological test that measures an individual’s ability to override their natural, habitual, or dominant behavioural response to a stimulus in order to implement more adaptive goal-oriented behaviours. Some of the neuropsychological tests that measure inhibitory control include the Stroop task, go/no-go task, Simon task, Flanker task, anti-saccade tasks, delay of gratification tasks, and stop-signal tasks.

Gender Differences

Females tend to have a greater basal capacity to exert inhibitory control over undesired or habitual behaviours and respond differently to modulatory environmental contextual factors relative to males. For example, listening to music tends to significantly improve the rate of response inhibition in females, but reduces the rate of response inhibition in males.

What is Interpersonal and Social Rhythm Therapy?

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Introduction

Interpersonal and social rhythm therapy (IPSRT) is an intervention for people with bipolar disorder (BD).

Its primary focus is stabilising the circadian rhythm disruptions that are common among people with bipolar disorder. IPSRT draws upon principles from interpersonal psychotherapy, an evidence-based treatment for depression and emphasizes the importance of daily routine (rhythm).

IPSRT was developed by Ellen Frank, PhD at the University of Pittsburgh who published a book on her theories: Treating Bipolar Disorder, a Clinician’s Guide Interpersonal and Social Rhythm Therapy. Her research on IPSRT has shown that, in combination with medication, solving interpersonal problems and maintaining regular daily rhythms of sleeping, waking, eating, and exercise can increase quality of life, reduce mood symptoms, and help prevent relapse in people with BD.

Social Zeitgeber Hypothesis

Zeitgebers (“time givers”) are environmental cues that synchronize biological rhythms to the 24-hour light/dark cycle. As the sun is a physical zeitgeber, social factors are considered social zeitgebers. These include personal relationships, social demands, or life tasks that entrain circadian rhythms. Disruptions in circadian rhythms can lead to somatic and cognitive symptoms, as seen in jet lag or during daylight saving time. Individuals diagnosed with, or at risk for, mood disorders may be especially sensitive to these disruptions and thus, vulnerable to episodes of depression or mania when circadian rhythm disruptions occur.

Changes in daily routines place stress on the body’s maintenance of sleep-wake cycles, appetite, energy, and alertness, all of which are affected during mood episodes. For example, depressive symptoms include disturbed sleep patterns (sleeping too much or difficulty falling asleep), changes in appetite, fatigue, and slowed movement or agitation. Manic symptoms include decreased need for sleep, excessive energy, and increase in goal-directed activity. When the body’s rhythms becomes desynchronised, it can result in episodes of depression and mania.

Aims of Treatment

Goals of IPSRT are to stabilise social rhythms (e.g. eating meals with other people) while improving the quality of interpersonal relationships and satisfaction with social roles. Stabilising social rhythms helps to protect against disruptions of biological rhythms; individuals are more likely to maintain a rhythm when other people are involved to hold them accountable.

Interpersonal work can involve addressing unresolved grief experiences including grief for the lost healthy self, negotiating a transition in a major life role, and resolving a role dispute with a significant other. These experiences can be disruptive to social rhythms and thus, serve as targets of treatment to prevent the onset and recurrence of mood episodes seen in bipolar disorder.

Phases of Treatment

IPSRT typically proceeds in four phases:

  1. The initial phase involves a review of the patient’s mental health history in order to elucidate patterns in the associations between social routine disruptions, interpersonal problems and affective episodes. Psychoeducation about BD and the importance of stable routines to mood maintenance is provided. Additionally, The Interpersonal Inventory is used to assess the quality of the patient’s interpersonal relationships. One of four interpersonal problem areas is chosen to focus on:
    • Grief (e.g. loss of loved one, loss of healthy self).
    • Role transitions (e.g. married-to-divorced, parenthood).
    • Role disputes (e.g. conflict with spouse or parents).
    • Interpersonal deficits (e.g. persistent social isolation).
      • The Social Rhythm Metric (SRM) is used to assess the regularity of social routines.
      • Target and actual time of the following activities are tracked on a daily basis: got out of bed; first contact with another person; started work, school, or housework; ate dinner; and went into bed.
      • The intensity of involvement with other people is also rated: 0 = alone, 1 = others present, 2 = others actively involved, and 3 = others very stimulating.
      • Finally, mood is rated on a scale of -5 to +5 at the end of each day.
  2. The intermediate phase focuses on bringing regularity to social rhythms and intervening in the interpersonal problem area of interest.
    • SRM is heavily used to assess amount of activity being engaged in and the impact of activity on mood. The regularity (or irregularity) of activities is examined, and the patient and therapist collaboratively plan how to stabilise the daily routine by making incremental behavioural modifications until a regular target time at which these activities are done is achieved.
    • Sources of interpersonal distress are explored, and individuals in the patient’s life who destabilise routine, along with those who are supportive, are identified. Frequency and intensity of social interactions, as well as other social rhythms (e.g. time at which returning home from school/work and then interacting with family), are discussed.
  3. The maintenance phase aims to reinforce the techniques learned earlier in treatment in order to maintain social rhythms and positive interpersonal relationships.
    • Discussion of early warning signs of episodes are reviewed.
    • Symptomatic and functional change is monitored at each session by asking the patient to rate their mood and note any shifts in routine using the SRM.
  4. The final phase involves termination in which sessions are gradually reduced in frequency.

Interpersonal Strategies

Once the interpersonal problem area of focus is chosen, the following strategies may be used:

  1. Grief:
    • This refers to symptoms resulting from incomplete mourning or unresolved feelings about the death of an important person.
    • This can also refer to grief for the loss of a healthy self (i.e. the person before the illness or the person one could have become, if not for BD).
    • Strategies include encouraging expression of painful feelings about lost hopes, ruined relationships, interrupted careers, and passed opportunities.
    • This is followed by encouragement to develop new relationships, establish new, more realistic goals, and focus on future opportunities.
  2. Interpersonal role disputes:
    • This refers to any close relationship in which there are nonreciprocal expectations, such as in marital conflict and arguments with parental figures.
    • Strategies include learning how to be more patient, tolerant, and accepting of limitations in self and others.
    • This, in turn, can lead to fewer critical and argumentative instincts.
  3. Role transition:
    • This refers to any major life role change, such as new employment, graduation, retirement, marriage, divorce, and giving birth.
    • This can also refer to the loss of previously pleasurable hypomania.
    • Strategies can include noting the negative consequences of hypomania and encouraging the identification of rewarding life goals as suitable alternatives.
  4. Interpersonal deficits:
    • This refers to a long-standing history of impoverished or contentious social relationships, leading to an overall feeling of dissatisfaction.
    • Strategies include identifying the common thread in the multiple disputes across one’s life and possibly working to restore “burnt bridges”.

Social Rhythm Strategies

Individuals with BD benefit from a higher level of stability in their sleep and daily routines than those with no history of affective illness. It is important to identify situations in which routines can be thrown off balance, whether by excessive activity and overstimulation or lack of activity and under-stimulation. Once destabilizing triggers are identified, reasonable goals for change are established. Specific strategies include:

  1. Encouraging proper sleep hygiene to introduce regularity to sleep-wake cycle.
    • Establish a regular wake and sleep time.
    • Avoid caffeine or other stimulants.
    • Use the bed only for sleep and sex, not for watching TV, doing homework, reading etc.
    • Align sunlight exposure with wake time to help set circadian clock.
  2. Maintaining regular meal times throughout the day.
    • Plan ahead by meal prepping the day before.
    • Include snack times if needed to encourage consistent eating habits.
  3. Encouraging medication adherence and establishing a regular schedule.
    • Use alarms on phone as reminders for when to take pills.
    • Use daily pillboxes to keep track of which pills to take at certain times.
  4. Monitoring frequency and intensity of social interactions using Social Rhythm Metric.
    • Note time at which interactions happen and adjust accordingly to establish regularity.
  5. Minimising overstimulation of social interactions.
    • Avoid frequent parties or events.
    • Use recovery days as needed.
  6. Addressing under-stimulation with behavioural activation.
    • Engage in activities that are pleasurable and that give one a sense of mastery.
    • Focus on small, manageable goals that can lead to engagement in other activities (e.g. start jogging to get in shape prior to joining a basketball team).
  7. Identifying interpersonal sources of stabilizing and destabilising influence.
    • Spend time with those who are supportive and stabilising.
    • Reduce time with those who are disruptive.

Evidence of IPSRT Efficacy

In a randomized controlled trial, those who received IPSRT during the acute treatment phase went longer without a new affective episode (depression or mania) than those who received intensive clinical management. Participants in the IPSRT group also had higher regularity of social rhythms at the end of acute treatment, which was associated with reduced likelihood of relapse during maintenance phase. Additionally, those who received IPSRT showed more rapid improvement in occupational functioning than those assigned to intensive clinical management. However, at the end of two years of maintenance treatment, there were no differences between treatment groups.

IPSRT was studied as one of three intensive psychosocial treatments in the NIMH-funded Systematic Treatment Enhancement Programme for Bipolar Disorder. STEP-BD was a long-term outpatient study investigating the benefits of psychotherapies in conjunction with pharmacotherapy in treating episodes of depression and mania, as well as preventing relapse in people with bipolar disorder. Patients were 1.58 times more likely to be well in any study month if they received intensive psychotherapy (cognitive-behavioural therapy, family focused therapy, or IPSRT) than if they received collaborative care in addition to pharmacotherapy. They also had significantly higher year-end recovery rates and shorter times to recovery.

In a trial conducted by a separate research group, 100 participants aged 15-36 years with bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified were randomised to IPSRT (n = 49) or specialist supportive care (n = 51). Both groups experienced improvement in depressive symptoms, social functioning, and manic symptoms, but there were no significant differences between the groups.

Adolescents

IPSRT was adapted to be delivered to adolescents with BD. In an open trial (N=12), feasibility and acceptability of IPSRT-A were high; 11/12 participants completed treatment, 97% of sessions were attended, and adolescent-rated satisfaction scores were high. IPSRT-A participants experienced significant decreases in manic, depressive, and general psychiatric symptoms over the 20 weeks of treatment. Participants’ global functioning increased significantly as well.

In an open trial aimed at prevention, adolescents (N=13) who were identified as high risk for bipolar disorder, due to having a first-degree relative with BD, received IPSRT. Significant changes in sleep/circadian patterns (i.e. less weekend sleeping in and oversleeping) were observed. Families reported high satisfaction with IPSRT, yet, on average, participants attended about half of scheduled sessions. Missed sessions were primarily associated with parental BD illness severity.

Group Therapy

IPSRT was adapted for a group therapy setting; administered over 16 sessions, in a semi-structured format. Patients (N=22) made interpersonal goals, reflected on how they managed their illness, and empathised with fellow group members. Patients were encouraged to react to each other from their own experience, express their feelings about what was said, and to give constructive feedback. Patients spent significantly less time depressed in the year following treatment than they did in the year prior to treatment.

In another small trial, patients with BD who experiencing a depressive episode (N = 9) received six IPSRT-G sessions across two weeks. Topics of discussion in group included defining interpersonal focus area, defining target times for daily routines, discussing grief and medication adherence, addressing interpersonal disputes and role transitions, and reviewing IPSRT strategies and relapse prevention. Depressive symptoms improved significantly at the end of the treatment; improvements were maintained 10 weeks following treatment end.

What is Lofepramine?

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Introduction

Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression.

The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.

Lofepramine is not available in the United States, Canada, Australia or New Zealand, although it is available in Ireland, Japan, South Africa and the United Kingdom, among other countries.

Brief History

Lofepramine was developed by Leo Läkemedel AB. It first appeared in the literature in 1969 and was patented in 1970. The drug was first introduced for the treatment of depression in either 1980 or 1983.

Depression

In the United Kingdom, lofepramine is licensed for the treatment of depression which is its primary use in medicine.

Lofepramine is an efficacious antidepressant with about 64% patients responding to it.

Contraindications

To be used with caution, or not at all, for people with the following conditions:

  • Heart disease.
  • Impaired kidney or liver function.
  • Narrow angle glaucoma.
  • In the immediate recovery period after myocardial infarction.
  • In arrhythmias (particularly heart block).
  • Mania.
  • In severe liver and/or severe renal impairment.

And in those being treated with amiodarone or terfenadine.

Pregnancy and Lactation

Lofepramine use during pregnancy is advised against unless the benefits clearly outweigh the risks. This is because its safety during pregnancy has not been established and animal studies have shown some potential for harm if used during pregnancy. If used during the third trimester of pregnancy it can cause insufficient breathing to meet oxygen requirements, agitation and withdrawal symptoms in the infant. Likewise its use by breastfeeding women is advised against, except when the benefits clearly outweigh the risks, due to the fact it is excreted in the breast milk and may therefore adversely affect the infant. Although the amount secreted in breast milk is likely too small to be harmful.

Side Effects

The most common adverse effects (occurring in at least 1% of those taking the drug) include agitation, anxiety, confusion, dizziness, irritability, abnormal sensations, like pins and needles, without a physical cause, sleep disturbances (e.g. sleeplessness) and a drop in blood pressure upon standing up. Less frequent side effects include movement disorders (like tremors), precipitation of angle closure glaucoma and the potentially fatal side effects paralytic ileus and neuroleptic malignant syndrome.

Dropout incidence due to side effects is about 20%.

Side effects with unknown frequency include (but are not limited to):

  • Digestive effects:
    • Constipation.
    • Diarrhoea.
    • Dry mouth.
    • Nausea.
    • Taste disturbances.
    • Vomiting.
  • Effects on the heart:
    • Arrhythmia.
    • ECG changes.
    • Abnormal heart rhythm.
    • Heart block.
    • Sudden cardiac death.
    • High heart rate.
  • Blood abnormalities:
    • Abnormal blood cell counts.
    • Blood sugar changes.
    • Low blood sodium levels.
  • Breast effects:
    • Breast enlargement, including in males.
    • Spontaneous breast milk secretion that is unrelated to breastfeeding or pregnancy.
  • Effects on the skin:
    • Abnormal sweating.
    • Hair loss.
    • Hives.
    • Increased light sensitivity.
    • Itching.
    • Rash.
  • Mental / neurologic effects:
    • Delusions.
    • Hallucinations.
    • Headache.
    • Hypomania/mania.
    • Seizures.
    • Suicidal behaviour.
  • Other effects:
    • Appetite changes.
    • Blurred vision.
    • Difficulty emptying the bladder.
    • Difficulty talking due to difficulties in moving the required muscles.
    • Liver problems.
    • Ringing in the ears.
    • Sexual dysfunction, such as impotence.
    • Swelling.
    • Weight changes.

Withdrawal

If abruptly stopped after regular use it can cause withdrawal effects such as sleeplessness, irritability and excessive sweating.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Compared to other TCAs, lofepramine is considered to be less toxic in overdose. Its treatment is mostly a matter of trying to reduce absorption of the drug, if possible, using gastric lavage and monitoring for adverse effects on the heart.

Interactions

Lofepramine is known to interact with:

  • Alcohol. Increased sedative effect.
  • Altretamine. Risk of severe drop in blood pressure upon standing.
  • Analgesics (painkillers). Increased risk of ventricular arrhythmias.
  • Anticoagulants (blood thinners). Lofepramine may inhibit the metabolism of certain anticoagulants leading to a potentially increased risk of bleeding.
  • Anticonvulsants. Possibly reduce the anticonvulsant effect of antiepileptics by lowering the seizure threshold.
  • Antihistamines. Possible increase of antimuscarinic (potentially increasing risk of paralytic ileus, among other effects) and sedative effects.
  • Antimuscarinics. Possible increase of antimuscarinic side-effects.
  • Anxiolytics and hypnotics. Increased sedative effect.
  • Apraclonidine. Avoidance advised by manufacturer of apraclonidine.
  • Brimonidine. Avoidance advised by manufacturer of brimonidine.
  • Clonidine. Lofepramine may reduce the antihypertensive effects of clonidine.
  • Diazoxide. Enhanced hypotensive (blood pressure-lowering) effect.
  • Digoxin. May increase risk of irregular heart rate.
  • Disulfiram. May require a reduction of lofepramine dose.
  • Diuretics. Increased risk of reduced blood pressure on standing.
  • Cimetidine, diltiazem, verapamil. May increase concentration of lofepramine in the blood plasma.
  • Hydralazine. Enhanced hypotensive effect.
  • Monoamine oxidase inhibitors (MAOIs). Advised not to be started until at least 2 weeks after stopping MAOIs. MAOIs are advised not to be started until at least 1-2 weeks after stopping TCAs like lofepramine.
  • Moclobemide. Moclobemide is advised not to be started until at least one week after treatment with TCAs is discontinued.
  • Nitrates. Could possibly reduce the effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth).
  • Rifampicin. May accelerate lofepramine metabolism thereby decreasing plasma concentrations of lofepramine.
  • Ritonavir. May increase lofepramine concentration in the blood plasma.
  • Sodium nitroprusside. Enhanced hypotensive effect.
  • Thyroid hormones. Effects on the heart of lofepramine may be exacerbated.

Pharmacology

Pharmacodynamics

Lofepramine is a strong inhibitor of norepinephrine reuptake and a moderate inhibitor of serotonin reuptake. It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors.

Lofepramine has been said to be a prodrug of desipramine, although there is also evidence against this notion.

Pharmacokinetics

Lofepramine is extensively metabolised, via cleavage of the p-chlorophenacyl group, to the TCA, desipramine, in humans. However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy. The p-chlorophenacyl group is metabolised to p-chlorobenzoic acid which is then conjugated with glycine and excreted in the urine. The desipramine metabolite is partly secreted in the faeces. Other routes of metabolism include hydroxylation, glucuronidation, N-dealkylation and N-oxidation.

Chemistry

Lofepramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, clomipramine, and trimipramine. Lofepramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Unlike other tertiary amine TCAs, lofepramine has a bulky 4-chlorobenzoylmethyl substituent on its amine instead of a methyl group. Although lofepramine is technically a tertiary amine, it acts in large part as a prodrug of desipramine, and is more similar to secondary amine TCAs in its effects. Other secondary amine TCAs besides desipramine include nortriptyline and protriptyline. The chemical name of lofepramine is N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C26H27ClN2O with a molecular weight of 418.958 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is not used. The CAS Registry Number of the free base is 23047-25-8 and of the hydrochloride is 26786-32-3.

Society and Culture

Generic Names

Lofepramine is the generic name of the drug and its INN and BAN, while lofepramine hydrochloride is its USAN, BANM, and JAN. Its generic name in French and its DCF are lofépramine, in Spanish and Italian and its DCIT are lofepramina, in German is lofepramin, and in Latin is lofepraminum.

Brand Names

Brand names of lofepramine include Amplit, Deftan, Deprimil, Emdalen, Gamanil, Gamonil, Lomont, Tymelet, and Tymelyt.

Availability

In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets and 70 mg/5 mL oral suspension.

Research

Fatigue

A formulation containing lofepramine and the amino acid phenylalanine is under investigation as a treatment for fatigue as of 2015.

What is Living Is For Everyone?

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Introduction

Living Is For Everyone (LIFE) is a suicide prevention initiative of the Australian Government’s National Suicide Prevention Strategy (NSPS).

Background

The National Suicide Prevention Strategy funds a number of programmes, some jointly funded with the National Mental Health Strategy.

The programmes, which operate in a range of settings, use population-based approaches with an emphasis on community capacity building.

The LIFE initiative has two main components:

  1. The LIFE resources; and
  2. The LIFE website.

The LIFE resources were redeveloped from a 2000 document and published in 2008. They are designed for people working with those at risk of suicide, with the broad intention of reducing the rate at which people take their own lives in Australia.

The LIFE resources have three components:

  1. The LIFE Framework: The Australian reference for suicide prevention activities;
  2. LIFE Research and Evidence: A review of statistics, trends, comparisons and issues in suicide and self-harm prevention; and
  3. LIFE fact sheets: A set of 24 fact sheets that provide summaries and advice about suicide prevention.

You can find the official website here.

What is Loxapine?

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Introduction

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is a typical antipsychotic medication used primarily in the treatment of schizophrenia.

The drug is a member of the dibenzoxazepine class and structurally related to clozapine. Several researchers have argued that loxapine may behave as an atypical antipsychotic.

Loxapine may be metabolised by N-demethylation to amoxapine, a tricyclic antidepressant.

Medical Uses

The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.

Available Forms

Loxapine can be taken by mouth as a capsule or a liquid oral concentrate. It is also available as an intramuscular injection and as a powder for inhalation.

Side Effects

Loxapine can cause side effects that are generally similar to that of other medications in the typical antipsychotic class of medications. These include, e.g. gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), and movement problems (i.e. extrapyramidal symptoms (EPS)). At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. Although it is structurally similar to clozapine, it does not have the same risk of agranulocytosis (which, even with clozapine, is less than 1%); however, mild and temporary fluctuations in blood leukocyte levels can occur. Abuse of loxapine has been reported.

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth.

Pharmacology

Mechanism of Action

Loxapine is a “mid-potency” typical antipsychotic. However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its high potency for the D2 receptor.

Pharmacokinetics

Loxapine is metabolised to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth.

Chemistry

Loxapine is a dibenzoxazepine and is structurally related to clozapine.

On This Day … 04 August

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People (

  • 1941 – Ted Strickland, American psychologist and politician, 68th Governor of Ohio.

Ted Strickland

Theodore Strickland (born 04 August 1941) is an American politician who was the 68th Governor of Ohio, serving from 2007 to 2011. A member of the Democratic Party, he previously served in the United States House of Representatives, representing Ohio’s 6th congressional district (1993-1995, 1997-2007).

A 1959 graduate of Northwest High School, Strickland went on to be the first member of his family to attend college. Strickland received a Bachelor of Arts degree in history with a minor in psychology from Asbury College in 1963. In 1966, he received a Master of Arts degree in guidance counselling from the University of Kentucky and a Master of Divinity (M.Div.) from the Asbury Theological Seminary in 1967. He then returned to the University of Kentucky to earn his Ph.D. in counselling psychology in 1980. He is married to Frances Strickland, an educational psychologist.

Strickland worked as a counselling psychologist at the Southern Ohio Correctional Facility in Lucasville. He was an administrator at a Methodist children’s home and was a professor of psychology at Shawnee State University. Strickland is an ordained minister in the United Methodist Church. He was a minister at a Methodist church in Portsmouth, Ohio.

In the 2006 gubernatorial election, Strickland was elected to succeed term-limited Republican incumbent Bob Taft, receiving 60% of the vote and defeating Ohio Secretary of State Ken Blackwell. He was narrowly defeated for re-election in the 2010 gubernatorial election by former US Representative John Kasich.

In April 2014, Strickland became president of the Centre for American Progress Action Fund, a progressive public policy research and advocacy organization. Strickland left that position in February 2015, and on 25 February 2015, he announced his intention to run for the United States Senate against incumbent Rob Portman. Strickland lost by 20 points. As of 2021, he is the last Democrat to serve as Governor of Ohio.