Tag: Antipsychotic

What is Amisulpride?

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Introduction

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes.

It is sold under the brand names Barhemsys (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic). It is also used to treat dysthymia.

It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.

Amisulpride is indicated for use in the US in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

Amisulpride is believed to work by blocking, or antagonising, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorised to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.

It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available. It is marketed in all English-speaking countries except for Canada. A New York City based company, LB Pharmaceuticals, has announced the ongoing development of LB-102, also known as N-methyl amisulpride, an antipsychotic specifically targeting the United States. A poster presentation at European Neuropsychopharmacology seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.

Brief History

The US Food and Drug Administration (FDA) approved amisulpride based on evidence from four clinical trials of 2323 subjects undergoing surgery or experiencing nausea and vomiting after the surgery. The trials were conducted at 80 sites in the United States, Canada and Europe.

Two trials (Trials 1 and 2) enrolled subjects scheduled to have surgery. Subjects were randomly assigned to receive either amisulpride or a placebo drug at the beginning of general anaesthesia. In Trial 1, subjects received amisulpride or placebo alone, and in Trial 2, they received amisulpride or placebo in combination with one medication approved for prevention of nausea and vomiting. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the surgery. The results then compared amisulpride to placebo.

The other two trials (Trials 3 and 4) enrolled subjects who were experiencing nausea and vomiting after surgery. In Trial 3, subjects did not receive any medication to prevent nausea and vomiting before surgery and in Trial 4 they received the medication, but the treatment did not work. In both trials, subjects were randomly assigned to receive either amisulpride or placebo. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the treatment. The trial compared amisulpride to placebo.

Medical Uses

Schizophrenia

Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia. Amisulpride augmentation, similarly to sulpiride augmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia. Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.

Postoperative Nausea and Vomiting

Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

Contraindications

Amisulpride’s use is contraindicated in the following disease states:

  • Pheochromocytoma.
  • Concomitant prolactin-dependent tumours e.g. prolactinoma, breast cancer.
  • Movement disorders (e.g. Parkinson’s disease and dementia with Lewy bodies).
  • Lactation.
  • Children before the onset of puberty.

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.

Adverse Effects

  • Very Common (≥10% incidence):
    • Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism).
  • Common (≥1%, <10% incidence):
    • Insomnia.
    • Hypersalivation.
    • Nausea.
    • Headache.
    • Hyperactivity.
    • Vomiting.
    • Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.).
    • Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine).
    • Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
      • Constipation.
      • Dry mouth.
      • Disorder of accommodation.
      • Blurred vision.
  • Rare (<1% incidence):
    • Hyponatraemia.
    • Bradycardia.
    • Hypotension.
    • Palpitations.
    • Urticaria.
    • Seizures.
    • Mania.
    • Oculogyric crisis.
    • Tardive dyskinesia.
    • Blood dyscrasias such as leucopenia, neutropenia and agranulocytosis.
    • QT interval prolongation (in a recent meta-analysis of the safety and efficacy of 15 antipsychotic drugs amisulpride was found to have the 2nd highest effect size for causing QT interval prolongation).
    • Somnolence.

Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2 receptors including those in the anterior pituitary.

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

Torsades de pointes is common in overdose. Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).

Interactions

Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.), reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.

Pharmacology

Pharmacodynamics

Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.

Amisulpride and its relatives sulpiride, levosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).

Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).

Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM). Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterise the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice. The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride. These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.

Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist. The clinical implications of this, if any, are unclear. In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.

Amisulpride shows stereoselectivity in its actions. Aramisulpride ((R)-amisulpride) has higher affinity for the 5-HT7 receptor (Ki = 47 nM vs. 1,900 nM) while esamisulpride ((S)-amisulpride) has higher affinity for the D2 receptor (4.0 nM vs. 140 nM). An 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) which provides more balanced 5-HT7 and D2 receptor antagonism than racemic amisulpride (50:50 ratio of enantiomers) is under development for the treatment of bipolar depression.

Society and Culture

Brand Names

Brand names include: Amazeo, Amipride (AU), Amival, Solian (AU, IE, RU, UK, ZA), Soltus, Sulpitac (IN), Sulprix (AU), Midora (RO) and Socian (BR).

Availability

Amisulpride was not approved by the Food and Drug Administration for use in the United States until February 2020, but it is used in Europe, Israel, Mexico, India, New Zealand and Australia to treat psychosis and schizophrenia.

An IV formulation of Amisulpride was approved for the treatment of postoperative nausea and vomiting (“PONV”) in the United States in February 2020.

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What is Benzatropine?

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Introduction

Benzatropine (an international non-proprietary name, INN), known as benztropine in the United States and Japan, is a medication used to treat a type of movement disorder due to antipsychotics known as dystonia and parkinsonism.

It is not useful for tardive dyskinesia. It is taken by mouth or by injection into a vein or muscle. Benefits are seen within two hours and last for up to ten hours.

Common side effects include dry mouth, blurry vision, nausea, and constipation. Serious side effect may include urinary retention, hallucinations, hyperthermia, and poor coordination. It is unclear if use during pregnancy or breastfeeding is safe. Benzatropine is an anticholinergic which works by blocking the activity of the muscarinic acetylcholine receptor.

Benzatropine was approved for medical use in the United States in 1954. It is available as a generic medication. In 2017, it was the 226th most commonly prescribed medication in the United States, with more than two million prescriptions. It is sold under the brand name Cogentin among others.

Medical Uses

Benzatropine is used to reduce extrapyramidal side effects of antipsychotic treatment. Benzatropine is also a second-line drug for the treatment of Parkinson’s disease. It improves tremor, and may alleviate rigidity and bradykinesia. Benzatropine is also sometimes used for the treatment of dystonia, a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.

Adverse Effects

These are principally anticholinergic:

  • Dry mouth.
  • Blurred vision.
  • Cognitive changes.
  • Drowsiness.
  • Constipation.
  • Urinary retention.
  • Tachycardia.
  • Anorexia.
  • Severe delirium and hallucinations (in overdose).

While some studies suggest that use of anticholinergics increases the risk of tardive dyskinesia (a long-term side effect of antipsychotics), other studies have found no association between anticholinergic exposure and risk of developing tardive dyskinesia, although symptoms may be worsened.

Drugs that decrease cholinergic transmission may impair storage of new information into long-term memory. Anticholinergic agents can also impair time perception.

Pharmacology

Benzatropine is a centrally acting anticholinergic/antihistamine agent. It is a selective M1 muscarinic acetylcholine receptor antagonist. Benzatropine partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity. Animal studies have indicated that anticholinergic activity of benzatropine is approximately one-half that of atropine, while its antihistamine activity approaches that of mepyramine. Its anticholinergic effects have been established as therapeutically significant in the management of Parkinsonism. Benzatropine antagonises the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early Parkinson’s disease.

Benzatropine analogues are atypical dopamine reuptake inhibitors, which might make them useful for people with akathisia secondary to antipsychotic therapy.

Benzatropine also acts as a functional inhibitor of acid sphingomyelinase (FIASMA).

Benzatropine has been also identified, by a high throughput screening approach, as a potent differentiating agent for oligodendrocytes, possibly working through M1 and M3 muscarinic receptors. In preclinical models for multiple sclerosis, benzatropine decreased clinical symptoms and enhanced re-myelination.

Other Animals

In veterinary medicine, benzatropine is used to treat priapism in stallions.

Naming

Since 1959, benzatropine is the official INN name of the medication under the INN scheme, the medication naming system coordinated by the World Health Organisation (WHO); it is also the British Approved Name (BAN) given in the British Pharmacopoeia, and has been the official non-proprietary name in Australia since 2015. Regional variations of the “a” spelling are also used in French, Italian, Portuguese, and Spanish, as well as Latin (all medications are assigned a Latin name by WHO).

“Benztropine” is the official United States Adopted Name (USAN), the medication naming system coordinated by the USAN Council, co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA). It is also the Japanese Accepted Name (JAN) and was used in Australia until 2015, when it was harmonised with the INN.

Both names may be modified to account for the methanesulfonate salt as which the medication is formulated: the modified INN (INNm) and BAN (BANM) is benzatropine mesilate, while the modified USAN is benztropine mesylate. The modified JAN is a hybrid form, benztropine mesilate.

The misspelling benzotropine is also occasionally seen in the literature.

What is Reduced Effect Display?

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Introduction

Reduced affect display, sometimes referred to as emotional blunting, is a condition of reduced emotional reactivity in an individual.

It manifests as a failure to express feelings (affect display) either verbally or nonverbally, especially when talking about issues that would normally be expected to engage the emotions. Expressive gestures are rare and there is little animation in facial expression or vocal inflection. Reduced affect can be symptomatic of autism, schizophrenia, depression, posttraumatic stress disorder, depersonalisation disorder, schizoid personality disorder or brain damage. It may also be a side effect of certain medications (e.g. antipsychotics and antidepressants).

Reduced affect should be distinguished from apathy and anhedonia, which explicitly refer to a lack of emotion, whereas reduced affect is a lack of emotional expression (affect display) regardless of whether emotion (underlying affect) is actually reduced or not.

Types

Constricted Affect

A restricted or constricted affect is a reduction in an individual’s expressive range and the intensity of emotional responses.

Blunted and Flat Affect

Blunted affect is a lack of affect more severe than restricted or constricted affect, but less severe than flat or flattened affect. “The difference between flat and blunted affect is in degree. A person with flat affect has no or nearly no emotional expression. They may not react at all to circumstances that usually evoke strong emotions in others. A person with blunted affect, on the other hand, has a significantly reduced intensity in emotional expression”.

Shallow Affect

Shallow affect has equivalent meaning to blunted affect. Factor 1 of the Psychopathy Checklist identifies shallow affect as a common attribute of psychopathy.

Brain structures

Individuals with schizophrenia with blunted affect show different regional brain activity in fMRI scans when presented with emotional stimuli compared to individuals with schizophrenia without blunted affect. Individuals with schizophrenia without blunted affect show activation in the following brain areas when shown emotionally negative pictures: midbrain, pons, anterior cingulate cortex, insula, ventrolateral orbitofrontal cortex, anterior temporal pole, amygdala, medial prefrontal cortex, and extrastriate visual cortex. Individuals with schizophrenia with blunted affect show activation in the following brain regions when shown emotionally negative pictures: midbrain, pons, anterior temporal pole, and extrastriate visual cortex.

Limbic Structures

Individuals with schizophrenia with flat affect show decreased activation in the limbic system when viewing emotional stimuli. In individuals with schizophrenia with blunted affect neural processes begin in the occipitotemporal region of the brain and go through the ventral visual pathway and the limbic structures until they reach the inferior frontal areas. Damage to the amygdala of adult rhesus macaques early in life can permanently alter affective processing. Lesioning the amygdala causes blunted affect responses to both positive and negative stimuli. This effect is irreversible in the rhesus macaques; neonatal damage produces the same effect as damage that occurs later in life. The macaques’ brain cannot compensate for early amygdala damage even though significant neuronal growth may occur. There is some evidence that blunted affect symptoms in schizophrenia patients are not a result of just amygdala responsiveness, but a result of the amygdala not being integrated with other areas of the brain associated with emotional processing, particularly in amygdala-prefrontal cortex coupling. Damage in the limbic region prevents the amygdala from correctly interpreting emotional stimuli in individuals with schizophrenia by compromising the link between the amygdala and other brain regions associated with emotion.

Brainstem

Parts of the brainstem are responsible for passive emotional coping strategies that are characterised by disengagement or withdrawal from the external environment (quiescence, immobility, hyporeactivity), similar to what is seen in blunted affect. Individuals with schizophrenia with blunted affect show activation of the brainstem during fMRI scans, particularly the right medulla and the left pons, when shown “sad” film excerpts. The bilateral midbrain is also activated in individuals with schizophrenia diagnosed with blunted affect. Activation of the midbrain is thought to be related to autonomic responses associated with perceptual processing of emotional stimuli. This region usually becomes activated in diverse emotional states. When the connectivity between the midbrain and the medial prefrontal cortex is compromised in individuals with schizophrenia with blunted affect an absence of emotional reaction to external stimuli results.

Prefrontal Cortex

Individuals with schizophrenia, as well as patients being successfully reconditioned with quetiapine for blunted affect, show activation of the prefrontal cortex (PFC). Failure to activate the PFC is possibly involved in impaired emotional processing in individuals with schizophrenia with blunted affect. The mesial PFC is activated in aver individuals in response to external emotional stimuli. This structure possibly receives information from the limbic structures to regulate emotional experiences and behaviour. Individuals being reconditioned with quetiapine, who show reduced symptoms, show activation in other areas of the PFC as well, including the right medial prefrontal gyrus and the left orbitofrontal gyrus.

Anterior Cingulate Cortex

A positive correlation has been found between activation of the anterior cingulate cortex and the reported magnitude of sad feelings evoked by viewing sad film excerpts. The rostral subdivision of this region is possibly involved in detecting emotional signals. This region is different in individuals with schizophrenia with blunted affect.

Diagnoses

Schizophrenia

Flat and blunted affect is a defining characteristic in the presentation of schizophrenia. To reiterate, these individuals have a decrease in observed vocal and facial expression as well as the use of gestures. One study of flat affect in schizophrenia found that “flat affect was more common in men, and was associated with worse current quality of life” as well as having “an adverse effect on course of illness”.

The study also reported a “dissociation between reported experience of emotion and its display” – supporting the suggestion made elsewhere that “blunted affect, including flattened facial expressiveness and lack of vocal inflection … often disguises an individual’s true feelings.” Thus, feelings may merely be unexpressed, rather than totally lacking. On the other hand, “a lack of emotions which is due not to mere repression but to a real loss of contact with the objective world gives the observer a specific impression of ‘queerness’ … the remainders of emotions or the substitutes for emotions usually refer to rage and aggressiveness”. In the most extreme cases, there is a complete “dissociation from affective states”. To further support this idea, a study examining emotion dysregulation found that individuals with schizophrenia could not exaggerate their emotional expression as healthy controls could. Participants were asked to express whatever emotions they had during a clip of a film, and the participants with schizophrenia showed deficits in behavioural expression of their emotions.

There is still some debate regarding the source of flat affect in schizophrenia. However, some literature indicates abnormalities in the dorsal executive and ventral affective systems; it is argued that dorsal hypoactivation and ventral hyperactivation may be the source of flat affect. Further, the authors found deficits in the mirror neuron system may also contribute to flat affect in that the deficits may cause disruptions in the control of facial expression.

Another study found that when speaking, individuals with schizophrenia with flat affect demonstrate less inflection than normal controls and appear to be less fluent. Normal subjects appear to express themselves using more complex syntax, whereas flat affect subjects speak with fewer words, and fewer words per sentence. Flat affect individuals’ use of context-appropriate words in both sad and happy narratives are similar to that of controls. It is very likely that flat affect is a result of deficits in motor expression as opposed to emotional processing. The moods of display are compromised, but subjective, autonomic, and contextual aspects of emotion are left intact.

Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) was previously known to cause negative feelings, such as depressed mood, re-experiencing and hyperarousal. However, recently, psychologists have started to focus their attention on the blunted affects and also the decrease in feeling and expressing positive emotions in PTSD patients. Blunted affect, or emotional numbness, is considered one of the consequences of PTSD because it causes a diminished interest in activities that produce pleasure (anhedonia) and produces feelings of detachment from others, restricted emotional expression and a reduced tendency to express emotions behaviourally. Blunted affect is often seen in veterans as a consequence of the psychological stressful experiences that caused PTSD. Blunted affect is a response to PTSD, it is considered one of the central symptoms in post-traumatic stress disorders and it is often seen in veterans who served in combat zones. In PTSD, blunted affect can be considered a psychological response to PTSD as a way to combat overwhelming anxiety that the patients feel. In blunted affect, there are abnormalities in circuits that also include the prefrontal cortex.

Assessment

In making assessments of mood and affect the clinician is cautioned that “it is important to keep in mind that demonstrative expression can be influenced by cultural differences, medication, or situational factors”; while the layperson is warned to beware of applying the criterion lightly to “friends, otherwise [he or she] is likely to make false judgments, in view of the prevalence of schizoid and cyclothymic personalities in our ‘normal’ population, and our [US] tendency to psychological hypochondriasis”.

R.D. Laing in particular stressed that “such ‘clinical’ categories as schizoid, autistic, ‘impoverished’ affect … all presuppose that there are reliable, valid impersonal criteria for making attributions about the other person’s relation to [his or her] actions. There are no such reliable or valid criteria”.

Differential Diagnosis

Blunted affect is very similar to anhedonia, which is the decrease or cessation of all feelings of pleasure (which thus affects enjoyment, happiness, fun, interest, and satisfaction). In the case of anhedonia, emotions relating to pleasure will not be expressed as much or at all because they are literally not experienced or are decreased. Both blunted affect and anhedonia are considered negative symptoms of schizophrenia, meaning that they are indicative of a lack of something. There are some other negative symptoms of schizophrenia which include avolition, alogia and catatonic behaviour.

Closely related is alexithymia – a condition describing people who “lack words for their feelings. They seem to lack feelings altogether, although this may actually be because of their inability to express emotion rather than from an absence of emotion altogether”. Alexithymic patients however can provide clues via assessment presentation which may be indicative of emotional arousal.

“If the amygdala is severed from the rest of the brain, the result is a striking inability to gauge the emotional significance of events; this condition is sometimes called ‘affective blindness'”. In some cases, blunted affect can fade, but there is no conclusive evidence of why this can occur.

What is Antipsychotic Switching?

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Introduction

Antipsychotic switching refers to the process of switching out one antipsychotic for another antipsychotic.

There are multiple indications for switching antipsychotics, including inadequate efficacy and drug intolerance. There are several strategies that have been theorised for antipsychotic switching, based upon the timing of discontinuation and tapering of the original antipsychotic and the timing of initiation and titration of the new antipsychotic. Major adverse effects from antipsychotic switching may include supersensitivity syndromes, withdrawal, and rebound syndromes.

Rationale

Antipsychotics may be switched due to inadequate efficacy, drug intolerance, patient/guardian preference, drug regimen simplification, or for economic reasons.

RationaleOutline
Inadequate Efficacy1. An inadequate treatment response to an antipsychotic, assuming that the lack of efficacy is due to an otherwise adequately dosed regimen for an appropriate duration, can result from failure to achieve therapeutic goals in any major treatment domain.
2. For example, this can refer to a patient who becomes acutely psychotic after being stable previously.
3. Other failures include persistent symptoms of schizophrenia, either positive or negative, problems with mood (including suicidality), or problems with cognition. Inadequate efficacy may be due to nonadherence to therapy, which can influence treatment decisions.
4. For example, long acting injectable (LAI) antipsychotics are often indicated in the setting of medication nonadherence.
Drug Intolerance1. Adverse effects can contribute to drug intolerance, potentially necessitating antipsychotic switching.
2. Adverse effects that threaten serious harm, aggravate other medical conditions, or make a person want to stop taking their medications are all examples of drug intolerance.
3. Certain drug interactions can cause adverse effects as well.
Patient/Guardian Preference1. A patient or caregiver may prefer a different antipsychotic.
2. This may be due to misinformation regarding the antipsychotic, including its side effects, a lack of insight into the importance of the medication and the severity of the disease, or overestimating the therapeutic effect.
Drug Regimen Simplification1. Adherence to medication therapy is inversely related to the frequency of dosing.
2. The antipsychotic quetiapine is typically dosed two to three times daily for the management of schizophrenia.
3. A simpler regimen would be a once daily administered antipsychotic.
4. For example, risperidone can be administered once daily.
5. A lack of adherence can lead to poor health outcomes, as well as unnecessary financial burden.
Economics1. A patient or caregiver may request antipsychotic switching to reduce medication costs.
2. The following is an estimate of the direct costs of living with schizophrenia per patient across select countries (annual direct costs in US$):
a. Belgium: 12,050.
b. People’s Republic of China: 700.
c. South Korea: 2,600.
d. Taiwan: 2,115.
e. UK: 3,420.
f. US: 15,464.

Contraindications

In general, contraindications to antipsychotic switching are cases in which the risk of switching outweighs the potential benefit. Contraindications to antipsychotic switching include effective treatment of an acute psychotic episode, patients stable on a LAI antipsychotic with a history of poor adherence, and stable patients with a history of self-injurious behaviour, violent behaviour, or significant self-neglect or other symptoms.

Strategies

There are multiple strategies available for switching antipsychotics. An abrupt switch involves abruptly switching from one antipsychotic to the other without any titration. A cross-taper is accomplished by gradually discontinuing the pre-switch antipsychotic while simultaneously up-titrating the new antipsychotic. An overlap and discontinuation switch involves maintaining the pre-switch antipsychotic until the new antipsychotic is gradually titrated up, then gradually titrating down on the pre-switch antipsychotic. Alternatively, in an ascending taper switch, the pre-switch antipsychotic can be abruptly discontinued. Another alternative, known as the descending taper switch, involves slowly discontinuing the pre-switch antipsychotic while abruptly starting the new antipsychotic. These switching strategies can be further subdivided by the inclusion or exclusion of a plateau period.

See the figure below for a graphic visualisation of the five main antipsychotic switching strategies discussed above.

Antipsychotic Switching Diagram.

Due to differences in how individual antipsychotics work, even within each generation, the process of switching between antipsychotics has become more complex.

Adverse Effects

The three major adverse effects of antipsychotic switching are supersensitivity syndromes, withdrawal, and rebound syndromes.

Supersensitivity Syndromes

Antipsychotics work by antagonising the dopamine receptor D2 (D2R) in the mesolimbic pathway of the brain. When the D2R is suppressed, the neurons may become sensitised to the effect of an endogenous ligand (i.e. dopamine) by up-regulating the production of postsynaptic D2Rs. If the D2 receptors are not subsequently suppressed at previous levels after an abrupt discontinuation of an antipsychotic (e.g. after switching to weak D2R antagonists quetiapine or clozapine), a rebound/supersensitivity psychosis may occur due to the overwhelming effect of endogenous dopamine on sensitised neurons. Supersensitivity psychosis, also called rapid-onset psychosis, must be distinguished from a relapse or exacerbation of the underlying disease (e.g. schizophrenia). Dopamine supersensitivity psychosis generally occurs around 6 weeks after an oral antipsychotic is discontinued, or 3 months after a LAI antipsychotic is discontinued. In addition, supersensitivity psychosis is generally easier to reverse by reintroducing D2R antagonism (i.e. restarting the discontinued drug), whereas a relapsed schizophrenia is more difficult to control.

Rebound Syndromes

The second-generation antipsychotic olanzapine is thought to have a rebound-induced hyperthermia, which may be mediated by serotonin receptors. Hyperthermia, or elevated core body temperature, is associated with neuroleptic malignant syndrome, a potentially lethal syndrome that commonly occurs due to excessive D2R antagonism (As a point of contrast, hypothermia, or low core body temperature, has most frequently occurred in the presence of olanzapine, risperidone, or haloperidol).

In general, rebound D2R activity may induce rebound parkinsonism and rebound akathisia.

Withdrawal

D2 receptor activity withdrawal may induce withdrawal dyskinesia. This late-onset, hypersensitivity-type dyskinesia is in contrast to the early-onset dyskinesia that can occur due to an over-compensatory dopamine release associated with abrupt dopamine antagonist withdrawal. Other symptoms of dopamine withdrawal include difficulty sleeping, anxiety, and restlessness.

Alternatives

An alternative to antipsychotic switching, in the setting of a person that is not responding to the initial dose of an antipsychotic, is to increase the dose of antipsychotic prescribed. A 2018 Cochrane review compared the evidence between the two strategies, but the authors were unable to draw any conclusions about whether either method was preferable due to limited evidence.

What is Chlorpromazine?

Published on by Andrew Marshall5 Comments

Introduction

Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication.

It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioural problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given by mouth, by injection into a muscle, or into a vein.

Chlorpromazine is in the typical antipsychotic class, and, chemically, is one of the phenothiazines. Its mechanism of action is not entirely clear but believed to be related to its ability as a dopamine antagonist. It also has anti-serotonergic and antihistaminergic properties.

Common side effects include movement problems, sleepiness, dry mouth, low blood pressure upon standing, and increased weight. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, severe lowering of the seizure threshold, and low white blood cell levels. In older people with psychosis as a result of dementia it may increase the risk of death. It is unclear if it is safe for use in pregnancy.

Chlorpromazine was developed in 1950 and was the first antipsychotic. It is on the World Health Organisation’s List of Essential Medicines. Its introduction has been labelled as one of the great advances in the history of psychiatry. It is available as a generic medication.

Brief History

In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs. A year later, the French surgeon Pierre Huguenard used promethazine together with pethidine as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon, Henri Laborit, believed the compound stabilized the central nervous system by causing “artificial hibernation”, and described this state as “sedation without narcosis”. He suggested to Rhône-Poulenc that they develop a compound with better stabilising properties. In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine.[5] Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats.

Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time. Known colloquially as “Laborit’s drug”, chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large “broad” and acti* “activity.

Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns, Raynaud’s phenomenon, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelia Quarti who was acting as a volunteer. Quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued (orthostatic hypotension is a known side effect of chlorpromazine). Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on 19 January 1952, it was administered (alongside pethidine, pentothal and ECT) to Jacques Lh. a 24-year-old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.

Pierre Deniker had heard about Laborit’s work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Sainte-Anne Hospital Centre in Paris where he was Men’s Service Chief. Together with the Director of the hospital, Professor Jean Delay, they published their first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. They also found that doses higher than those used by Laborit were required, giving patients 75-100 mg daily.

Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients’ symptoms resolving after many years of unrelenting psychosis. By 1954, chlorpromazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders. Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today’s GlaxoSmithKline) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases. But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotics were developed. It also led to the discovery of antidepressants.

Chlorpromazine largely replaced electroconvulsive therapy, hydrotherapy, psychosurgery, and insulin shock therapy. By 1964, about 50 million people worldwide had taken it. Chlorpromazine, in widespread use for 50 years, remains a “benchmark” drug in the treatment of schizophrenia, an effective drug although not a perfect one. The relative strengths or potencies of other antipsychotics are often ranked or measured against chlorpromazine in aliquots of 100 mg, termed chlorpromazine equivalents or CPZE.

In the movie: “Shutter Island”, chlorpromazine is presented as being the new medicament for psychosis treatment however with adverse effects like tremors or abstinence syndrome.

Brand Names

Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by Bayer in West-Germany since July 1953).

Medical Uses

Chlorpromazine is used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder, as well as amphetamine-induced psychosis.

In a 2013 comparison of 15 antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. It was 13% more effective than lurasidone and iloperidone, approximately as effective as ziprasidone and asenapine, and 12–16% less effective than haloperidol, quetiapine, and aripiprazole.

A 2014 systematic review carried out by Cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. Compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. No difference was found between the two groups beyond two years of follow-up. Patients under chlorpromazine showed a global improvement in symptoms and functioning. The systematic review also highlighted the fact that the side effects of the drug were ‘severe and debilitating’, including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of suffering from acute movement disorders. They also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. They called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide.

Chlorpromazine has also been used in porphyria and as part of tetanus treatment. It still is recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe hiccups, severe nausea/emesis, and preanesthetic conditioning are other uses. Symptoms of delirium in hospitalised AIDS patients have been effectively treated with low doses of chlorpromazine.

Other

Chlorpromazine is occasionally used off-label for treatment of severe migraine. It is often, particularly as palliation, used in small doses to reduce nausea suffered by opioid-treated cancer patients and to intensify and prolong the analgesia of the opioids as well. Efficacy has been shown in treatment of symptomatic hypertensive emergency.

In Germany, chlorpromazine still carries label indications for insomnia, severe pruritus, and preanaesthesia.

Chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases.

Adverse Effects

There appears to be a dose-dependent risk for seizures with chlorpromazine treatment. Tardive dyskinesia (involuntary, repetitive body movements) and akathisia (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol or trifluoperazine, and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as risperidone or olanzapine.

Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.

Contraindications

  • Absolute contraindications include:
    • Circulatory depression.
    • CNS depression.
    • Coma.
    • Drug intoxication.
    • Bone marrow suppression.
    • Phaeochromocytoma.
    • Hepatic failure.
    • Active liver disease.
    • Previous hypersensitivity (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.
  • Relative contraindications include:
    • Epilepsy.
    • Parkinson’s disease.
    • Myasthenia gravis.
    • Hypoparathyroidism.
    • Prostatic hypertrophy.

Very rarely, elongation of the QT interval may occur, increasing the risk of potentially fatal arrhythmias.

Interactions

Consuming food prior to taking chlorpromazine orally limits its absorption, likewise cotreatment with benztropine can also reduce chlorpromazine absorption. Alcohol can also reduce chlorpromazine absorption. Antacids slow chlorpromazine absorption. Lithium and chronic treatment with barbiturates can increase chlorpromazine clearance significantly. Tricyclic antidepressants (TCAs) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure. Cotreatment with CYP1A2 inhibitors like ciprofloxacin, fluvoxamine or vemurafenib can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects. Chlorpromazine can also potentiate the CNS depressant effects of drugs like barbiturates, benzodiazepines, opioids, lithium and anaesthetics and hence increase the potential for adverse effects such as respiratory depression and sedation.

It is also a moderate inhibitor of CYP2D6 and also a substrate for CYP2D6 and hence can inhibit its own metabolism. It can also inhibit the clearance of CYP2D6 substrates such as dextromethorphan and hence also potentiate their effects. Other drugs like codeine and tamoxifen which require CYP2D6-mediated activation into their respective active metabolites may have their therapeutic effects attenuated. Likewise CYP2D6 inhibitors such as paroxetine or fluoxetine can reduce chlorpromazine clearance and hence increase serum levels of chlorpromazine and hence potentially also its adverse effects. Chlorpromazine also reduces phenytoin levels and increases valproic acid levels. It also reduces propranolol clearance and antagonises the therapeutic effects of antidiabetic agents, levodopa (a Parkinson’s medication. This is likely due to the fact that chlorpromazine antagonises the D2 receptor which is one of the receptors dopamine, a levodopa metabolite, activates), amphetamines and anticoagulants. It may also interact with anticholinergic drugs such as orphenadrine to produce hypoglycaemia (low blood sugar).

Chlorpromazine may also interact with epinephrine (adrenaline) to produce a paradoxical fall in blood pressure. Monoamine oxidase inhibitors (MAOIs) and thiazide diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment. Quinidine may interact with chlorpromazine to increase myocardialdepression. Likewise it may also antagonize the effects of clonidine and guanethidine. It also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered. Prochlorperazine and desferrioxamine may also interact with chlorpromazine to produce transient metabolic encephalopathy.

Other drugs that prolong the QT interval such as quinidine, verapamil, amiodarone, sotalol and methadone may also interact with chlorpromazine to produce additive QT interval prolongation.

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.

Pharmacology

Chlorpromazine is classified as a low-potency typical antipsychotic. Low-potency antipsychotics have more anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol) have the reverse profile.

Pharmacodynamics

Chlorpromazine is a very effective antagonist of D2 dopamine receptors and similar receptors, such as D3 and D5. Unlike most other drugs of this genre, it also has a high affinity for D1 receptors. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects. Dopamine, unable to bind with a receptor, causes a feedback loop that causes dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the synaptic cleft. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.

Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic and presynaptic receptors:

  • Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects.
  • Serotonin receptors (5-HT2, 5-HT6 and 5-HT7), with anxiolytic, antidepressant and anti-aggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
  • Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain).
  • α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor).
  • M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).

The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.

Chlorpromazine and other typical antipsychotics are primarily blockers of D2 receptors. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug’s affinity for the D2 receptor. Therefore, a larger dose is required if the drug’s affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for dopamine receptors. Chlorpromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics.

Chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at histamine H1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines.

In addition to influencing the neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves direct effects on antipsychotic drugs on glutamate receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on NMDA receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in glutamate and glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.

Chlorpromazine does also act as a FIASMA (functional inhibitor of acid sphingomyelinase).

Peripheral Effects

Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as a “dirty drug”.

Veterinary Use

The veterinary use of chlorpromazine has generally been superseded by use of acepromazine.

Chlorpromazine may be used as an antiemetic in dogs and cats, or, less often, as sedative before anaesthesia. In horses, it often causes ataxia and lethargy, and is therefore seldom used.

It is commonly used to decrease nausea in animals that are too young for other common anti-emetics. It is also sometimes used as a preanesthetic and muscle relaxant in cattle, swine, sheep, and goats.

The use of chlorpromazine in food-producing animals is not permitted in the EU, as a maximum residue limit could not be determined following assessment by the European Medicines Agency.

Research

Chlorpromazine has tentative benefit in animals infected with Naegleria fowleri. and shows antifungal and antibacterial activity in vitro.

An Overview of the Treatment of Bipolar Disorder

Published on by Andrew MarshallLeave a comment

Introduction

The emphasis of the treatment of bipolar disorder is on effective management of the long-term course of the illness, which can involve treatment of emergent symptoms.

Treatment methods include pharmacological and psychological techniques.

Principles

The primary treatment for bipolar disorder consists of medications called mood stabilisers, which are used to prevent or control episodes of mania or depression. Medications from several classes have mood stabilising activity. Many individuals may require a combination of medication to achieve full remission of symptoms. As it is impossible to predict which medication will work best for a particular individual, it may take some trial and error to find the best medication or combination for a specific patient. Psychotherapy also has a role in the treatment of bipolar disorder. The goal of treatment is not to cure the disorder but rather to control the symptoms and the course of the disorder. Generally speaking, maintenance treatment of bipolar disorder continues long after symptom control has been achieved.

Following diagnostic evaluation, the treating clinician must determine the optimal treatment setting in order to ensure the patient’s safety. Assessment of suicide risk is key, as the rate of suicide completion among those with bipolar disorder may be as high as 10-15%. Hospitalisation should be considered in patients whose judgement is significantly impaired by their illness, and those who have not responded to outpatient treatment; this may need to be done on an involuntary basis. Treatment setting should regularly be re-evaluated to ensure that it is optimal for the patient’s needs.

Mood Stabilisers

Lithium Salts

Lithium salts have been used for centuries as a first-line treatment for bipolar disorder. In ancient times, doctors would send their mentally ill patients to drink from “alkali springs” as a treatment. Although they were not aware of it, they were actually prescribing lithium, which was present in high concentration within the waters. The therapeutic effect of lithium salts appears to be entirely due to the lithium ion, Li+.

Its exact mechanism of action is uncertain, although there are several possibilities such as inhibition of inositol monophosphatase, modulation of G proteins or regulation of gene expression for growth factors and neuronal plasticity. There is strong evidence for its effectiveness in acute treatment and prevention of recurrence of mania. It can also be effective in bipolar depression, although the evidence is not as strong. It is also effective in reducing the risk of suicide in patients with mood disorders.

Potential side effects from lithium include gastrointestinal upset, tremor, sedation, excessive thirst, frequent urination, cognitive problems, impaired motor coordination, hair loss, and acne. Excessive levels of lithium can be harmful to the kidneys, and increase the risk of side effects in general. As a result, kidney function and blood levels of lithium are monitored in patients being treated with lithium. Therapeutic plasma levels of lithium range from 0.5 to 1.5 mEq/L, with levels of 0.8 or higher being desirable in acute mania.

Lithium levels should be above 0.6 mEq/L to reduce both manic and depressive episodes in patients. A recent review concludes that the standard lithium serum level should be 0.60-0.80 mmol/L with optional reduction to 0.40-0.60 mmol/L in case of good response but poor tolerance or an increase to 0.80-1.00 mmol/L in case of insufficient response and good tolerance.

Monitoring is generally more frequent when lithium is being initiated, and the frequency can be decreased once a patient is stabilised on a given dose. Thyroid hormones should also be monitored periodically, as lithium can increase the risk of hypothyroidism.

Anticonvulsants

A number of anti-convulsant drugs are used as mood stabilisers, and the suspected mechanism is related to the theory that mania can “kindle” further mania, similar to the kindling model of seizures. Valproic acid, or valproate, was one of the first anti-convulsants tested for use in bipolar disorder. It has proven to be effective for treating acute mania. The mania prevention and antidepressant effects of valproic acid have not been well demonstrated. Valproic acid is less effective than lithium at preventing and treating depressive episodes.

Carbamazepine was the first anti-convulsant shown to be effective for treating bipolar mania. It has not been extensively studied in bipolar depression. It is generally considered a second-line agent due to its side effect profile. Lamotrigine is considered a first-line agent for the treatment of bipolar depression. It is effective in preventing the recurrence of both mania and depression, but it has not proved useful in treating acute mania.

Zonisamide (trade name Zonegran), another anti-convulsant, also may show promise in treating bipolar depression. Various other anti-convulsants have been tested in bipolar disorder, but there is little evidence of their effectiveness. Other anti-convulsants effective in some cases and being studied closer include phenytoin, levetiracetam, pregabalin and valnoctamide.

Each anti-convulsant agent has a unique side-effect profile. Valproic acid can frequently cause sedation or gastrointestinal upset, which can be minimised by giving the related drug divalproex, which is available in an enteric-coated tablet. These side effects tend to disappear over time. According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician. Excessive levels of valproate can lead to impaired liver function, and liver enzymes and serum valproate level, with a target of 50–125 µg/L, should be monitored periodically.

Side effects of carbamazepine include blurred vision, double vision, ataxia, weight gain, nausea, and fatigue, as well as some rare but serious side effects such as blood dyscrasias, pancreatitis, exfoliative dermatitis, and hepatic failure. Monitoring of liver enzymes, platelets, and blood cell counts are recommended.

Lamotrigine generally has minimal side effects, but the dose must be increased slowly to avoid rashes, including exfoliative dermatitis.

Atypical Antipsychotic Drugs

Antipsychotics work best in the manic phase of bipolar disorder. Second-generation or atypical antipsychotics (including aripiprazole, olanzapine, quetiapine, paliperidone, risperidone, and ziprasidone) have emerged as effective mood stabilisers. The evidence for this is fairly recent, as in 2003 the American Psychiatric Press noted that atypical anti-psychotics should be used as adjuncts to other anti-manic drugs because their mood stabilising properties had not been well established. The mechanism is not well known, but may be related to effects on glutamate activity. Several studies have shown atypical antipsychotics to be effective both as single-agent and adjunctive treatments. Antidepressant effectiveness varies, which may be related to different serotonergic and dopaminergic receptor binding profiles. Quetiapine and the combination of olanzapine and fluoxetine have both demonstrated effectiveness in bipolar depression.

In light of recent evidence, olanzapine (Zyprexa) has been US Food and Drug Administration (FDA) approved as an effective monotherapy for the maintenance of bipolar disorder. A head-to-head randomised control trial (RCT) in 2005 has also shown olanzapine monotherapy to be just as effective and safe as lithium in prophylaxis.

The atypical antipsychotics differ somewhat in side effect profiles, but most have some risk of sedation, weight gain, and extrapyramidal symptoms (including tremor, stiffness, and restlessness). They may also increase the risk of metabolic syndrome, so metabolic monitoring should be performed regularly, including checks of serum cholesterol, triglycerides, and glucose, weight, blood pressure, and waist circumference. Taking antipsychotics for long periods or at high doses can also cause tardive dyskinesia – a sometimes incurable neurological disorder resulting in involuntary, repetitive body movements. The risk of tardive dyskinesia appears to be lower in second-generation antipsychotics than in first-generation antipsychotics but as with first-generation drugs, increases with time spent on medications and in older patients.

New Treatments

A variety of other agents have been tried in bipolar disorder, including benzodiazepines, calcium channel blockers, L-methylfolate, and thyroid hormone. Modafinil (Provigil) and Pramipexole (Mirapex) have been suggested for treating cognitive dysfunction associated with bipolar depression, but evidence supporting their use is quite limited. In addition riluzole, a glutamatergic drug used in ALS has been studied as an adjunct or monotherapy treatment in bipolar depression, with mixed and inconsistent results. The selective oestrogen receptor modulator medication tamoxifen has shown rapid and robust efficacy treating acute mania in bipolar patients. This action is likely due not to tamoxifen’s oestrogen-modulating properties, but due to its secondary action as an inhibitor of protein Kinase C.

Cognitive Effects of Mood Stabilisers

Bipolar patients taking antipsychotics have lower scores on tests of memory and full-scale IQ than patients taking other mood stabilisers. Use of both typical and atypical antipsychotics is associated with risk of cognitive impairment, but the risk is higher for antipsychotics with more sedating effects.

Among bipolar patients taking anticonvulsants, those on lamotrigine have a better cognitive profile than those on carbamazepine, valproate, topiramate, and zonisamide.

Although decreased verbal memory and slowed psychomotor speed are common side effects of lithium use these side effects usually disappear after discontinuation of lithium. Lithium may be protective of cognitive function in the long term since it promotes neurogenesis in the hippocampus and increases grey matter volume in the prefrontal cortex.

Antidepressants

Antidepressants should only be used with caution in bipolar disorder, as they may not be effective and may even induce mania. They should not be used alone, but may be considered as an adjunct to lithium.

A recent large-scale study found that severe depression in patients with bipolar disorder responds no better to a combination of antidepressant medications and mood stabilisers than it does to mood stabilisers alone and that antidepressant use does not hasten the emergence of manic symptoms in patients with bipolar disorder.

The concurrent use of an antidepressant and a mood stabiliser, instead of mood stabiliser monotherapy, may lower the risk of further bipolar depressive episodes in patients whose most recent depressive episode has been resolved. However, some studies have also found that antidepressants pose a risk of inducing hypomania or mania, sometimes in individuals with no prior history of mania. Saint John’s Wort, although a naturally occurring compound, is thought to function in a fashion similar to man-made antidepressants, and so unsurprisingly, there are reports that suggest that it can also induce mania. For these reasons, some psychiatrists are hesitant to prescribe antidepressants for the treatment of bipolar disorder unless mood stabilisers have failed to have an effect, however, others feel that antidepressants still have an important role to play in treatment of bipolar disorder.

Side effects vary greatly among different classes of antidepressants.

Antidepressants are helpful in preventing suicides in people suffering from bipolar disorder when they go in for the depressive phase.

NMDA-Receptor Antagonists

In a double-blind, placebo-controlled, proof-of-concept study, researchers administered an N-methyl-d-aspartate-receptor antagonist (ketamine) to 18 patients already on treatment with lithium (10 patients) or valproate (8 patients) for bipolar depression. From 40 minutes following intravenous injection of ketamine hydrochloride (0.5 mg/kg), the researchers observed significant improvements in depressive symptoms, as measured by standard tools, that were maintained for up to 3 days, an effect not observed in subjects who received the placebo. Five subjects dropped out of the ketamine study; of these, four were taking valproate and one was being treated with lithium. One patient showed signs of hypomania following ketamine administration and two experienced low mood. This study demonstrates a rapid-onset antidepressant effect of ketamine in a small group of patients with bipolar depression. The authors acknowledged the study’s limitations, including the dissociative disturbances in patients receiving ketamine that could have compromised the study blinding, and they emphasised the need for further research.

A more recent double-blind, placebo-controlled study by the same group found that ketamine treatment resulted in a similarly rapid alleviation of suicidal ideation in 15 patients with bipolar depression.

Ketamine is used as a dissociative anaesthetic, and is a Class C substance in the United Kingdom; as such, it should only be used under the direction of a health professional.

Dopamine Agonists

In a single controlled study of twenty one patients, the dopamine D3 receptor agonist pramipexole was found to be highly effective in the treatment of bipolar depression. Treatment was initiated at 0.125 mg t.i.d. and increased at a rate of 0.125 mg t.i.d. to a limit of 4.5 mg qd until the patients’ condition satisfactorily responded to the medication or they could not abide the side effects. The final average dosage was 1.7 mg ± .90 mg qd. The incidence of hypomania in the treatment group was no greater than in the control group.

Psychotherapy

Certain types of psychotherapy, used in combination with medication, may provide some benefit in the treatment of bipolar disorders. Psychoeducation has been shown to be effective in improving patients’ compliance with their lithium treatment. Evidence of the efficacy of family therapy is not adequate to support unrestricted recommendation of its use. There is “fair support” for the utility of cognitive therapy. Evidence for the efficacy of other psychotherapies is absent or weak, often not being performed under randomised and controlled conditions. Well-designed studies have found interpersonal and social rhythm therapy to be effective.

Although medication and psychotherapy cannot cure the illness, therapy can often be valuable in helping to address the effects of disruptive manic or depressive episodes that have hurt a patient’s career, relationships or self-esteem. Therapy is available not only from psychiatrists but from social workers, psychologists and other licensed counsellors.

Jungian Therapy

Jungian authors have likened the mania and depression of bipolar disorder to the Jungian archetypes ‘puer’ and ‘senex’. The puer archetype is defined by the behaviours of spontaneity, impulsiveness, enthusiasm or mania and is symbolised by characters such as Peter Pan or the Greek god Hermes. The senex archetype is defined by behaviours of order, systematic thought, caution, and depression and is symbolised by characters such as the Roman god Saturn or the Greek god Kronos. Jungians conceptualise the puer and senex as a coexistent bipolarity appearing in human behaviour and imagination, but in neurotic manifestations appears as extreme oscillations and as unipolar manifestations. In the case of the split puer-senex bipolarity the therapeutic task is to bring the puer and senex back into correlation by working with the patient’s mental imagery.”

Lifestyle Changes

Sufficient Sleep

If sleeping is disturbed, the symptoms can occur. Sleep disruption may actually exacerbate the mental illness state. Those who do not get enough sleep at night, sleep late and wake up late, or go to sleep with some disturbance (e.g. music or charging devices) have a greater chance of having the symptoms and, in addition, depression. It is highly advised to not sleep too late and to get enough high quality sleep.

Self-Management and Self-Awareness

Understanding the symptoms, when they occur and ways to control them using appropriate medications and psychotherapy has given many people diagnosed with bipolar disorder a chance at a better life. Prodrome symptom detection has been shown to be used effectively to anticipate onset of manic episodes and requires high degree of understanding of one’s illness. Because the offset of the symptoms is often gradual, recognising even subtle mood changes and activity levels is important in avoiding a relapse. Maintaining a mood chart is a specific method used by patients and doctors to identify mood, environmental and activity triggers.

Stress Reduction

Forms of stress may include having too much to do, too much complexity and conflicting demands among others. There are also stresses that come from the absence of elements such as human contact, a sense of achievement, constructive creative outlets, and occasions or circumstances that will naturally elicit positive emotions. Stress reduction will involve reducing things that cause anxiety and increasing those that generate happiness. It is not enough to just reduce the anxiety.

Co-Morbid Substance Use Disorder

Co-occurring substance misuse disorders, which are extremely common in bipolar patients can cause a significant worsening of bipolar symptomatology and can cause the emergence of affective symptoms. The treatment options and recommendations for substance use disorders is wide but may include certain pharmacological and nonpharmacological treatment options.

Other Treatments

Omega-3 Fatty Acids

Omega-3 fatty acids may also be used as a treatment for bipolar disorder, particularly as a supplement to medication. An initial clinical trial by Stoll et al. (1999) produced positive results. However, since 1999 attempts to confirm this finding of beneficial effects of omega-3 fatty acids in several larger double-blind clinical trials have produced inconclusive results. It was hypothesized that the therapeutic ingredient in omega-3 fatty acid preparations is eicosapentaenoic acid (EPA) and that supplements should be high in this compound to be beneficial. A 2008 Cochrane systematic review found limited evidence to support the use of Omega-3 fatty acids to improve depression but not mania as an adjunct treatment for bipolar disorder.

Omega-3 fatty acids may be found in fish, fish oils, algae, and to a lesser degree in other foods such as flaxseed, flaxseed oil and walnuts. Although the benefits of Omega-3 fatty acids remain debated, they are readily available at drugstores and supermarkets, relatively inexpensive, and have few known side effects (All of these oils, however, have the capacity to exacerbate GERD (gastroesophageal reflux disease) – food sources may be a good alternative in such cases).

Exercise

Exercise has also been shown to have antidepressant effects.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) may have some effectiveness in mixed mania states, and good effectiveness in bipolar depression, particularly in the presence of psychosis. It may also be useful in the treatment of severe mania that is non-responsive to medications.

The most frequent side effects of ECT include memory impairment, headaches, and muscle aches. In some instances, ECT can produce significant and long-lasting cognitive impairment, including anterograde amnesia, and retrograde amnesia.

Ketogenic Diet

Because many of the medications that are effective in treating epilepsy are also effective as mood stabilizers, it has been suggested that the ketogenic diet – used for treating paediatric epilepsy – could have mood stabilising effects. Ketogenic diets are diets that are high in fat and low in carbohydrates, and force the body to use fat for energy instead of sugars from carbohydrates. This causes a metabolic response similar to that seen in the body during fasting. This idea has not been tested by clinical research, and until recently, was entirely hypothetical. Recently, however, two case studies have been described where ketogenic diets were used to treat bipolar II. In each case, the patients found that the ketogenic diet was more effective for treating their disorder than medication and were able to discontinue the use of medication. The key to efficacy appears to be ketosis (a metabolic state characterised by elevated levels of ketone bodies in the blood or urine), which can be achieved either with a classic high-fat ketogenic diet, or with a low-carbohydrate diet similar to the induction phase of the Atkins Diet. The mechanism of action is not well understood. It is unclear whether the benefits of the diet produce a lasting improvement in symptoms (as is sometimes the case in treatment for epilepsy) or whether the diet would need to be continued indefinitely to maintain symptom remission.

The Role of Cannabinoids

Acute cannabis intoxication transiently produces perceptual distortions, psychotic symptoms and reduction in cognitive abilities in healthy persons and in severe mental disorder, and may impair the ability to safely operate a motor vehicle.

Cannabis use is common in bipolar disorder, and is a risk factor for a more severe course of the disease by increasing frequency and duration of episodes. It is also reported to reduce age at onset.

Alternative Medicine

Several studies have suggested that omega-3 fatty acids may have beneficial effects on depressive symptoms, but not manic symptoms. However, only a few small studies of variable quality have been published and there is not enough evidence to draw any firm conclusions.

What is Perphenazine?

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Introduction

Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades.

Perphenazine is roughly ten times as potent as chlorpromazine at the dopamine-2 (D2) receptor; thus perphenazine is considered a medium-potency antipsychotic.

Medical Uses

In low doses it is used to treat agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows. Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting (emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients.

Perphenazine has been used in low doses as a ‘normal’ or ‘minor’ tranquiliser in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.

Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients.

A valuable off-label indication is the short-time treatment of hyperemesis gravidarum, in which pregnant women experience violent nausea and vomiting. This problem can become severe enough to endanger the pregnancy. As perphenazine has not been shown to be teratogenic and works very well, it is sometimes given orally in the smallest possible dose.

Effectiveness

Perphenazine is used to treat psychosis (e.g. in people with schizophrenia and the manic phases of bipolar disorder). Perphenazine effectively treats the positive symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness in treating the negative symptoms of schizophrenia, such as flattened affect and poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms, but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics.

Side Effects

As a member of the phenothiazine type of antipsychotics, perphenazine shares in general all allergic and toxic side-effects of chlorpromazine. A 2015 systematic review of the data on perphenazine conducted by the Cochrane Collaboration concluded that “there were no convincing differences between perphenazine and other antipsychotics” in the incidence of adverse effects. Perphenazine causes early and late extrapyramidal side effects more often than placebo, and at a similar rate to other medium-potency antipsychotics and the atypical antipsychotic risperidone.

When used for its strong antiemetic or antivertignosic effects in cases with associated brain injuries, it may obscure the clinical course and interferes with the diagnosis. High doses of perphenazine can cause temporary dyskinesia. As with other typical antipsychotics, permanent or lasting tardive dyskinesia is a risk.

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.

Pharmacology

Pharmacokinetics

Perphenazine has an oral bioavailability of approximately 40% and a half-life of 8 to 12 hours (up to 20 hours), and is usually given in 2 or 3 divided doses each day. It is possible to give two-thirds of the daily dose at bedtime and one-third during breakfast to maximise hypnotic activity during the night and to minimise daytime sedation and hypotension without loss of therapeutic activity.

Formulations

It is sold under the brand names Trilafon (single drug) and Etrafon/Triavil/Triptafen (contains fixed dosages of amitriptyline). A brand name in Europe is Decentan pointing to the fact that perphenazine is approximately 10-times more potent than chlorpromazine. Usual oral forms are tablets (2, 4, 8, 16 mg) and liquid concentrate (4 mg/ml).

The ‘Perphenazine injectable USP’ solution is intended for deep intramuscular (IM) injection, for patients who are not willing to take oral medication or if the patient is unable to swallow. Due to a better bioavailability of the injection, two-thirds of the original oral dose is sufficient. The incidence of hypotension, sedation and extrapyramidal side-effects may be higher compared to oral treatment. IM-injections are appropriate for a few days, but oral treatment should start as soon as possible.

In many countries, depot forms of perphenazine exist (as perphenazine enanthate and perphenazine decanoate). One injection works for 1 to 4 weeks depending on the dose of the depot-injection. Depot-forms of perphenazine should not be used during the initial phase of treatment as the rare neuroleptic malignant syndrome may become more severe and uncontrollable with this form. Extrapyramidal side-effects may be somewhat reduced due to constant plasma-levels during depot-therapy. Also, patient compliance is sure, as many patients do not take their oral medication, particularly if feeling better once improvement in psychosis is achieved.

Interactions

Fluoxetine causes higher plasma levels and a longer elimination half-life of perphenazine, therefore a dose reduction of perphenazine might be necessary.

Perphenazine intensifies the central depressive action of drugs with such activity (tranquilizers, hypnotics, narcotics, antihistaminics, OTC-antiemetics etc.). A dose reduction of perphenazine or the other drug may be necessary.

In general, all neuroleptics may lead to seizures in combination with the opioid tramadol (Ultram).

Perphenazine may increase the insulin needs of diabetic patients. Monitor blood glucose levels of insulin-dependent patients regularly during long-term treatment.

What is the Texas Medication Algorithm Project?

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Introduction

The Texas Medication Algorithm Project (TMAP) is a controversial decision-tree medical algorithm, the design of which was based on the expert opinions of mental health specialists.

It has provided and rolled out a set of psychiatric management guidelines for doctors treating certain mental disorders within Texas’ publicly funded mental health care system, along with manuals relating to each of them. The algorithms commence after diagnosis and cover pharmacological treatment (hence “Medication Algorithm”).

Brief History

TMAP was initiated in the fall (winter) of 1997 and the initial research covered around 500 patients.

TMAP arose from a collaboration that began in 1995 between the Texas Department of Mental Health and Mental Retardation (TDMHMR), pharmaceutical companies, and the University of Texas Southwestern. The research was supported by the National Institute of Mental Health, the Robert Wood Johnson Foundation, the Meadows Foundation, the Lightner-Sams Foundation, the Nanny Hogan Boyd Charitable Trust, TDMHMR, the Centre for Mental Health Services, the Department of Veterans Affairs, the Health Services Research and Development Research Career Scientist Award, the United States Pharmacopoeia Convention Inc. and Mental Health Connections.

Numerous companies that invent and develop antipsychotic medications provided use of their medications and furnished funding for the project. Companies did not participate in the production of the guidelines.

In 2004 TMAP was mentioned as an example of a successful project in a paper regarding implementing mental health screening programmes throughout the United States, by the President George W. Bush’s New Freedom Commission on Mental Health, which looks to expand the programme federally. The President had previously been Governor of Texas, in the period when TMAP was implemented. Similar programmes have been implemented in about a dozen States, according to a 2004 report in the British Medical Journal.

Similar algorithms with similar prescribing advice have been produced elsewhere, for instance at the Maudsley Hospital, London.

What is Barbiturate Dependence?

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Introduction

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.

Refer to Barbiturate Overdose.

Background

Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.

Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.

The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.

The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.

What is a Paradoxical Reaction?

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Introduction

A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.

Antibiotics

The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.

Antidepressants

In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.

Antipsychotics

Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.

Barbiturates

Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.

Benzodiazepines

Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.

Causes

The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.