Tag: Antipsychotic

What is Lurasidone?

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Introduction

Lurasidone, sold under the trade name Latuda among others, is an antipsychotic medication used to treat schizophrenia and bipolar disorder. It is taken by mouth.

Common side effects include sleepiness, movement disorders, nausea, and diarrhoea. Serious side effects are valid for all atypical antipsychotics and may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, angioedema, and high blood sugar levels, although lurasidone is less likely to cause high blood sugar levels in most patients, hyperosmolar hyperglycaemic syndrome may occur. In older people with psychosis as a result of dementia, it may increase the risk of dying. Use during pregnancy is of unclear safety.

Lurasidone was first approved for medical use in the United States in 2010. In 2013, it was approved in Canada, and by the United States Food and Drug Administration, to treat bipolar depression, either as monotherapy or adjunctively with lithium or valproate. Generic versions were approved in the United States in 2019, and became available in 2023. In 2020, it was the 259th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

Brief History

Lurasidone was first synthesised circa 2003.

Lurasidone is a structural analogue of ziprasidone. Lurasidone shows a very close pharmacological profile and has been synthesized similarly to ziprasidone.

Lurasidone is chemically similar to perospirone (also a chemical analogue of ziprasidone), as well as risperidone, paliperidone and iloperidone.

It has approval from the US Food and Drug Administration (FDA) for treating schizophrenia since 2010, and for treating depressive episodes in adults with bipolar I disorder since 2013.

Medical Uses

Lurasidone is used to treat schizophrenia and bipolar disorder. In bipolar disorder, It has been studied both as a monotherapy and adjunctive treatment to lithium or valproate.

The European Medicines Agency approved lurasidone for the treatment of schizophrenia for people aged 13 years and older, but not for bipolar disorder. In the United States, it is used to treat schizophrenia for people aged 13 years and older, as well as depressive episodes of bipolar disorder age 10 and over as a monotherapy, and in conjunction with lithium or valproate in adults.

In July 2013, lurasidone received approval for bipolar I depression.

In June 2020, lurasidone was approved in Japan, eight years after its first approval in the United States. In Japan it is approved for bipolar depression and schizophrenia.

Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine, olanzapine and possibly asenapine) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity, which is yet to be clearly demonstrated for lurasidone.

In the early post approval period lurasidone-treated patients with bipolar disorder were retrospectively found to have more complex clinical profiles, comorbidities, and prior treatment history compared to patients initiated with other atypical antipsychotics. The study authors suggest this may be due to:

“the overall clinical profile of lurasidone, the role perceived for lurasidone in the therapeutic armamentarium by practitioners, and the recent introduction of lurasidone into clinical practice during the study period.”

Lurasidone is not approved by the FDA for the treatment of behaviour disorders in older adults with dementia.

Contraindications

Lurasidone is contraindicated in individuals who are taking strong inhibitors of the liver enzyme CYP3A4 (ketoconazole, clarithromycin, ritonavir, levodropropizine, etc.) or inducers (carbamazepine, St. John’s wort, phenytoin, rifampicin etc.). The use of lurasidone in pregnant women has not been studied and is not recommended; in animal studies, no risks have been found. Excretion in breast milk is also unknown; lurasidone is not recommended for breastfeeding women. In the United States it is not indicated for use in children. The enzyme CYP3A4 is involved in the digestion of drugs. Inhibitors such as grapefruit juice block its function resulting in too much drug in the body.

Side Effects

Side effects are generally similar to other antipsychotics. The drug has a relatively well tolerated side effect profile, with low propensity for QTc interval changes, weight gain and lipid-related adverse effects. In a 2013 meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone, and aripiprazole).

As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes. Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with antipsychotic use.

Weight gain is reported in up to 15% and 16% of users. Other possible side effects include vomiting, akathisia, dystonia, parkinsonism, somnolence, dizziness, sedation and nausea.

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.

Interactions

Blood plasma concentrations may be increased when combined with CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, and voriconazole) possibly leading to more side effects. This has been clinically verified for ketoconazole, which increases lurasidone exposure by a factor of 9, and is also expected for other 3A4 inhibitors such as grapefruit juice. Co-administration of CYP3A4 inducers like rifampicin, carbamazepine or St. John’s wort can reduce plasma levels of lurasidone and its active metabolite, and consequently decrease the effects of the drug. For rifampicin, the reduction was sixfold in a study.

Pharmacology

Pharmacodynamics

Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl]-cyclohexylmethyl}-hexahydro-4,7-methano-2Hisoindole-1,3-dione hydrochloride]] is an azapirone derivative and acts as an antagonist of the dopamine D2 and D3 receptors, and the serotonin 5-HT2A and 5-HT7 receptors, and the α2C-adrenergic receptor, and as a partial agonist of the serotonin 5-HT1A receptor. It has moderate-affinity antagonism at α2C-adrenergic receptors; low to very low-affinity antagonism at α1A-adrenergic α2A-adrenergic receptors.

It has only low and likely clinically unimportant affinity for the serotonin 5-HT2C receptor, which may underlie its low propensity for appetite stimulation and weight gain. The drug also has negligible affinity for the histamine H1 receptor and the muscarinic acetylcholine receptors, and hence has no antihistamine or anticholinergic effects. Drowsiness (somnolence) side effect is not explained by its antagonist activity to histamine.

The relationship between dose and D2 receptor occupancy levels were 41–43% for 10 mg, 51–55% for 20 mg, 63–67% for 40 mg, 77–84% for 60 mg, and 73–79% for 80 mg.

Pharmacokinetics

Lurasidone is taken by mouth and has an estimated absorption rate of 9 to 19%. Studies have shown that when lurasidone is taken with food, absorption increases about twofold. Peak blood plasma concentrations are reached after one to three hours. About 99% of the circulating substance are bound to plasma proteins. Efficacy data for lurasidone have been evaluated for doses of 20 mg to 120 mg daily

Lurasidone is extensively metabolised by CYP3A4 leading to contraindication of both strong inhibitors as well as strong inducers of this enzyme, but has negligible affinity to other cytochrome P450 enzymes. It is transported by P-glycoprotein and ABCG2 and also inhibits these carrier proteins in vitro. It also inhibits the solute carrier protein SLC22A1, but no other relevant transporters.

Main metabolism pathways are oxidative N-dealkylation between the piperazine and cyclohexane rings, hydroxylation of the norbornane ring, and S-oxidation. Other pathways are hydroxylation of the cyclohexane ring and reductive cleavage of the isothiazole ring followed by S-methylation. The two relevant active metabolites are the norbornane hydroxylation products called ID-14283 and ID-14326, the former reaching pharmacologically relevant blood plasma concentrations. The two major inactive metabolites are the N-dealkylation products (the carboxylic acid ID-20219 and the piperazine ID-11614), and a norbornane hydroxylated derivative of ID-20219 (ID-20220). Of lurasidone and its metabolites circulating in the blood, the native drug makes up 11%, the main active metabolite 4%, and the inactive carboxylic acids 24% and 11%, respectively. Several dozen metabolites have been identified altogether.

Biological half-life is given as 18 hours or 20 to 40 hours in different sources. 80% or 67% of a radiolabelled dose was recovered from the faeces, and 9% or 19% from the urine.

Society and Culture

Cost

In Canada, as of 2014, lurasidone is generally more expensive than risperidone and quetiapine but less expensive than aripiprazole.

In the US, because a number of doses have the same price per tablet, pill splitting has been used to decrease costs. In 2019, generic versions were approved in the United States; however, they only became available in 2023 due to drug patents.

Brand Names

In India, this drug is available under the brand names of Atlura, Lurace, Lurafic, Luramax (Sun Pharma), Lurasid, Lurastar, Latuda, Lurata and additionally as Alsiva, Emsidon, Lurakem, Luratrend, Tablura, and Unison.

Regulatory Approval

Lurasidone was approved in the United States for the treatment of schizophrenia in October 2010 and for the treatment of depressive episodes associated with bipolar I disorder in June 2013. It received regulatory approval in the United Kingdom in September 2014. In October 2014, NHS Scotland advised use of lurasidone for schizophrenic adults who have not seen improvements with previous antipsychotics due to problems that arise from weight gain or changes in metabolic pathways when taking other medications. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for it in January 2014, and it was approved for medical use by the EMA in March 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on 15 October 2012. European Commission has granted a marketing authorization for once-daily oral lurasidone for the treatment of schizophrenia in adults. It is approved for use in the EU.

Generic versions of lurasidone were approved for use in the United States in January 2019 and became available in 2023.

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What is Dopamine Supersensitivity Psychosis?

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Introduction

Dopamine supersensitivity psychosis is a hypothesis that attempts to explain the phenomenon in which psychosis (e.g. having hallucinations, which can mean hearing or seeing things that other people do not see or hear) occurs despite treatment with escalating doses of antipsychotics. Dopamine supersensitivity may be caused by the dopamine receptor D2 antagonising effect of antipsychotics, causing a compensatory increase in D2 receptors within the brain that sensitizes neurons to endogenous release of the neurotransmitter dopamine. Because psychosis is thought to be mediated—at least in part—by the activity of dopamine at D2 receptors, the activity of dopamine in the presence of supersensitivity may paradoxically give rise to worsening psychotic symptoms despite antipsychotic treatment at a given dose. This phenomenon may co-occur with tardive dyskinesia, a rare movement disorder that may also be due to dopamine supersensitivity.

Brief History

When supersensitivity psychosis was explored in 1978, a featured concern was increasing resistance to medication, requiring higher doses or not responding to higher doses. Some articles use the term tardive psychosis to reference to this specific concept. However, articles have disputed its validity. The condition has been discovered in very few people. Palmstierna asserts that tardive psychosis is a combination of “several different and not necessarily correlated phenomena related to neuroleptic treatment of schizophrenia.”

Mechanism

Dopamine supersensitivity psychosis may occur due to upregulation of dopamine 2 receptors (D2). The D2 receptor is the primary target of almost all antipsychotics, which oppose the action of the neurotransmitter dopamine at this receptor. The antagonising or “blockade” of D2 by antipsychotics may cause neurons, a type of cell within the brain, to undergo compensatory changes to make up for the loss of activity at D2 receptors. The D2 signalling pathway within neurons is complex, and involves multiple enzymes and other secondary messengers. It may be the case that, in response to antipsychotics, neurons increase the production of D2 receptors (upregulation), thereby sensitizing the neuron to dopamine. However, this is likely an oversimplification, as—despite differences in sensitivity to dopamine of around 3-fold in people that have taken antipsychotics chronically, there is a disproportionately low increase in the amount of D2 receptors in the brain in these people (around 1.4-fold in the striatum of the brain in people with schizophrenia). Other hypotheses include increases in the “active” D2 receptors (termed D2High) relative to the “inactive” conformation (D2Low).

The result is dopamine supersensitivity. It is thought that the psychotic symptoms within schizophrenia are primarily due to overactive dopamine activity in the mesolimbic area of the brain. Therefore, dopamine supersensitivity may reduce the effect of antipsychotics and increase the brain’s response to endogenous dopamine, leading to worsening psychosis.

Tardive dyskinesia, a type of rare movement disorder that can be caused by antipsychotics, may also be caused by dopamine receptor sensitization. This may explain why, for people with tardive dyskinesia, increasing the dose of the antipsychotic may temporarily improve symptoms.

Diagnosis

The original criteria for dopamine supersensitivity psychosis were the following:

A. Continuous use of antipsychotics for at least 3 months.
B. One of the following:

  1. Rebound psychosis within 6 weeks of a change (e.g. dose reduction, or antipsychotic switching) in an oral antipsychotic regimen or 3 months for long-acting injectable antipsychotics
  2. Tolerance to antipsychotic effects (requiring escalating doses, even beyond what has controlled symptoms in the past)
  3. Presence of tardive dyskinesia (which should occur when antipsychotics are withdrawn, and improve or disappear when antipsychotics are restarted)

Differential Diagnosis

It may sometimes be impossible to distinguish dopamine supersensitivity psychosis from psychosis that occurs “naturally” in the course of a primary psychotic disorder like schizophrenia, including cases in which the person was not taking their antipsychotic medication. Even in the presence of an alternative aetiology, or when it is impossible to determine the precise aetiology for a psychotic episode, it is possible that dopamine supersensitivity psychosis can play a role in the presentation. Recognising the possible role of dopamine supersensitivity psychosis in a psychotic episode has implications for how to best manage someone’s antipsychotic therapy.

Society and Culture

Dopamine supersensitivity is often dismissed as an inconsequential factor in the progression of psychotic disorders by psychiatrists in the medical literature. The dopamine supersensitivity hypothesis was discussed by investigative journalist and author Robert Whitaker in his book Anatomy of an Epidemic, published in 2010.

Research

As of 2017, much of the evidence for dopamine supersensitivity psychosis comes from studies performed in animals. There is still a need for robust, human research.

In a cohort study of people taking chronic antipsychotic therapy with either schizophrenia or schizoaffective disorder that presented for psychiatric care due to a relapse of their psychotic symptoms without a clear precipitating cause (e.g. new or worsening substance abuse, evidence of nonadherence to antipsychotics), 39% of the sample met the authors’ checklist for dopamine supersensitivity psychosis. The people that met the criteria were more likely than others to have worse symptoms when their psychosis returned (relapsed), have residual psychotic symptoms, had overall worse health outcomes at 6-month follow-ups, and were more likely to live in residential care.

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

What is the Dopamine Hypothesis of Schizophrenia?

Published on by Andrew Marshall1 Comment

Introduction

The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction.

The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.

Refer to Glutamate Hypothesis of Schizophrenia.

Introduction

Some researchers have suggested that dopamine systems in the mesolimbic pathway may contribute to the ‘positive symptoms’ of schizophrenia, whereas problems concerning dopamine function within the mesocortical pathway may be responsible for the ‘negative symptoms’, such as avolition and alogia. Abnormal expression, thus distribution of the D2 receptor between these areas and the rest of the brain may also be implicated in schizophrenia, specifically in the acute phase. A relative excess of these receptors within the limbic system means Broca’s area, which can produce illogical language, has an abnormal connection to Wernicke’s area, which comprehends language but does not create it. Note that variation in distribution is observed within individuals, so abnormalities of this characteristic likely play a significant role in all psychological illnesses. Individual alterations are produced by differences within glutamatergic pathways within the limbic system, which are also implicated in other psychotic syndromes. Among the alterations of both synaptic and global structure, the most significant abnormalities are observed in the uncinate fasciculus and the cingulate cortex. The combination of these creates a profound dissymmetry of prefrontal inhibitory signaling, shifted positively towards the dominant side. Eventually, the cingulate gyrus becomes atrophied towards the anterior, due to long-term depression (LTD) and long-term potentiation (LTP) from the abnormally strong signals transversely across the brain. This, combined with a relative deficit in GABAergic input to Wernicke’s area, shifts the balance of bilateral communication across the corpus callosum posteriorly. Through this mechanism, hemispherical communication becomes highly shifted towards the left/dominant posterior. As such, spontaneous language from Broca’s can propagate through the limbic system to the tertiary auditory cortex. This retrograde signalling to the temporal lobes that results in the parietal lobes not recognising it as internal results in the auditory hallucinations typical of chronic schizophrenia.

In addition, significant cortical grey matter volume reductions are observed in this disorder. Specifically, the right hemisphere atrophies more, while both sides show a marked decrease in frontal and posterior volume. This indicates that abnormal synaptic plasticity occurs, where certain feedback loops become so potentiated, others receive little glutaminergic transmission. This is a direct result of the abnormal dopaminergic input to the striatum, thus (indirectly) disinhibition of thalamic activity. The excitatory nature of dopaminergic transmission means the glutamate hypothesis of schizophrenia is inextricably intertwined with this altered functioning. 5-HT also regulates monoamine neurotransmitters, including dopaminergic transmission. Specifically, the 5-HT2A receptor regulates cortical input to the basal ganglia and many typical and atypical antipsychotics are antagonists at this receptor. Several antipsychotics are also antagonists at the 5-HT2C receptor, leading to dopamine release in the structures where 5-HT2C is expressed; striatum, prefrontal cortex, nucleus accumbens, amygdala, hippocampus (all structures indicated in this disease), and currently thought to be a reason why antipsychotics with 5HT2C antagonistic properties improves negative symptoms. More research is needed to explain the exact nature of the altered chemical transmission in this disorder.

Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (PCP, Angel Dust), or excess steroids, or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D2 receptors in the high-affinity state for dopamine. This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical. Combined with less inhibitory signalling from the thalamus and other basal ganglic structures, from hyoptrophy the abnormal activation of the cingulate cortex, specifically around Broca’s and Wernicke’s areas, abnormal D2 agonism can facilitate the self-reinforcing, illogical patterns of language found in such patients. In schizophrenia, this feedback loop has progressed, which produced the widespread neural atrophy characteristic of this disease. Patients on neuroleptic or antipsychotic medication have significantly less atrophy within these crucial areas. As such, early medical intervention is crucial in preventing the advancement of these profound deficits in bilateral communication at the root of all psychotic disorders. Advanced, chronic schizophrenia can not respond even to clozapine, regarded as the most effective antipsychotic, as such, a cure for highly advanced schizophrenia is likely impossible through the use of any modern antipsychotics, so the value of early intervention cannot be stressed enough.

Discussion

Evidence for the Dopamine Hypothesis

Stimulants such as amphetamine, and cocaine increase the levels of dopamine in the brain and can cause symptoms of psychosis, particularly after large doses or prolonged use. This is often referred to as “amphetamine psychosis” or “cocaine psychosis,” but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. Similarly, those treated with dopamine enhancing levodopa for Parkinson’s disease can experience psychotic side effects mimicking the symptoms of schizophrenia. Up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate or amphetamine or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.

Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia. Since the 2000s, several PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.

A group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, has been found to antagonise dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. The link was strengthened by experiments in the 1970s which suggested that the binding affinity of antipsychotic drugs for D2 dopamine receptors seemed to be inversely proportional to their therapeutic dose. This correlation, suggesting that receptor binding is causally related to therapeutic potency, was reported by two laboratories in 1976.

People with Schizophrenia appear to have a high rate of self-medication with nicotine; the therapeutic effect likely occurs through dopamine modulation by nicotinic acetylcholine receptors.

However, there was controversy and conflicting findings over whether post-mortem findings resulted from drug tolerance to chronic antipsychotic treatment. Compared to the success of post-mortem studies in finding profound changes of dopamine receptors, imaging studies using SPECT and PET methods in drug naïve patients have generally failed to find any difference in dopamine D2 receptor density compared to controls. Comparable findings in longitudinal studies show: ” Particular emphasis is given to methodological limitations in the existing literature, including lack of reliability data, clinical heterogeneity among studies, and inadequate study designs and statistic,” suggestions are made for improving future longitudinal neuroimaging studies of treatment effects in schizophrenia A recent review of imaging studies in schizophrenia shows confidence in the techniques, while discussing such operator error. In 2007 one report said, “During the last decade, results of brain imaging studies by use of PET and SPECT in schizophrenic patients showed a clear dysregulation of the dopaminergic system.”

Recent findings from meta-analyses suggest that there may be a small elevation in dopamine D2 receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful. While the review by Laruelle acknowledged more sites were found using methylspiperone, it discussed the theoretical reasons behind such an increase (including the monomer-dimer equilibrium) and called for more work to be done to ‘characterise’ the differences. In addition, newer antipsychotic medication (called atypical antipsychotic medication) can be as potent as older medication (called typical antipsychotic medication) while also affecting serotonin function and having somewhat less of a dopamine blocking effect. In addition, dopamine pathway dysfunction has not been reliably shown to correlate with symptom onset or severity. HVA levels correlate trendwise to symptoms severity. During the application of debrisoquin, this correlation becomes significant.

Giving a more precise explanation of this discrepancy in D2 receptor has been attempted by a significant minority. Radioligand imaging measurements involve the monomer and dimer ratio, and the ‘cooperativity’ model. Cooperativitiy is a chemical function in the study of enzymes. Dopamine receptors interact with their own kind, or other receptors to form higher order receptors such as dimers, via the mechanism of cooperativity. Philip Seeman has said: “In schizophrenia, therefore, the density of [11C] methylspiperone sites rises, reflecting an increase in monomers, while the density of [11C] raclopride sites remains the same, indicating that the total population of D2 monomers and dimers does not change.” (In another place Seeman has said methylspiperone possibly binds with dimers) With this difference in measurement technique in mind, the above-mentioned meta-analysis uses results from 10 different ligands. Exaggerated ligand binding results such as SDZ GLC 756 (as used in the figure) were explained by reference to this monomer-dimer equilibrium.

According to Seeman, “…Numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia”. However, the authors were concerned the effect of medication may not have been fully accounted for. The study introduced an experiment by Anissa Abi-Dargham et al. (2000) in which it was shown medication-free live people with schizophrenia had more D2 receptors involved in the schizophrenic process and more dopamine. Since then another study has shown such elevated percentages in D2 receptors is brain-wide (using a different ligand, which did not need dopamine depletion). In a 2009 study, Abi-Dargham et al. confirmed the findings of her previous study regarding increased baseline D2 receptors in people with schizophrenia and showing a correlation between this magnitude and the result of amphetamine stimulation experiments.

Some animal models of psychosis are similar to those for addiction – displaying increased locomotor activity. For those female animals with previous sexual experience, amphetamine stimulation happens faster than for virgins. There is no study on male equivalent because the studies are meant to explain why females experience addiction earlier than males.

Even in 1986 the effect of antipsychotics on receptor measurement was controversial. An article in Science sought to clarify whether the increase was solely due to medication by using drug-naive people with schizophrenia: “The finding that D2 dopamine receptors are substantially increased in schizophrenic patients who have never been treated with neuroleptic drugs raises the possibility that dopamine receptors are involved in the schizophrenic disease process itself. Alternatively, the increased D2 receptor number may reflect presynaptic factors such as increased endogenous dopamine levels (16). In either case, our findings support the hypothesis that dopamine receptor abnormalities are present in untreated schizophrenic patients.” (The experiment used 3-N-[11C]methylspiperone – the same as mentioned by Seeman detects D2 monomers and binding was double that of controls.)

It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypostimulation of D1 receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and underactivity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them. Increased dopamine sensitivity may be a common final pathway. Gründer and Cumming assert that of those living with schizophrenia and other dopaminergic related illnesses, up to 25% of these patients may appear to have dopaminergic markers within the normal range.

Another finding is a six-fold excess of binding sites insensitive to the testing agent, raclopride; Seeman said this increase was probably due to the increase in D2 monomers. Such an increase in monomers may occur via the cooperativity mechanism which is responsible for D2High and D2Low, the supersensitive and lowsensitivity states of the D2 dopamine receptor. More specifically, “an increase in monomers, may be one basis for dopamine supersensitivity”.

Genetic and Other Biopsychosocial Risk Factors

Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Advanced technology has led to the possibility of performing Genome-Wide Association (GWA) studies. These studies identify frequently seen single nucleotide polymorphisms (SNP) that are associated with common, yet complex disorders. Genetic variants found due to GWA studies may offer insight concerning impairments in dopaminergic function. Dopamine-related genes linked to psychosis in this way include COMT, DRD4, and AKT1.

While genetics play an important role in the occurrence of schizophrenia, other biopsychosocial factors must also be taken into consideration. While focusing on the risk of schizophrenia in second generation migrants, Hennsler and colleagues relay that the dopamine hypothesis of schizophrenia may be an explanation. Some migrants who have had adverse experiences in their host country, such as racism, xenophobia, and poor living conditions, were found to have high stress levels, which increased dopaminergic neurotransmission. This increase in dopaminergic neurotransmission can be seen in the striatum and amygdala, both of which are areas in the brain that process aversive stimuli.

Evidence Against the Dopamine Hypothesis

Further experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D2 receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D2 occupancy of 60-70%. The antipsychotic aripiprazole occupies over 90% of D2 receptors, but this drug is both an agonist and an antagonist at D2 receptors.

Furthermore, although dopamine-inhibiting medications modify dopamine levels within minutes, the associated improvement in patient symptoms is usually not visible for at least several days, suggesting that dopamine may be indirectly responsible for the illness.

Similarly, the second generation of antipsychotic drugs – the atypical antipsychotics – were found to be just as effective as older typical antipsychotics in controlling psychosis, but more effective in controlling the negative symptoms, despite the fact that they have lower affinity for dopamine receptors than for various other neurotransmitter receptors. More recent work, however, has shown that atypical antipsychotic drugs such as clozapine and quetiapine bind and unbind rapidly and repeatedly to the dopamine D2 receptor. All of these drugs exhibit inverse agonistic effects at the 5-HT2A/2C receptors, meaning serotonin abnormalities are also involved in the complex constellation of neurologic factors predisposing one to the self reinforcing language-based psychological deficits found in all forms of psychosis.

The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine (also known as PCP or “Angel Dust”) and ketamine, both of which block glutamate (NMDA) receptors, are known to cause psychosis at least somewhat resembling schizophrenia, further suggesting that psychosis and perhaps schizophrenia cannot fully be explained in terms of dopamine function, but may also involve other neurotransmitters.

Similarly, there is now evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in grey matter density in the frontal and temporal lobes. It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions. Many argue that other theories concerning the cause of schizophrenia may be more reliable in some cases, such as the glutamate hypothesis, GABA hypothesis, dysconnection hypothesis, and Bayesian inference hypothesis.

Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as a deliberate and calculated simplification for the benefit of drug marketing.

Relationship with Glutamate

Research has shown the importance of glutamate receptors, specifically N-methyl-D-aspartate receptors (NMDARs), in addition to dopamine in the aetiology of schizophrenia. Abnormal NMDAR transmission may alter communication between cortical regions and the striatum. Mice with only 5% of the normal levels of NMDAR’s expressed schizophrenic-like behaviours seen in animal models of schizophrenia while mice with 100% of NMDAR’s behaved normally. Schizophrenic behaviour in low NMDAR mice has been effectively treated with antipsychotics that lower dopamine. NMDAR’s and dopamine receptors in the prefrontal cortex are associated with the cognitive impairments and working memory deficits commonly seen in schizophrenia. Rats that have been given a NMDAR antagonist exhibit a significant decrease in performance on cognitive tasks. Rats given a dopamine antagonist (antipsychotic) experience a reversal of the negative effects of the NMDAR antagonist. Glutamate imbalances appear to cause abnormal functioning in dopamine. When levels of glutamate are low dopamine is overactive and results in the expression schizophrenic symptoms.

Combined Networks of Dopamine, Serotonin, and Glutamate

Psychopharmacologist Stephen M. Stahl suggested in a review of 2018 that in many cases of psychosis, including schizophrenia, three interconnected networks based on dopamine, serotonin, and glutamate – each on its own or in various combinations – contributed to an overexcitation of dopamine D2 receptors in the ventral striatum.

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

What is Amisulpride?

Published on by Andrew Marshall3 Comments

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?

Published on by Andrew Marshall2 Comments

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 Marshall11 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?

Published on by Andrew Marshall2 Comments

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.

Refer to Perphenazine Enanthate.

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.