Neurological disease

Migraine

Migraine is a complex condition, but it is characterised as a moderate to severe, pulsating headache that is typically unilateral, and is often accompanied by nausea and disturbed vision (aura). Migraines can last from two hours to several days. Associated symptoms can include nausea and vomiting, as well as sensitivities to light, sound or smell.

Medical intervention is indicated when the migraines become frequent and/or are severe.

Treatments for acute migraine

Simple analgesics including aspirin, paracetamol and NSAIDs may provide symptomatic relief. Concomitant anti-emetic treatment (e.g. metoclopramide or domperidone, or phenothiazine and antihistamine antiemetics) may be beneficial.

If analgesics are ineffective, acute attacks can be treated with 5HT1-receptor agonists (triptans). The triptans available to treat acute migraine include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. 5HT1-receptor agonists can be co-administered with a NSAID such as naproxen in patients with prolonged and recurrent attacks.

Historically ergot alkaloids such as ergotamine were used to treat migraine, but since efficacy is limited (by difficulties in absorption and adverse side-effects) their use is best avoided.

Migraine prophylaxis

For patients experiencing frequent attacks, identifying and reducing potential provoking factors (such as stress, lack of sleep, or chemical triggers including alcohol and nitrates) can be beneficial.

Preventative treatments should be considered for patients who:

  • experience >2 attacks per month
  • experience increasing attack frequency
  • experience significant resistance to prescribed treatments
  • are intolerant to suitable anti-migraine treatments
  • suffer from rare migraine subtypes or are at risk of migrainous infarction.

In these patients groups beta-blockers (propranolol, atenolol, metoprolol, nadolol, and timolol) can be effective. Tricyclic antidepressants, topiramate, valproic acid, and gabapentin show some efficacy, but use of these drugs as migraine prophylactics is unlicensed. Botulinum toxin type A is licensed for the prophylaxis of headaches in adults with chronic migraine.

Novel mechanistic approach to migraine prophylaxis

A recent advance in migraine prophylaxis saw the FDA approval (in May 2018) of the first-in-class biologic drug erenumab (Aimovig).  Erenumab acts as a functional calcitonin receptor-like receptor (CGRPR) antagonist, by selectively blocking binding of endogenous calcitonin-related polypeptide (CGRP) to its receptor complex and arresting downstream signalling. CGRP is a neuropeptide that is involved in migraine pathophysiology (Hansen et al., 2010), and the receptor-ligand pathway has been validated as a novel mechanistic target for drug discovery as a migraine prevention strategy by erenumab's clinical approval (Edvinsson et al., 2018; Edvinsson, 2018). As a result of the long serum half-life of monoclonal antibodies, erenumab need only be administered once-monthly. See Dodick et al. (2018) for detailed results from the Phase 3 ARISE clinical trial.

Epilepsy

These 40 slides focus on the drugs used to treat epilepsy (anti-epileptic drugs). The anti-epileptic drugs presented are classified according to their main molecular mechanism of action. Additionally, there is information presented for the indication for epilepsy type, principal side effects and a brief summary of the pharmacokinetics of the anti-epileptic drugs. These slides are intended for pharmacology, medical and/or pharmacy students at an intermediate level. Produced for the PEP by Stephen Kelley (University of Dundee, UK).

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These 27 slides correspond to the pathophysiology of seizures and epilepsy. In particular, the slides focus on the current and proposed classifications of the various types of epileptic seizures and epilepsies. The classifications provide useful information for clinicians, as seizure or epilepsy type can help determine which anti-epileptic drug should be used.  These slides are intended for pharmacology, medical and/or pharmacy students at an intermediate level. Produced for the PEP by Stephen Kelley (University of Dundee, UK).

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Schizophrenia

Schizophrenia is a disorder of the mind that is debilitating and chronic. The prevalence of this disorder is about 1% of the population and seems to affect all areas of the globe equally. It is not well understood what causes the disorder. Some combination of genetic and environmental factors contributes toward the development of this disease, which is characterized by an alteration of brain structure and chemistry mainly involved in dopamine and glutamate pathways.

Symptoms include hallucinations, delusions and disorganized thoughts and behaviors that cause an individual to withdraw socially and exhibit psychosis such that they are unable to differentiate the hallucinations and delusions from reality. As with most diseases, schizophrenia can range in severity. Some individuals exhibit mild symptoms and are able to live relatively normal lives while others exhibit severe symptoms requiring hospitalization and specialized care.

Symptom onset typically begins in early adulthood. Diagnosis is made based upon the symptoms exhibited instead of on lab tests. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) lists the criteria by which a schizophrenia diagnosis is made. DSM-5 lists both positive and negative symptoms of the disease, which are included below.

Positive Symptoms

  • Hallucinations – sensing things that are not real (hearing voices, seeing things)
  • Delusions – believing things that are not real (the doctor is poisoning me through my medications)
  • Disorganized thoughts/behaviors – incoherent speech, purposeless behavior, difficulty communicating thoughts (jumbling words together meaninglessly or stopping in the middle of a sentence)

Negative Symptoms

  • Loss of interest in everyday activities
  • Lack of emotion
  • Poor hygiene
  • Social withdrawal
  • Loss of motivation
  • Lack of speech

Schizophrenia is believed to be a disorder involving abnormalities in brain chemistry. Patients with schizophrenia have elevated dopamine levels within certain parts of their brain and also altered glutamate levels. The role of glutamate is not well understood, so treatment primarily involves blockade of dopamine receptors. Newer agents also block other receptors including serotonin, but as the pathophysiology of the disease is not fully understood, it is unclear how alteration of other neurotransmitter pathways exert therapeutic effects. Drugs are effective at treating positive symptoms of the disorder, but often are poor at treating the negative symptoms. If negative symptoms do respond to treatment, they typically take longer to correct compared with positive symptoms.

First Generation Antipsychotics (FGAs) such as chlorpromazine, thioridazine, perphenazine, thiothixene, and haloperidol work primarily by blocking dopamine (D2) receptors and also block serotonin (5-Hydroxytryptamine) receptors in the brain to a lesser extent. Most first generation antipsychotics carry a risk of extra-pyramidal symptoms (EPS), sedation, orthostatic hypotension, tachycardia and anticholinergic effects. Other side effects include weight gain and sexual dysfunction. In addition, thioridazine and haloperidol carry risks of QT prolongation.

Second Generation Antipsychotics (SGAs) such as clozapine and aripiprazole work by blocking D2 and serotonin receptors; however, some agents have additional mechanisms of action. Aripiprazole, brexpiprazole and cariprazine are D2 and serotonin 5-HT1A receptor partial agonists. Brexpiprazole also acts as a serotonin 5-HT2A antagonist. SGAs have multiple unwanted effects including metabolic side effects (hyperglycemia, weight gain and lipid abnormalities) and increased prolactin levels (risperidone and paliperidone) causing gynecomastia, irregular menstrual cycles, and sexual dysfunction. QT prolongation is a concern with ziprasidone, quetiapine and risperidone. Clozapine is one of the most effective agents for treatment resistant schizophrenia, but carries a host of black box warnings for seizures, agranulocytosis, myocarditis and metabolic abnormalities. As a result of clozapine’s side effects, absolute neutrophil count and white blood cell count must be monitored at baseline before initiation of the medication, periodically thereafter as long as the patient remains on therapy, and for 4 weeks after therapy is discontinued. SGAs typically have a lower risk of EPS compared to FGAs, but they can still occur, especially at higher doses.

Some antipsychotic agents carry an increased risk of cerebrovascular effects (e.g. stroke) when used to treat dementia-related psychosis in elderly patients. 

Schizophrenia/psychosis is a concern in patients with Parkinson’s disease because agents used to treat Parkinson’s disease typically increase dopamine levels. Almost half of patients with Parkinson’s disease will experience hallucinations or delusions at some point during their treatment. Treating psychosis in these patients can be difficult because antipsychotics that antagonize dopamine receptors can worsen movement disorders in these patients. As a result, quetiapine is typically used because it carries the least risk of EPS among all antipsychotics. Additionally, pimavanserin can be used in this patient population because it treats psychosis by altering serotonin levels and does not affect dopamine levels, minimizing the risk of EPS and disrupting Parkinson therapy.

Medication adherence is poor among schizophrenia patients. Delusions can lead these patients to believe that the medication prescribed is actually poison; medication side effects can be difficult to tolerate, and disorganized thought patterns can lead to the belief that the medication is unnecessary, causing patients to stop taking prescribed therapies. To aid with adherence, some medications are available in formulations aimed to improve medication adherence. Long acting depot injections are popular and are available for several FGAs and SGAs; effects last between 2 weeks and 3 months per injection. Also, orally disintegrating tablets are popular methods in improving adherence; these tablets dissolve as soon as they reach the mouth and prevent “cheeking” of medications (storing medication in the cheeks and spitting out when medical professionals exit the room).

Finally, antipsychotics, especially FGAs, cause a variety of EPS ranging from akathisia (restless movements of extremities accompanied by anxiety), parkinsonism and tardive dyskinesias (TD). Akathisia is treated utilizing central anticholinergics such as diphenhydramine. It can also be treated with propranolol. Parkinsonism looks like Parkinson’s disease with tremors, rigidity and abnormal gait. It is caused by imbalance of dopamine levels in the basal ganglia and can be treated with central-acting anticholinergics, and more importantly the fine titration of the antipsychotic drugs. TD involves abnormal involuntary movements of the tongue, lips, face, trunk or eyes. If TD develops, the FGA must be discontinued and replaced with an SGA with low EPS risk such as quetiapine or clozapine. TD can be irreversible and the risk of it becoming irreversible affects the duration of the treatment.  

Daniel Paul, Kelly Karpa

This is a 6-minute narrated, animated video describing the treatment of schizophrenia, including first and second generation antipsychotics. It is suitable for beginners.

Produced by the Khan Academy.

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Schizophrenia is a disorder of the mind that is debilitating and chronic. The prevalence of this disorder is about 1% of the population and seems to affect all areas of the globe equally. It is not well understood what causes the disorder. Some combination of genetic and environmental factors contributes toward the development of this disease, which is characterized by an alteration of brain structure and chemistry mainly involved in dopamine and glutamate pathways.

Symptoms include hallucinations, delusions and disorganized thoughts and behaviors that cause an individual to withdraw socially and exhibit psychosis such that they are unable to differentiate the hallucinations and delusions from reality. As with most diseases, schizophrenia can range in severity. Some individuals exhibit mild symptoms and are able to live relatively normal lives while others exhibit severe symptoms requiring hospitalization and specialized care.

Symptom onset typically begins in early adulthood. Diagnosis is made based upon the symptoms exhibited instead of on lab tests. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) lists the criteria by which a schizophrenia diagnosis is made. DSM-5 lists both positive and negative symptoms of the disease, which are included below.

Positive Symptoms

  • Hallucinations – sensing things that are not real (hearing voices, seeing things)
  • Delusions – believing things that are not real (the doctor is poisoning me through my medications)
  • Disorganized thoughts/behaviors – incoherent speech, purposeless behavior, difficulty communicating thoughts (jumbling words together meaninglessly or stopping in the middle of a sentence)

Negative Symptoms

  • Loss of interest in everyday activities
  • Lack of emotion
  • Poor hygiene
  • Social withdrawal
  • Loss of motivation
  • Lack of speech

Schizophrenia is believed to be a disorder involving abnormalities in brain chemistry. Patients with schizophrenia have elevated dopamine levels within certain parts of their brain and also altered glutamate levels. The role of glutamate is not well understood, so treatment primarily involves blockade of dopamine receptors. Newer agents also block other receptors including serotonin, but as the pathophysiology of the disease is not fully understood, it is unclear how alteration of other neurotransmitter pathways exert therapeutic effects. Drugs are effective at treating positive symptoms of the disorder, but often are poor at treating the negative symptoms. If negative symptoms do respond to treatment, they typically take longer to correct compared with positive symptoms.

First Generation Antipsychotics (FGAs) such as chlorpromazine, thioridazine, perphenazine, thiothixene, and haloperidol work primarily by blocking dopamine (D2) receptors and also block serotonin (5-Hydroxytryptamine) receptors in the brain to a lesser extent. Most first generation antipsychotics carry a risk of extra-pyramidal symptoms (EPS), sedation, orthostatic hypotension, tachycardia and anticholinergic effects. Other side effects include weight gain and sexual dysfunction. In addition, thioridazine and haloperidol carry risks of QT prolongation.

Second Generation Antipsychotics (SGAs) such as clozapine and aripiprazole work by blocking D2 and serotonin receptors; however, some agents have additional mechanisms of action. Aripiprazole, brexpiprazole and cariprazine are D2 and serotonin 5-HT1A receptor partial agonists. Brexpiprazole also acts as a serotonin 5-HT2A antagonist. SGAs have multiple unwanted effects including metabolic side effects (hyperglycemia, weight gain and lipid abnormalities) and increased prolactin levels (risperidone and paliperidone) causing gynecomastia, irregular menstrual cycles, and sexual dysfunction. QT prolongation is a concern with ziprasidone, quetiapine and risperidone. Clozapine is one of the most effective agents for treatment resistant schizophrenia, but carries a host of black box warnings for seizures, agranulocytosis, myocarditis and metabolic abnormalities. As a result of clozapine’s side effects, absolute neutrophil count and white blood cell count must be monitored at baseline before initiation of the medication, periodically thereafter as long as the patient remains on therapy, and for 4 weeks after therapy is discontinued. SGAs typically have a lower risk of EPS compared to FGAs, but they can still occur, especially at higher doses.

Some antipsychotic agents carry an increased risk of cerebrovascular effects (e.g. stroke) when used to treat dementia-related psychosis in elderly patients. 

Schizophrenia/psychosis is a concern in patients with Parkinson’s disease because agents used to treat Parkinson’s disease typically increase dopamine levels. Almost half of patients with Parkinson’s disease will experience hallucinations or delusions at some point during their treatment. Treating psychosis in these patients can be difficult because antipsychotics that antagonize dopamine receptors can worsen movement disorders in these patients. As a result, quetiapine is typically used because it carries the least risk of EPS among all antipsychotics. Additionally, pimavanserin can be used in this patient population because it treats psychosis by altering serotonin levels and does not affect dopamine levels, minimizing the risk of EPS and disrupting Parkinson therapy.

Medication adherence is poor among schizophrenia patients. Delusions can lead these patients to believe that the medication prescribed is actually poison; medication side effects can be difficult to tolerate, and disorganized thought patterns can lead to the belief that the medication is unnecessary, causing patients to stop taking prescribed therapies. To aid with adherence, some medications are available in formulations aimed to improve medication adherence. Long acting depot injections are popular and are available for several FGAs and SGAs; effects last between 2 weeks and 3 months per injection. Also, orally disintegrating tablets are popular methods in improving adherence; these tablets dissolve as soon as they reach the mouth and prevent “cheeking” of medications (storing medication in the cheeks and spitting out when medical professionals exit the room).

Finally, antipsychotics, especially FGAs, cause a variety of EPS ranging from akathisia (restless movements of extremities accompanied by anxiety), parkinsonism and tardive dyskinesias (TD). Akathisia is treated utilizing central anticholinergics such as diphenhydramine. It can also be treated with propranolol. Parkinsonism looks like Parkinson’s disease with tremors, rigidity and abnormal gait. It is caused by imbalance of dopamine levels in the basal ganglia and can be treated with central-acting anticholinergics, and more importantly the fine titration of the antipsychotic drugs. TD involves abnormal involuntary movements of the tongue, lips, face, trunk or eyes. If TD develops, the FGA must be discontinued and replaced with an SGA with low EPS risk such as quetiapine or clozapine. TD can be irreversible and the risk of it becoming irreversible affects the duration of the treatment.  

Daniel Paul, Kelly Karpa

This summary, created by the National Institute of Mental Health, provides a written overview of schizophrenia, detailing its signs and symptoms, risk factors and treatments. It is suitable for beginners.

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