NS 09-28-16 08AM Antipsychotic Drugs French[NS 09-28-16 8am - French]

Pharmacologic Properties of Antipsychotic Drugs I. Neuroanatomical Substrates of Schizophrenia

The biologic basis of schizophrenia is postulated to derive from dysfunction in a number of brain neurotransmitter systems, chief among them being dopamine, serotonin, glutamate. The normal functions of these neurotransmitter pathways as well as abnormalities seen in schizophrenia and the purported therapeutic effects of anti-psychotic drugs are discussed below.

A. Dopamine

Dopamine Hypothesis of Schizophrenia. The most developed of several hypotheses for schizophrenia and has had moderate success in explanation of disease although it is considered to no longer be adequate to explain all aspects of the disease, especially the cognitive impairment. It provided the basis for much of the early rationale for antipsychotic therapy.

The hypothesis states that the abnormality in brain function in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in mesolimbic pathway

Support for this hypothesis comes from several lines of circumstantial evidence: Virtually all effective antipsychotics block CNS dopamine receptors (postsynaptic D2) Drugs that increase dopaminergic activity (levodopa, dopamine precursor; cocaine-

amphetamine, dopamine releaser) can aggravate or produce de novo schizophrenia Postmortem and in vivo imaging studies have found increased dopamine receptor densities and

other measures consistent with increased striatal dopamine synthesis and release Limitations to the dopamine hypothesis include these observations:

Postmortem and in vivo imaging studies show diminished DA activity in cortical and hippocampal regions that may underlie negative symptoms and cognitive impairment

Clozapine is weak D2 blocker but still is an effective antipsychotic agent Evidence exists for role of serotonin (5-HT) and glutamate neurotransmitter systems (via

modulation of dopamine neurotransmission [?]) Brain Dopamine Pathways

1) Mesolimbic pathway . Limbic structures are thought to subserve the integration of sensory input and motor responses with affective or emotional data . Hyperactivity in this pathway is believed to contribute to the occurrence of positive symptoms. Antipsychotic agents (via D2 dopamine receptor blockade) are most effective in reducing these

positive symptoms - delusions, hallucinations, and disordered cognition

1: Mesolimbic2: Mesocortical3: Nigrostriatal4: Tuberoinfindibular

NS 09-28-16 08AM Antipsychotic Drugs French2) Mesocortical pathway . Cortical structures (dorsolateral prefrontal cortex and ventromedial prefrontal

cortex) are involved in communication and social abilities . It is believed that hypoactivity due to cell loss in the prefrontal cortex contributes to presence of negative symptoms (poverty of speech, anhedonia, lack of motivation, social isolation). These negative symptoms generally respond poorly to conventional antipsychotics (due to block of

D2 dopamine receptors), but often respond well to the atypical antipsychotic agents such as clozapine or olanzapine (via additional block of 5HT2A receptors)

3) Nigrostriatal pathway . This dopaminergic tract is part of a larger subcortical circuit known as the basal ganglia (historically described as the extrapyramidal tract, a term in use today to describe antipsychotic drug side effects). It plays a central role in planned, coordinated movement. Loss of dopamine in this region results in dysregulation of movement (Parkinson’s disease hypoactivity, bradykinesia, and tremor). Antipsychotic drug use (via D2 dopamine receptor blockade) can result in unwanted

extrapyramidal side effects4) Tuberoinfundibular pathway . Hypothalamic neurons release DA in pituitary to inhibit prolactin

release. Antipsychotic drug use (via D2 dopamine receptor blockade) can cause side effects of

hyperprolactinemia as well as interference with regulation of body temperature (poikilothermia) and alteration of eating behavior (weight gain)

B. Serotonin

Serotonin Role. Evolved from discovery that indoleamine hallucinogens (mescaline – LSD) act in CNS as serotonin agonists. Subsequent identification of multiple serotonin receptor subtypes led to finding that activation of 5HT2A receptors was the basis for the hallucinatory effects.

Brain Serotonin Pathways. Projections from brainstem nuclei to prefrontal cortical areas, limbic region, and striatum have important modulatory actions on dopamine and glutamate neurons

The 5HT2A subtype is located on glutamate pyramidal neurons in cortical regions and on dopamine nerve terminals in striatal and cortical pathways.

Activation of 5HT2A receptors on DA neurons in the PFC decrease DA release negative symptoms

Activation of 5HT2A receptors on glutamate pyramidal cells in the PFC (not shown here) result in stimulation of DA neurons in VTA increase DA release in the mesolimbic pathway positive symptoms

Therapeutic utility of an antagonist of both 5HT2A and D2 receptors in schizophrenia is obvious: an improvement in both positive and negative symptoms

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NS 09-28-16 08AM Antipsychotic Drugs FrenchC. Glutamate

Glutamate Hypothesis

Evolved from observations that antagonists of the NMDA receptor-ion channel, phencyclidine (PCP) and ketamine, exacerbated both psychosis and cognitive impairment in schizophrenic patients

Hypothesis states hypofunction of NMDA receptors located on GABAergic interneurons in the PFC leads to diminished inhibitory influences that affect both mesolimbic and mesocortical dopamine pathways giving rise to both positive and negative symptoms.

Brain Glutamate PathwaysC ortical – Brainstem VTA [increased cortical output increased mesolimbic DA release]

Cortical glutamate neurons to VTA directly innervate and stimulate the mesolimbic DA neurons. Activation of the cortical glutamate neurons leads to activation of mesolimbic DA neurons. NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output.

Hypofunction in these cortical NMDA-Glu neurons can result in loss of cortical GABA inhibition and increased activity of cortical glutamate neurons resulting in hyper activity in the mesolimbic pathway and positive symptoms of schizophrenia.

Cortical - Brainstem VTA [increased cortical output decreased mesocortical DA release]

A different population of cortical glutamate neurons regulate mesocortical DA release indirectly via GABA interneurons in VTA that innervate the mesocortical DA neurons selectively. Activation of the cortical glutamate neurons leads first to activation of the VTA GABA interneurons, then inhibition of mesocortical DA neurons. Again, NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output.

Hypofunction in these cortical NMDA-Glu neurons can result in loss of cortical GABA inhibition and increased activity of cortical glutamate neurons resulting in hypo activity in the mesocortical pathway and negative symptoms of schizophrenia.

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NS 09-28-16 08AM Antipsychotic Drugs FrenchII. Pharmacology of Antipsychotic Agents

A. Targets for Antipsychotic Agents. Effects are attributable to blocking actions at a remarkable number of receptors including: dopaminergic (D2 - D4), alpha-adrenergic (α1), muscarinic cholinergic (M), histaminergic (H1), and serotonin (5HT2) receptors.

Relative Receptor Blocking Activity of Antipsychotic Drugs

Dopaminergic Systems and Serotoninergic Systems. Most relevant for targets of current antipsychotic agents.

KEY POINT: Consistent with the dopamine theory of schizophrenia, blockade of dopamine D2 receptors explains the most significant pharmacologic effects of antipsychotic agents.

BUT efficacy has been found in antipsychotic agents that block 5HT 2 receptors without possessing potent blockade of D2 receptors (thus reduced extrapyramidal side effects).

Other Neuronal Systems. All effective agents block dopamine D2 receptors, but the degree of D2

receptor blockade in relation to blockade of other receptors varies considerably among agents. Several other neurotransmitter systems, particularly norepinephrine, acetylcholine (nicotinic

cholinergic) and glutamate, interact strongly with dopamine pathways and may be important in relation to antipsychotic drug action and/or the etiology of schizophrenia.

On the other hand, block of muscarinic, α1 adrenergic, or histamine H1 receptors may explain some adverse effects of antipsychotic agents.

B. Classification of Antipsychotic Agents. Structure related to antipsychotic potency and side effects. Main categories of antipsychotic agents are typical (1st generation) and atypical (2nd generation).

The distinction between the two classes at the molecular level appears to primarily depend on the ratio of D2 to 5HT2A blocking activity. This molecular distinction is then associated with a number of important differences at the clinical level.

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NS 09-28-16 08AM Antipsychotic Drugs French Typical agents are characterized by a high D2 / 5HT2A ratio corresponding to good D2 block and good

efficacy against positive symptoms of schizophrenia. But this good D2 block is also associated with a high incidence of extrapyramidal toxicity.

Within the class of typical agents are those with high clinical potency (haloperidol-effective in lower doses) because of greater D2 blocking activity that then display an even greater risk of extrapyramidal toxicity.

Typical agents with low clinical potency (chlorpromazine-effective in higher doses) do not block D2 receptors as well and have relatively less extrapyramidal toxicity. BUT, the larger doses that are necessary for comparable antipsychotic efficacy produce side effects at other receptors (antimuscarinic [dry mouth, sedation], α1-blockade [hypotension], antihistamine [sedation])

Atypical agents are characterized by a low D2 / 5HT2A ratio corresponding to poor D2 block yet good efficacy in schizophrenia (an “atypical” observation). The good 5HT2A block is thought to be associated with good efficacy against negative symptoms of schizophrenia as well as efficacy in treatment-resistant individuals.

Typical Agents Atypical Agents Chlorpromazine Aripiprazole (Abilify®) Olanzapine (Zyprexa®)Fluphenazine Asenapine (Saphris®) Paliperidone (Invega®)Haloperidol (Haldol®) Clozapine (Clozaril®) Quetiapine (Seroquel®)Thioridazine Iloperidone (Fanapt®) Risperidone (Risperdal®)Thiothixene Lurasidone (Latuda®) Ziprasidone (Geodon®)

SUMMARY: Relationship of Class to Clinical Potency and Toxicity

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NS 09-28-16 08AM Antipsychotic Drugs FrenchC. Side Effects [see appendix for further detail on individual agents]

Autonomic nervous system (high with chlorpromazine): Dry mouth / tachycardia / loss of accommodation / difficulty urinating / constipation (due to

muscarinic blockade) Orthostatic hypotension / impotence (due to α1-adrenergic blockade)

Sedation: Via antimuscarinic and antihistaminic activity in CNS (high with chlorpromazine) Cardiovascular: EKG abnormalities, QT interval arrhythmias (high with ziprasidone) Extrapyramidal symptoms (dopaminergic blockade) (high with haloperidol).

Acute dystonia (onset 1-5 d): Torticollis, swollen tongue, trismus, oculogyric crisis, opisthotonos. Treatment: Antimuscarinic agents (diphenhydramine, benztropine).

Akathisia (onset 6-60 d): Motor restlessness, inability to sit still (not anxiety or agitation). Treatment (difficult): Reduce dose or change drug; add anticholinergic and / or possibly β-blocker, benzodiazepines.

Pseudoparkinsonism (onset 5-90 d): Tremor, bradykinesia, rigidity, shuffling gait. Treatment: Anticholinergic agents or amantadine (dopamine agonist).

Tardive dyskinesias (onset 3-6 months, [?] supersensitivity of dopamine receptors): Involuntary repetitive movement of lips, tongue, choreoathetoid movements of arms, legs. Worsens upon withdrawal of antipsychotic drug. Common in elderly women; usually irreversible; overall 20-40% incidence with chronic treatment. Treatment: Rarely effective, so must weigh benefit-risk ratio for use; best strategy is prevention.

Other effects Agranulocytosis with clozapine (leading to restricted use); also hypersalivation Weight gain (Type 2 diabetes possible, esp. with newer atypical agents; need to monitor

weight, blood pressure, glucose, lipids), altered thermoregulation (poikilothermia), galactorrhea. Results from block of hypothalamic DA receptors.

Photosensitivity (advise use of sun screens), allergic reactions Lowered seizure threshold Retinopathy with thioridazine Neuroleptic malignant syndrome (catatonia, stupor, fever, unstable blood pressure). Rare, but

potentially fatal. Treat with sodium dantrolene [Dantrium].

D. Pharmacokinetics. As a class, all antipsychotics are handled by the body in a similar fashion. Absorption. Most are incompletely absorbed (inter- and intrapatient variation can be reduced with use

of liquid formulations). Many have significant first pass effect. Route and formulations : Influence onset of action and duration of action

o Oral immediate-release tabs-caps available for all agents and suitable for most chronic dosing situations (1-3 times a day). Orally disintegrating tablets (can be taken without fluids) for olanzapine, risperidone, and clozapine.

o IM solutions available for rapid treatment of acute psychotic agitation or when patient can’t take oral meds (chlorpromazine, haloperidol, olanzapine, aripiprazole). IV administration is generally not advisable.

o IM depot suspensions can be used to improve adherence to maintenance therapy (q 2-3-4 weeks). Long-acting formulations for haloperidol and chlorpromazine as well as for more costly 2nd generation agents (risperidone and olanzapine).

Distribution. Most are extensively protein bound in plasma (85%). High lipid solubility (concentrated in lipid-rich tissues, including CNS) extends clinical t1/2 beyond plasma t1/2. Brain levels may exceed plasma levels; will cross the placenta to exert effects in the fetus.

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NS 09-28-16 08AM Antipsychotic Drugs French Metabolism / Excretion. Little excretion of unchanged drug via kidney, almost completely

metabolized to more polar substances (oxidized by P450 system [phase I], then conjugated). Can be excreted in breast milk.

III. Clinical Pharmacology

A. Drug Choice and Dosing Considerations Choice of antipsychotic agent based mainly on differences in adverse effects and possible differences in

efficacy. Note that use of older drugs is still widespread, especially in the public sector, so knowledge of agents like chlorpromazine and haloperidol is still relevant. Their lower cost contributes to this use, despite risk of EPS effects.

Majority of patients with schizophrenia and bipolar disorders with psychotic features will have equal control of positive symptoms with either typical or atypical agents. Atypical agents preferred for patients with negative symptoms and cognition deficits and to decrease risk of EPSE symptoms.

Within a class, the overall efficacy is probably similar, but patients may respond to one drug and not another. If a relative has been treated successfully, it is possible that patient would respond similarly to same agent (symptom control, side effects, dose).

Gradual response expected from several weeks until several months (2-3 weeks for positive response, 6 weeks to 6 months for maximum benefit). Larger-than-usual doses are sometimes required with the dose dictated by severity of symptoms (higher during acute episode). Natural course fluctuates; no time limit for duration, non-compliance is common cause of relapse.

Clozapine is effective in majority of schizophrenic patients that are refractory to other drugs. It should be reserved for this specific indication because of frequency of substantial increases in weight and lipids as well as a 1-2 % incidence of agranulocytosis. High dose olanzapine may also be effective in these patients, but it also associated with weight gain and development of diabetes.

Managing side effects of atypical agents. Weight gain and metabolic effects : Highest with olanzapine, clozapine, quetiapine; minimal

with aripiprazole, lurasidone Extrapyramidal symptoms : Highest with risperidone-paliperidone; lower with quetiapine,

iloperidone. Sedation : Minimal with aripiprazole, risperidone; use quetiapine or olanzapine for patients

with insomnia or agitation. QT prolongation : Greatest potential with ziprasidone; least with aripiprazole

B. Psychiatric Uses Schizophrenia (primary indication) Schizoaffective disorders Manic episode in bipolar affective disorder Tourette syndrome Treatment-resistant depression

C. Nonpsychiatric Uses: Strong antiemetic action (block of DA receptors in chemoreceptor trigger zone) [prochlorperazine

(Compazine)] Relief of pruritus / preoperative sedative (H1 blocking effect) [promethazine (Phenergan)] Treatment of intractable hiccoughs [chlorpromazine]

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Summary: Clinical Aspects of Some Representative Antipsychotic Drugs

References 1. Molecular Pharmacology, 3rd Ed. (2015), Nestler, Hyman, & Malenka, McGraw-Hill, N.Y., Chapter 17.2. Basic and Clinical Pharmacology, 13th Ed. (2014), Katzung, ed.; McGraw-Hill, New York, NY, Chapter 29.3. Stahl’s Essential Psychopharmacology, 3rd Ed. (2013), Stahl, Cambridge University Press, New York, N.Y., Chapters 4-5.

Tom French, Ph.D.Fall 2016

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