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CHAPTER 161

AntipsychoticsMary A. Wittler and Eric J. Lavonas

PERSPECTIVE

The first antipsychotic, chlorpromazine, was used for the treat-ment of psychosis in France in 1951 and in the United States in 1954. Antipsychotic use has expanded significantly since then. The historic term neuroleptic, used with antipsychotic medication, is no longer appropriate because newer agents cause less sedation. The term antipsychotic is now preferred. In 2009, U.S. poison control centers reported more than 4700 exposures to phenothi-azines and 43,000 exposures to atypical antipsychotics, resulting in 0 and 8 deaths, respectively.1

PRINCIPLES OF DISEASE

Antipsychotic medications are used to treat agitation and psycho-sis caused by schizophrenia, mania, acute idiopathic psychosis, substance-induced psychosis, and dementia. The antipsychotic medications are divided into three broad categories on the basis of their receptor profiles, clinical effects, and adverse effects (Table 161-1). All antipsychotic medications effectively treat the positive symptoms of psychotic disorders; they reduce hallucinations, control agitation, and aid in restructuring of disordered thinking. In general, the low-potency first-generation antipsychotics (FGAs) are the most sedating. Movement disorders, including extrapyra-midal symptoms (EPS) and tardive dyskinesia (TD), are signifi-cant problems with both low-potency and high-potency FGAs. In addition to producing less sedation and fewer movement disor-ders, the atypical or second-generation antipsychotics (SGAs) assist with the negative symptoms of psychotic disorders, such as flat affect, avolition, social withdrawal, and impoverished thought and speech.2 Although neuroleptic malignant syndrome (NMS) occurs with all agents, it occurs least with SGAs.

Anatomy and Physiology

Antipsychotic drugs block dopamine receptors in several areas of the brain, including the cerebral cortex, basal ganglia, limbic system, hypothalamus, and chemoreceptor trigger zone. All anti-psychotic agents reduce the positive symptoms of schizophrenia by blocking the dopamine D2 receptor subtype in the mesolimbic region of the brain. However, blockade of D2 receptors in the nigrostriatal brain region produces undesired EPS. In addition, blockade of D2 receptors in the mesocortical brain region impairs cognition and worsens the negative symptoms of schizophrenia. SGAs block both D2 and serotonin 5-HT2A receptors. Because these agents have lower affinity for dopamine receptor antagonism and more selective binding of D2 receptors in the mesolimbic versus nigrostriatal areas of the brain, SGAs should have a lower rate of EPS and TD. The serotonin receptor antagonism is thought

to reduce EPS effects and to improve the negative symptoms of schizophrenia.3,4 However, studies have found no significant dif-ference in reported rates of EPS and TD between perphenazine (a FGA) and several SGAs.5,6 Antipsychotic medications also block other receptor types (see Table 161-1).

Some antipsychotic medications have additional clinical uses. The antiemetic effect of prochlorperazine, promethazine, and dro-peridol is from blockade of dopamine receptors in the chemore-ceptor trigger zone of the medulla. Hydroxyzine controls itching by blocking histamine (H1) receptors. Prochlorperazine and dro-peridol abort migraine headaches by preventing dopamine-mediated meningeal artery vasodilation. Chlorpromazine can treat severe hiccups, and haloperidol is the drug of choice for certain movement disorders, including Tourettes syndrome and Huntingtons chorea.

Pathophysiology

EPS can be immediate or delayed after initiation of drug therapy. The acute EPS include dystonia, akathisia, and parkinsonism, which are caused by blockade of nigrostriatal D2 receptors and reduced by blockade of muscarinic receptors. The propensity for antipsychotics to produce EPS is inversely proportional to the agents muscarinic receptor antagonism.4 The delayed-onset syn-dromes, including TD and tardive dystonia, develop after pro-longed use of antipsychotic medications and are thought to occur from chronic dopamine receptor blockade in the nigrostriatal area leading to D2 receptor upregulation and hypersensitivity to dopamine.7-9 The pathophysiologic mechanism of NMS, an idio-syncratic reaction to antipsychotic medication, is unknown but thought to be neuroregulatory dysfunction secondary to D2 recep-tor blockade in the nigrostriatum and hypothalamus, leading to rigidity and hyperthermia, respectively.10 NMS is not associated with ryanodine receptor (RYR) gene mutations, which are associ-ated with malignant hyperthermia.

Antipsychotic medications produce cardiovascular side effects, most commonly orthostatic hypotension with reflexive tachycar-dia due to alpha-adrenergic blockade. Many agents cause conduc-tion delays, predominantly QT prolongation, resulting in prolonged repolarization and potentially torsades de pointes (TdP).11 The degree of prolongation varies between antipsychotic agents, increasing with dose and with concomitant use of other drugs that prolong the QT interval.12,13 The phenothiazines, par-ticularly thioridazine and mesoridazine, have the greatest risk of cardiac toxicity. QT prolongation has also been reported with the butyrophenones haloperidol and droperidol.12,14 The atypical antipsychotics produce less cardiotoxicity than the traditional agents do, although most can cause repolarization abnormalities in therapeutic doses and overdose.12,15,16 Ultimately, a correlation

2048 PART IV Environment and Toxicology / Section Two Toxicology

MEDICATION RECEPTORS BLOCKED CLINICAL EFFECTS ADVERSE EFFECTS

Low Potency (First-Generation Antipsychotics)

ChlorpromazineChlorprothixeneFluphenazineHydroxyzineMesoridazineMolindonePerphenazineProchlorperazinePromethazineThioridazine

Dopamine D2 (moderate affinity in mesolimbic and nigrostriatal areas)

Acetylcholine muscarinic (generally strong affinity)

Histamine H1 (strong affinity)Alpha-adrenergic (moderate affinity)Dopamine D1, D3, D4, D5 (variable affinity)

Control positive symptoms of psychotic disorders:HallucinationsDelusionsAgitationDisordered thoughts

Extrapyramidal syndromes (common)Tardive dyskinesia (common)Sedation (common)Orthostatic hypotension (common)Anticholinergic symptoms (common):

Dry mouthBlurred visionImpaired sweatingConstipationWeight gainUrinary retentionAngle-closure glaucoma

High Potency (First-Generation Antipsychotics)

DroperidolHaloperidolLoxapinePimozideThiothixeneTrifluoperazine

Dopamine D2 (strong affinity in mesolimbic and nigrostriatal areas)

Acetylcholine muscarinic, histamine H1, alpha-adrenergic (weak affinity)

Dopamine D1, D3, D4, D5 (variable affinity)

Control positive symptoms of psychotic disorders

Extrapyramidal syndromes (common)Tardive dyskinesia (common)Sedation, orthostatic hypotension,

and anticholinergic symptoms (uncommon in usual clinical doses)

Atypical (Second-Generation Antipsychotics)

AripiprazoleAsenapineClozapineIloperidoneOlanzapinePaliperidoneQuetiapineRisperidoneZiprasidone

Serotonin 5-HT2A (strong)Dopamine D2 (mild to moderate affinity,

selective for mesolimbic areas)Dopamine D1, D3, D4, D5 (variable affinity)

Control positive symptoms of psychotic disorders

Control negative symptoms of psychotic disorders:Social withdrawalFlattened affectDecreased activityPaucity of speechPseudodementia

Extrapyramidal syndromes and tardive dyskinesia (uncommon)

Endocrine effectsProlactin elevation

Table 161-1 Selected Antipsychotic Agents Approved or Nearing Approval for Use in the United States

between QT prolongation and dysrhythmias or TdP has not been established,3 but antipsychotics are associated with an increased risk of sudden death, particularly with heart disease and in elderly patients.17,18 However, psychotic disorders themselves are associ-ated with an increased risk of sudden death.

Clozapine produces agranulocytosis in 1 or 2% of treated patients; however, this has been reduced to 0.4% after strict adher-ence to labeling requirements.19 Although the mechanism of agranulocytosis is unknown, research supports an immunogenic cause and direct cytotoxic effect on human bone marrow mesen-chymal stromal cells.20 Seizure rarely occurs with antipsychotic drugs, but clozapine has the highest seizure incidence. Drug dosing and the patients seizure risk profile influence seizure sus-ceptibility.21 FGAs and SGAs have been associated with weight gain, glycemic dysregulation, and dyslipidemia. The cause is not fully understood but partly blamed on the pharmacodynamic profile of these agents.22

CLINICAL FEATURES

Acute Overdose

In overdose, antipsychotic medications produce signs and symp-toms that are exaggerations of the clinical effects. Most patients will have symptoms within a few hours. Central nervous system (CNS) depression is universally present, ranging from mild seda-tion and confusion to coma and loss of brainstem reflexes. Airway reflexes can be impaired. Respiratory depression can occur after a massive overdose with profound CNS depression. Pupils can be of any size. Mild orthostatic hypotension is a common finding from alpha-adrenergic blockade. Overdose with low-potency FGAs can

cause an anticholinergic delirium. EPS have been reported with the FGAs and SGAs.

Atypical antipsychotic overdose is similar to that of traditional antipsychotics. Overdoses are characterized by CNS depression and tachycardia.23-30 Miosis may be present, potentially mimicking opioid toxicity.31 Extremity twitching is common. With the excep-tion of clozapine, seizures rarely occur in overdose. Acute EPS have been reported, especially for risperidone overdose.32

Acute Extrapyramidal Syndromes

Acute dystonia is manifested as intermittent, involuntary motor tics or spasms of antagonistic muscle groups that most often involve the facial, neck, back, or limb muscles. This results in trismus, facial grimacing, dysarthria, tongue and lip distortion, torticollis, or oculogyric crisis. Dystonic reactions usually develop within the first several doses of treatment or after a large increase in dosage.33 Laryngeal dystonia is a rare but life-threatening form of dystonia that is manifested as stridor, difficulty in breathing, or choking sensation.5,34 Increased risk of death due to choking has been documented in schizophrenia patients.35

Akathisia is a subjective feeling of restlessness associated with objective motor restlessness, including repetitive foot shuffling, truncal rocking, or pacing. The subjective distress may precipitate aggressive behavior.5,36 Akathisia usually develops within the first few days of treatment, but 40% of patients given 10 mg of intra-venous prochlorperazine developed akathisia within 1 hour.37

A parkinsonian syndrome of bradykinesia, masked facies, shuf-fling gait, muscle rigidity, and resting tremor frequently develops during the first month of treatment; 90% of cases occur within 3 months of treatment. Perioral tremor (rabbit syndrome), in which

Chapter 161 / Antipsychotics 2049

the lip and nose movements resemble those of a rabbit, can also develop after prolonged therapy.5

Tardive Dyskinesia

TD is a chronic movement disorder induced by prolonged use of antipsychotic medication. Typical signs of TD include quick, involuntary movements of the face (blinking, grimaces, tongue movements, and chewing), extremities, or trunk. Twenty percent of patients treated with long-term traditional antipsychotics are affected. TD is difficult to treat and is frequently permanent. Anti-cholinergic agents may worsen TD; reduction of the antipsychotic dose or a change to an alternative agent should be considered.5,38 TD improves in some patients switched to clozapine; amantadine improved symptoms compared with placebo in a small study.39,40

Respiratory dyskinesia, a variant of TD, is characterized by oro-facial dyskinesia, dyspnea, dysphonia, and respiratory alkalosis. This chronic disorder often goes undiagnosed and can cause repeated bouts of aspiration pneumonia.

Neuroleptic Malignant Syndrome

NMS is a serious idiosyncratic drug reaction that typically devel-ops during the first month of therapy but has occurred during stable drug regimens. Risk factors include rapid drug loading, high dosage, high-potency antipsychotics, parenteral formulations, dehydration, preceding psychomotor agitation, and previous epi-sodes of NMS.41,42 Other medications may contribute to NMS, including lithium, which inhibits dopamine secretion, as can withdrawal from dopaminergic agents used to treat Parkinsons disease.5,10,43 The incidence of NMS in patients treated with antipsychotics is approximately 0.02%.41 Atypical antipsychotic agents, including clozapine, risperidone, olanzapine, quetiapine, ziprasidone, amisulpride, and aripiprazole, have been associated with NMS.44

Table 161-2 lists the diagnostic criteria for NMS. Other features of NMS may include sialorrhea, dysarthria, dysphagia, metabolic

CRITERIA AND FEATURES PREVALENCE

A. Development of severe muscle rigidity and elevated temperature associated with the use of a neuroleptic/antipsychotic medication

Rigidity: 97%Fever: 98%

B. Two (or more) of the following are present: Diaphoresis 98% Dysphagia Tremor Incontinence Change in level of consciousness ranging from

confusion to coma97%

Mutism Tachycardia 88% Elevated or labile blood pressure 61% Leukocytosis 98% Laboratory evidence of muscle injury (e.g., elevated

creatine kinase)95%

C. Symptoms in criteria A and B are not caused by another substance (e.g., phencyclidine), a neurologic or other general medical condition (e.g., viral encephalitis), or another mental disorder (e.g., mood disorder with catatonic features).

Modified from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric Association, 2000. Prevalence data from Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 77:185, 1993.

Table 161-2Diagnostic Criteria and Clinical Features of Neuroleptic Malignant Syndrome

acidosis, liver function elevations, sodium imbalance, dehydra-tion, elevations in serum catecholamines, coagulopathy, general-ized slowing on the electroencephalogram, pulmonary embolism, and renal failure.42 Atypical presentations may lack full diagnostic criteria for NMS.44,45

Most patients have the cardinal features of altered mental status, muscle rigidity, hyperthermia, and autonomic nervous system instability during several hours to days. However, the signs of NMS may develop gradually and in any order. Agitation, often mistaken for worsening psychosis, may occur first. Physicians should consider discontinuation of antipsychotic drugs in a patient who has one or more of the major manifestations of NMS. Most episodes resolve within 2 weeks after cessation of the offend-ing medication, but some cases last several months.

Cardiovascular Toxicity and Dysrhythmias

The most common cardiac effect is sinus tachycardia with a normal QRS duration. If QRS prolongation is present, another drug effect should be suspected. QT prolongation occurs during therapeutic dosing of many antipsychotic agents. Therapeutic doses of thioridazine, followed by ziprasidone, prolong the QT interval more than risperidone, olanzapine, quetiapine, or halo-peridol does.15,16 QT prolongation associated with TdP is a well-described adverse effect of thioridazine, mesoridazine, droperidol, sertindole, and haloperidol.12 Among FGAs, thioridazine carries the greatest risk of cardiotoxicity. Among SGA overdoses, whereas ziprasidone carries the greatest risk of QTc prolongation,46,47 TdP has been reported with amisulpride overdose.30 QT prolonga-tion should be considered a class effect of all antipsychotic medications.

Agranulocytosis

Clozapine produces agranulocytosis; 75% of occurrences develop within the first 18 weeks after initiation of therapy, peaking at 3 months.19 The concomitant use of other bone marrowsuppressing agents (e.g., carbamazepine) should be avoided. Clo-zapine administration must be halted if the total white blood cell count falls below 3000 cells/mL or if the absolute neutrophil count is less than 1500 cells/mL. Agranulocytosis has not been reported after an acute overdose. Olanzapine, whose chemical structure is similar to that of clozapine, has also been associated with neutro-penia and agranulocytosis, but all patients recovered after discon-tinuation of olanzapine.48

Seizures

Antipsychotic medications can lower the seizure threshold and induce epileptiform electroencephalographic abnormalities in many asymptomatic patients. However, antipsychotic-induced seizures are rare except for clozapine, which causes a dose-related increase in risk of seizures (approximately 5% at high doses). Antipsychotics can be prescribed for patients with known seizure disorder.20,21,49

DIFFERENTIAL CONSIDERATIONS

Differential considerations include a broad list of agents and clin-ical conditions that produce altered mental status, orthostatic hypotension, anticholinergic syndrome, seizure, QT prolonga-tion, or TdP. Although the signs of NMS are similar, serotonin syndrome is more likely to have clonus, heatstroke is evident from the circumstances, and the causes of these conditions are quite different (Table 161-3). Malignant hyperthermia should be considered in patients receiving inhalational anesthetics or succinylcholine.

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DISEASE* PATHOLOGIC MECHANISM DIFFERENTIATING FACTOR TIME COURSE TREATMENT

Neuroleptic malignant syndrome

Impaired thermoregulation in hypothalamus and basal ganglia due to relative lack of dopamine activity

Antipsychotic medication use, muscle rigidity (diagnostic criteria in Table 161-2)

Gradual, progresses during several days

Stop offending medicationHydrationActive coolingIntravenous benzodiazepines

to relax muscles and control agitation

Neuromuscular blockade (nondepolarizing agents)

Controversial: Bromocriptine or

amantadine Dantrolene

Serotonin syndrome Excess serotonin and dopamine levels in central nervous system

Medications (usually a combination) that increase serotonin levels (e.g., SSRIs, MAOIs, dextromethorphan, lithium, meperidine, tramadol, tryptophan); muscle rigidity

Usually rapid after introduction of new medication or increase in dose; can be gradual

Stop offending medicationHydrationActive coolingCyproheptadine

Heatstroke Environmental heat stress Environmental exposure history; muscle rigidity rare

Rapid or gradual Hydration

Active cooling

Malignant hyperthermia

Genetic instability of sarcoplasmic reticulum, causing massive calcium release after administration of triggering medication

Occurs after administration of inhalational anesthetic or succinylcholine; muscle rigidity

Sudden, provoked by administration of anesthetic

Stop anestheticHydrationActive coolingDantrolene

MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.*Other clinical entities to consider in the diagnosis of these conditions include Addisons syndrome, central nervous system infection, delirium tremens, hypocalcemia, hypoglycemia, hyponatremia, intracranial hemorrhage, lethal catatonia, poisoning (e.g., amphetamines, anticholinergics, cocaine, nicotine, salicylates, sympathomimetics, strychnine, theophylline), sedative-hypnotic drug withdrawal, sepsis, status epilepticus (including nonconvulsive status), tetanus, thalamic infarct, thyroid storm, and psychotic agitation.

Table 161-3 Differential Diagnosis of Neuroleptic Malignant Syndrome

DIAGNOSTIC STRATEGIES

Blood levels are neither readily available nor helpful. As with any patient who presents with altered mental status, vital signs, blood glucose concentration, and pulse oximetry are indicated.

An electrocardiogram should be obtained in patients with sig-nificant antipsychotic overdose and in symptomatic patients taking thioridazine, mesoridazine, droperidol, or sertindole. Patients receiving high-dose intravenous haloperidol or droperi-dol for sedation may need rhythm monitoring, and if QT prolon-gation is present, serum potassium, calcium, and magnesium levels should be measured.

Patients who have NMS, parkinsonism with marked muscle rigidity, or prolonged seizures are at risk for rhabdomyolysis and should have serum creatine kinase, renal function, and urine myo-globin measured. Patients taking clozapine or olanzapine who present with infection or fever should be checked for leukopenia. Olanzapine and clozapine have been associated with new-onset diabetes with ketoacidosis.3

Other testing, such as brain computed tomography, lumbar puncture, serum acetaminophen level, and electrolyte measure-ments, may be helpful in some cases but are not indicated when the context and presentation support antipsychotic toxicity as the cause.

MANAGEMENT

Acute Overdose

Treatment is supportive; there is no specific antidote. Endotra-cheal intubation may be required to prevent aspiration or, less often, to support respiration. Hypotension is generally mild and

responds to intravenous crystalloids. An alpha-adrenergic pressor such as norepinephrine may be used if needed. If sedation and miosis suggest opioid intoxication, a trial of naloxone is war-ranted. Physostigmine and flumazenil are not indicated and may precipitate seizures.

Activated charcoal has no proven benefit and may increase the morbidity of the overdose if it is administered to a patient with altered mental status at risk for aspiration.

Acute Extrapyramidal Syndromes

Dystonia will usually respond within 30 minutes to diphenhydr-amine 25 to 50 mg intravenously, intramuscularly, or orally or benztropine 1 to 2 mg intramuscularly or orally. Benzodiazepines may also be effective. If relief is not achieved, an alternative diag-nosis should be sought. Akathisia is treated similarly or with a lipophilic beta-adrenergic blocker (e.g., propranolol). Treatment of parkinsonism syndrome may include anticholinergic agents. Patients with EPS who respond to diphenhydramine or benztro-pine should continue therapy for at least 48 hours to prevent recurrence.5,50 In addition, patients should be referred to their treating physician, who may reduce the antipsychotic dose or change to an alternative agent as necessary. Benztropine, diphen-hydramine, and the older antipsychotic medications cause anti-cholinergic effects, so combination therapy may worsen dry mouth, blurred vision, and urinary retention.

QT Prolongation and Torsades de Pointes

Correction of hypokalemia, hypomagnesemia, and hypocalcemia shortens the QT interval. Treatment of TdP includes intravenous magnesium sulfate, overdrive pacing, and possibly isoproterenol.

Chapter 161 / Antipsychotics 2051

critical care unit. Patients with a prolonged QT interval (QTc > 460 milliseconds) or symptomatic ingestions of thioridazine or mesoridazine should have at least 12 hours of cardiac monitoring. Patients with minimal signs of toxicity should be observed in the emergency department for a minimum of 4 hours from the time of ingestion, with hospitalization for persistent or worsening signs and symptoms. Criteria for hospital discharge include return to normal mental status and resolution of any vital sign, metabolic, and electrocardiographic abnormalities. Psychiatric consultation may be necessary to assess the risk of suicide.

Antiarrhythmic drugs that prolong the QT interval should be avoided.

Neuroleptic Malignant Syndrome

Treatment of NMS consists of supportive care and discontinua-tion of the offending medication. Agitation, psychomotor hyper-activity, and muscle rigidity should be treated with liberal doses of intravenous benzodiazepines. Lorazepam can be administered intravenously, 1 or 2 mg every 3 minutes, until muscle rigidity improves. Refractory cases or cases at risk for aspiration can be managed with rapid sequence intubation and neuromuscular blockade with a nondepolarizing agent (e.g., rocuronium and vecuronium). Hyperthermia should be managed with intravenous fluids and active external cooling with mist and fans. If rhabdo-myolysis is present, intravenous hydration and urinary alkaliniza-tion are used to prevent renal damage.

Bromocriptine and amantadine have been suggested for treat-ment of NMS but do not consistently show a benefit.43,51 Bro-mocriptine is administered orally or by nasogastric tube, beginning with 5 mg every 8 hours and titrated to a maximum of 20 mg per dose. The dose of amantadine for NMS is 200 mg orally every 12 hours. Response to therapy requires at least 24 hours. Dantrolene, which inhibits the release of calcium from the sarcoplasmic reticu-lum, has no proven benefit.51 Because the muscle rigidity of NMS is thought to be from dopamine blockade in the CNS rather than a muscle abnormality, dantrolene offers no advantage over benzo-diazepines and neuromuscular blockade.

DISPOSITION

Patients with NMS and overdose patients with hypotension, coma, TdP, or airway compromise should be admitted, usually to a

Extrapyramidalmovementdisordersareacommoncomplicationofantipsychoticmedicationsandaretreatedwithbenztropine,diphenhydramine,andbenzodiazepines.

Themostcommonfindinginantipsychoticoverdoseiscentralnervoussystemdepression.Treatmentcentersonsupportivecare,airwaycontrol,andcardiacmonitoring.

QTprolongationandtorsadesdepointesarepotentialcomplicationsofmanyantipsychoticmedicationsinoverdoseandcanoccurwiththerapeuticdosesofsomeagents.

Theneurolepticmalignantsyndromeischaracterizedbyalteredmentalstatus,hyperthermia,musclerigidity,andautonomicinstability.Supportivecareincludesairwaymanagement,benzodiazepines,neuromuscularblockade,andactivecooling.

KEY CONCEPTS

The references for this chapter can be found online by accessing the accompanying Expert Consult website.

Chapter 161 / Antipsychotics 2051.e1

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161 AntipsychoticsPerspectivePrinciples of DiseaseAnatomy and PhysiologyPathophysiology

Clinical FeaturesAcute OverdoseAcute Extrapyramidal SyndromesTardive DyskinesiaNeuroleptic Malignant SyndromeCardiovascular Toxicity and DysrhythmiasAgranulocytosisSeizures

Differential ConsiderationsDiagnostic StrategiesManagementAcute OverdoseAcute Extrapyramidal SyndromesQT Prolongation and Torsades de PointesNeuroleptic Malignant Syndrome

DispositionReferences