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ANTIDEPRESSANTS

Dr. Bushra Hasan KhanJR-1

Department of PharmacologyJNMC, AMU, Aligarh.

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OUTLINE

• DEPRESSION CRITERIA

• EPIDEMIOLOGY

• PHARMACOLOGY OF ANTIDEPRESSANT DRUGS

• OTHER TREATMENT MODALITIES

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MAJOR DEPRESSION

AT LEAST 5 OF THESE 9 SYMPTOMS , PRESENT NEARLY EVERY DAY:

1. DEPRESSED MOOD OR IRRITABLE MOST OF THE DAY

2. DECREASED INTEREST OR PLEASURE IN ACTIVITIES

3. SIGNIFICANT WEIGHT CHANGE (5%) OR CHANGE IN APPETITE

4. CHANGE IN SLEEP : INSOMNIA OR HYPERSOMNIA

5. CHANGE IN ACTIVITY : PSYCHOMOTOR AGITATION OR RETARDATION

6. FATIGUE OR LOSS OF ENERGY7. GUILT/WORTHLESSNESS 8. CONCENTRATION - DIMINISHED ,

INDECISIVENESS 9. SUICIDALITY: THOUGHTS OF DEATH OR

SUICIDE, OR HAS SUICIDE PLAN

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• PREVALENCE OF MAJOR DEPRESSION IS 5%

• MALE: FEMALE = 1:2

• INCIDENCE INCREASES WITH AGE IN BOTH SEXES

• 15% POPULATION - MAJOR DEPRESSIVE EPISODE AT

SOME POINT IN LIFE

• 10–15% OF DEPRESSION CASES : SECONDARY TO

GENERAL MEDICAL ILLNESS OR SUBSTANCE ABUSE

• APPROXIMATELY 4–5% OF ALL DEPRESSED PATIENTS

COMMIT SUICIDE

EPIDEMIOLOGY

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DEPRESSION : SECONDARY TO GENERAL MEDICAL ILLNESSES

• Endocrine disturbances (hyper- or hypocortisolemia, Hyper- or hypothyroidism), • Autoimmune diseases, • Parkinson's disease, • Traumatic brain injury, • Certain cancers, • Asthma, • Diabetes, and • Stroke. Depression and obesity/metabolic syndrome are

important risk factors for each other.

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CLASSIFICATION OF ANTIDEPRESSANT DRUGS

1)SSRIs: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline.

2)SNRIs: Duloxetine, Venlafaxine, Desvenlafaxine, Milnacipram.

3)SEROTONIN RECEPTOR ANTAGONIST: Mirtazapine, Nefazodone, Trazodone, Atomoxetine, Bupropion, Mianserin.

4)MAOIs: Phenelzine, Selegiline, Tranylcypromine, Moclobemide.

5)TCAs: Amitriptyline, Clomipramine, Doxepin, Imipramine,Trimipramine, Reboxetine ,Amoxapine, Desipramine, Maprotiline, Nortriptyline, Protriptyline.

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SITES OF ACTION OF ANTIDEPRESSANTS

NORADRENERGIC NERVE TERMINAL

SEROTONERGIC NERVE TERMINAL

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SELECTIVE SEROTONIN REUPTAKE INHIBITORS

CITALOPRAM ESCITALOPRAM FLUOXETINE PAROXETINE FLUVAXAMINE SERTRALINE VORTIOXETINE VILAZODONE

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• SSRI initially blocks SERT and results in enhanced serotonergic neurotransmission by blocking the reuptake of serotonin by SERT.

• Increased synaptic availability of serotonin stimulates a large number of postsynaptic 5-HT receptor subtypes, as well as presynaptic terminal receptors that regulate serotoninergic neuron activity and serotonin release.

• SSRI treatment causes stimulation of 5-HT1A and 5-HT7 autoreceptors on cell bodies in the raphe nucleus and of 5-HT1D autoreceptors on serotonergic terminals, and this reduces serotonin synthesis and release toward pre-drug levels.

SSRIs MECHANISM OF ACTION

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SSRIs MECHANISM OF ACTION (contd.)

• With repeated treatment with SSRIs, there is a gradual down-

regulation and desensitization of these autoreceptors.

• In addition, down-regulation of postsynaptic 5-HT2A receptors

may contribute to antidepressant efficacy directly or by

influencing the function of noradrenergic and other neurons

via serotonergic heteroreceptors.

• Other postsynaptic 5-HT receptors likely remain responsive to

increased synaptic concentrations of 5-HT and contribute to

the therapeutic effects of the SSRIs.

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SSRIs PHARMACOKINETICS

• All of the SSRIs are orally active

• Once-daily dosing .

• Hepatic metabolism: CYP2D6

• In post-menopausal women taking Tamoxifen ; the parent

molecule is converted to a more active metabolite by CYP2D6,

and SSRIs may inhibit this activation and diminish the

therapeutic activity of tamoxifen.

• Care should be used in combining SSRIs with drugs that are

metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g., Warfarin,

tricyclic antidepressants, paclitaxel).

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SSRIs uses

• Depression (CITALOPRAM 20mg/day)• Anxiety : generalized anxiety, panic, social

anxiety, and obsessive-compulsive disorders. • Posttraumatic stress disorder (Sertraline and

Paroxetine )• Premenstrual dysphoric syndrome • Vasovagal symptoms in post-menopausal• Obsessive-compulsive disorder

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SSRIs ADVERSE EFFECTS

• Excessive stimulation of brain 5-HT2 receptors : insomnia,

increased anxiety, irritability, and decreased libido.

• Excess activity at spinal 5-HT2 receptors : sexual side

effects including erectile dysfunction, anorgasmia, and

ejaculatory delay

• Stimulation of 5-HT3 receptors in the CNS and periphery -

GI effects : nausea , diarrhea and emesis.

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SSRIs ADVERSE EFFECTS (contd.)

• Withdrawal syndrome : dizziness, headache,

nervousness, nausea, and insomnia.

• Paroxetine - risk of congenital cardiac malformations.

• Venlafaxine - risk of perinatal complications.

• Citalopram – QT Prolongation (>40 mg / day)

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SSRIs DRUG INTERACTIONS

• Paroxetine and fluoxetine are potent inhibitors of

CYP2D6 : increase in plasma concentrations of drugs

metabolized by CYP2D6 when doses of these drugs are

increased.

• Fluvoxamine directly inhibits CYP1A2 and CYP2C19

• Fluoxetine and Fluvoxamine also inhibit CYP3A4.

• Increase in TCA exposure may be observed during co-

administration of TCAs and SSRIs.

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• MAOIs enhance the effects of SSRIs due to inhibition of

serotonin metabolism.

• Serotonin syndrome :

Hyperthermia, muscle rigidity, myoclonus, tremors,

autonomic instability, confusion, irritability, and

agitation; this can progress toward coma and death.

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• Since MAOIs bind irreversibly to MAO and block the

enzymatic metabolism of monoaminergic neurotransmitters,

SSRIs should not be started until at least 14 days following

discontinuation of treatment with MAOI; this allows for

synthesis of new MAO.

• For all SSRIs but Fluoxetine, at least 14 days should pass prior

to beginning treatment with MAOI following the end of

treatment with an ssri.

• Since the active metabolite norfluoxetine has a t1/2 of 1-2

weeks, at least 5 weeks should pass between stopping

fluoxetine and beginning MAOI.

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SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS

• VENLAFAXINE

• DESVENLAFAXINE

• DULOXETINE

• MILNACIPRAN

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SNRIs MECHANISM OF ACTION

• SNRIs inhibit both SERT and NET.

• SNRIs cause enhanced serotonergic and/or noradrenergic neurotransmission.

• The initial inhibition of SERT induces activation of 5-HT1A and 5-HT1D autoreceptors. This action decreases

serotonergic neurotransmission by a negative feedback mechanism until these serotonergic autoreceptors are desensitized.

• Then, the enhanced serotonin concentration in the synapse can interact with postsynaptic 5-HT receptors.

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VENLAFAXINE

• The reuptake effects of venlafaxine are dose-

dependent.

• At low doses (<150 mg/day), it acts only on serotonergic

transmission.

• At moderate doses (>150 mg/day), it acts on

serotonergic and noradrenergic systems

• Whereas at high doses (>300 mg/day), it also affects

dopaminergic neurotransmission.

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SNRIs PHARMACOKINETICS

• The elimination half-life : Venlafaxine - 5 hours

Desmethylvenlafaxine -11 hours

• Desmethylvenlafaxine is eliminated by hepatic

metabolism and by renal excretion.

• Duloxetine has a t1/2 of 12 hours.

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USES OF SNRIs

• Major Depressive Disorder (MDD)• Generalised Anxiety Disorder (GAD)• Social Anxiety Disorder (SAD)• Panic Disorder• Neuropathic Pain (Duloxetine )• Fibromyalgia (Milnacipram , Duloxetine)• Chronic Musculoskeletal Pain• Stress Urinary Incontinence (Duloxetine)• PTSD (Venlafaxine)

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SNRIs ADVERSE EFFECTS

• Nausea, constipation, insomnia, headaches, and sexual dysfunction.

• Venlafaxine : cardiotoxicity• Duloxetine : hepatic failure

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SNRIs DRUG INTERACTIONS

• While 14 days are suggested to elapse from ending

MAOI therapy and starting Venlafaxine treatment, an

interval of only 7 days after stopping Venlafaxine is

considered safe before beginning MAOI.

• Duloxetine has a similar interval to initiation following

MAOI therapy, but requires only a 5-day waiting period

to begin MAOI treatment after ending Duloxetine.

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SEROTONIN RECEPTOR ANTAGONISTS

• MIRTAZAPINE

• BUPROPION

• TRAZODONE

• NEFAZODONE

• MIANSERIN

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SEROTONIN RECEPTOR ANTAGONISTSMECHANISM OF ACTION

• TRAZODONE : Blocks 5-HT2A receptor, inhibits reuptake of 5-HT

and desensitises 5-HT autoreceptor, enhances 5-HT release.

TRAZODONE also blocks Alpha1 adrenergic receptors.

• NEFAZODONE : blockade of the 5-HT2 receptors.

• MIRTAZAPINE: Tetracyclic structure : stimulates norepinephrine

and serotonin release through its central presynaptic Alpha2-

adrenergic antagonist effects ; potent antagonist of 5-HT2c and

histamine receptors

• MIANSERIN: blocks presynaptic Alpha2 receptors

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SEROTONIN RECEPTOR ANTAGONISTSPHARMACOKINETICS

• Mirtazapine : Elimination t1/2 : 20 to 40 hours

• Trazodone : Elimination t1/2 : 7-10 hours

• Nefazodone : Elimination t1/2 : 2-4 hours

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SEROTONIN RECEPTOR ANTAGONISTS : USES

• Depression : Trazodone typically is started at 150 mg/day in

divided doses with 50 mg increments every 3-4 days. The

maximally recommended dose is 400 mg/day for

outpatients and 600 mg/day for inpatients.

• Insomnia : Low doses of Trazodone (50-100 mg)

• Depressed patients with Insomnia : Mianserin and

Mirtazapine

• Mirtazapine : 15 mg po hs ; may increase dose no more

frequently than 1-2weeks; not to exceed 45 mg hs

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SEROTONIN RECEPTOR ANTAGONISTSADVERSE EFFECTS

• Mirtazapine : somnolence, increased appetite,

weight gain, Xerostomia, constipation.

• Trazodone : Blurred vision, Dizziness, Headache ,

Drowsiness, Dry mouth, Fatigue, Nausea,

vomiting, Postural Hypotension , Priapism.

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SEROTONIN RECEPTOR ANTAGONISTSDRUG INTERACTIONS

• Trazodone dosing may need to be lowered when given together with drugs that inhibit CYP3A4.

• Trazodone and nefazodone are weak inhibitors of serotonin uptake and should not be administered with MAOIs due to concerns about the serotonin syndrome.

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BUPROPION

• Norepinephrine dopamine reuptake inhibitor

• May act through dopaminergic or

noradrenergic pathways

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BUPROPION PHARMACOKINETICS

• Peak serum time: 2 hr (immediate-release)

3 hr (extended-release)

• Metabolism : Hepatic via CYP2B6

• Elimination t1/2 : 8-24 hours

• Elimination : hepatic and renal

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BUPROPION USES

• Depression : Bupropion is widely used in

combination with SSRIs

• Prevention of seasonal depressive disorder

• Smoking cessation treatment

• ADHD: 150 mg per day

• Neuropathic pain : 150 mg BD for 6 weeks

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BUPROPION ADVERSE EFFECTS

• Headache

• Dizziness

• Insomnia

• Agitation

• Dry mouth

• Nausea

• Risk of seizures

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BUPROPION DRUG INTERACTIONS

• The major route of metabolism for Bupropion is CYP2B6

• Consideration for a decreased dose should be

made in cases of -

oPatients with severe hepatic cirrhosis

oRenal impairment.

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MONOAMINE OXIDASE INHIBITORS

• MOCLOBEMIDE

• SELEGILINE

• TRANYLCYPROMINE

• PHENELZINE

• ISOCARBOXAZID

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MECHANISM OF ACTION OF MONOAMINE OXIDASE INHIBITORS

• The MAOIs nonselectively and irreversibly inhibit both MAO-A

and MAO-B, which are located in the mitochondria and

metabolize (inactivate) monoamines, including 5-HT and NE

• Selegiline inhibits MAO-B at lower doses, with effects on

MAO-A at higher doses.

• Selegiline also is a reversible inhibitor of monoamine oxidase,

which may reduce the potential for serious adverse drug and

food interactions.

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MONOAMINE OXIDASE INHIBITORSPHARMACOKINETICS

• MAOIs are metabolized by acetylation.

• A significant portion of the population are "slow acetylators"

and will exhibit elevated plasma levels.

• The nonselective MAOIs used in the treatment of depression

are irreversible inhibitors ; thus, it takes up to 2 weeks for

MAO activity to recover, even though the parent drug is

excreted within 24 hours.

• Recovery of normal enzyme function is dependent on synthesis

and transport of new MAO to monoaminergic nerve terminals.

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MONOAMINE OXIDASE INHIBITORS ADVERSE EFFECTS

• HYPERTENSIVE CRISIS :

MAO-A within the intestinal wall and MAO-A and MAO-B in the liver

normally degrade dietary tyramine.

However, when MAO-A is inhibited, the ingestion of certain aged

cheeses, red wines, sauerkraut, fava beans, and a variety of other

tyramine-containing foods leads to accumulation of tyramine in

adrenergic nerve endings and neurotransmitter vesicles and induces

norepinephrine and epinephrine release.

• HEPATOTOXICITY

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MONOAMINE OXIDASE INHIBITORSDRUG INTERACTIONS

• CNS depressants including Meperidine and other narcotics,

alcohol, and anesthetic agents should not be used with

MAOIs. Meperidine and other opioid agonists in combination

with MAOIs also induce the serotonin syndrome.

• SSRIs and SNRIs are contraindicated in patients on MAOIs, and

vice versa, to avoid the serotonin syndrome.

• In general, other antidepressants such as TCAs and bupropion

also should be avoided in patients taking an MAOI.

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TRICYCLIC ANTIDEPRESSANTS• IMIPRAMINE• CLOMIPRAMINE• AMITRIPTYLINE• DOXEPIN• DESIPRAMINE• NORTRIPTYLINE• PROTRIPTYLINE• AMOXAPINE• REBOXETINE• MAPROTILINE

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TRICYCLIC ANTIDEPRESSANTS MECHANISM OF ACTION

• SERT and NET blocker (Imipramine, Amitriptyline)

• NET blocker (Desipramine, Nortriptyline, Protriptyline,

Amoxapine)

• (H1, 5-HT2, Alpha1, and Muscarinic).

• Amoxapine - also a dopaminergic receptor antagonist :

extrapyramidal side effects such as tardive dyskinesia.

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TRICYCLIC ANTIDEPRESSANTSPHARMACOKINETICS

• The TCAs, or their active metabolites, have plasma

exposure half-lives of 8-80 hours; once-daily dosing.

• Steady-state concentrations occur within several days

to several weeks of beginning treatment.

• TCAs are largely eliminated by hepatic CYPs.

• Determination of plasma levels may be useful in

identifying patients who appear to have toxic effects

and may have excessively high levels of the drug.

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• Narrow therapeutic window.

About 7% of patients metabolize TCAs slowly due

to a variant CYP2D6 isoenzyme, causing a 30-fold

difference in plasma concentrations among

different patients given the same TCA dose.

To avoid toxicity in "slow metabolizers," plasma

levels should be monitored and doses adjusted

downward.

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TRICYCLIC ANTIDEPRESSANTSADVERSE EFFECTS

• H1 receptor antagonism : sedative effects of TCAs

• Antagonism of muscarinic receptors : cognitive dulling , blurred

vision, dry mouth, tachycardia, constipation, difficulty urinating.

• Antagonism of 1 adrenergic receptors : orthostatic hypotension

and sedation.

• Weight gain.

• Quinidine-like effects on cardiac conduction : limit the use of

TCAs in patients with coronary heart disease.

• TCAs also lower the seizure threshold.

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TRICYCLIC ANTIDEPRESSANTSDRUG INTERACTIONS

• Drugs that inhibit CYP2D6, such as SSRIs, may increase

plasma exposures of TCAs.

• TCAs can potentiate the actions of sympathomimetic

amines and should not be used concurrently with MAOIs or

within 14 days of stopping MAOIs.

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PSYCHIATRIC USES

ENDOGENOUS DEPRESSION

PANIC DISORDERS

OCDADHD

SCHOOL PHOBIA,PTSD,

IMPULSE CONTROL

DISORDERS

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ENURESISANDBEDWETTING IN CHILDREN

CHRONIC NEUROPATHIC PAIN

MIGRAINE

ETHANOL ABUSE

NON PSYCHIATRIC

USES

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MISCELLANEOUS USES

•ATOPIC DERMATITIS•LICHEN SIMPLEX

5% TOPICAL DOXEPIN

•BULLIMIA NERVOSAFLUVOXAMINE FLUOXETINE

•SMOKING CESSATIONBUPROPION

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Electroconvulsive therapy • Onset of action may be more rapid than that of drug treatments,

with benefit often seen within 1 week of commencing treatment.• A course of ECT (usually up to 12 sessions) is the treatment of

choice for patients who do not respond to drug therapy.

Indications for the use of ECT :• Need for a rapid antidepressant response• Failure of drug therapies• History of good response to ECT• Patient preference• High risk of suicide• High risk of medical morbidity and mortality

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BRIGHT-LIGHT THERAPY

• Bright-light therapy for seasonal affective disorder is used at an intensity of 10,000 lux for 30-90 minutes daily, usually within 1 hour of arising in the morning.

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• Psychotherapy :

o Cognitive behavioral therapy

o Family therapy

o Interpersonal therapy

• Other non-pharmacological interventions :

o Transmagnetic stimulation of the brain

oDeep brain stimulation

o Vagus nerve stimulation

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THANK YOU

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Sites of action of Antidepressants

• SSRIs, SNRIs, and TCAs increase noradrenergic or serotonergic neurotransmission by blocking the norepinephrine or serotonergic transporter at presynaptic terminals (NET, SERT).

• MAOIs inhibit the catabolism of norepinephrine and serotonin.

• Chronic treatment with a number of antidepressants desensitizes presynaptic autoreceptors and heteroreceptors, producing long-lasting changes in monoaminergic neurotransmission.

• Post-receptor effects of antidepressant treatment, including modulation of GPCR signaling and activation of protein kinases and ion channels, are involved in the mediation of the long-term effects of antidepressant drugs. Note that NE and 5-HT also affect each other's neurons.