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• Two principle types of affective disorder – Major depression • Unipolar disorder – Bipolar disorder • Sometimes referred to as manic-depressive disorder Major Depression • We all have experienced the essential feelings associated with depression – Feel down and listless – Lack energy to do things • If the result of a life event such as death of a loved one, loss of job, or breakup of a relationship – Considered reactive depression – Does not constitute mental illness unless the symptoms last longer than normal or are abnormally intense • However, clinical depression is different from these normal reactions to life events. Major Depression • In clinical depression the mood disorder is severe. – – – – A more intense emotional reaction Lasts longer Individual withdraws from life and social interactions Anhedonia • inability to experience pleasure in anything – Often stop eating, bathing, caring for themselves • May remain in bed for prolonged periods – suicidal thoughts and/or attempts • One estimate is that 7-15% of depressed individuals commit suicide • Compared to 1-1.5% of general population • Most episodes of unipolar depression will improve in 6-9 months. • However, the episodes usually recur throughout life – Increasing in frequency and intensity • Stress is often associated with the first episode of depression – Later episodes can occur in the absence of significant stressors • About 3-4% of men experience unipolar depression • About 5-9% of women • Mean onset of unipolar depression is about 27 years • Diagnosis of depression has been on the rise, and occurring earlier in life – Americans born before 1905 • 1% developed depression by age 75 – Americans born since 1955 • 6% developed depression by age 24 Bipolar disorder • Depressive and manic phases alternate. • We have already discussed depressive symptoms • The primary symptom of mania is elation – Sometimes they can be irritable, impatient, or belligerent • Their thoughts are and ideas are racing • Everyone else is so slow • Approximately 1% of the population is diagnosed with bipolar depression – No gender differences – Onset is between 20-30 years of age – Episodes continue throughout lifetime Mental illness and creativity • A high proportion of creative individuals in the arts and sciences have experienced bipolar disorder – Some find the manic phases to be very productive times • Is creativity linked to mental illness? Box 16.1 Mood Disorders and Creativity Biological risk factors • Scientists agree that psychiatric disorders develop as a result of an interaction of genes and environmental events. • Role of heredity – Adoption studies – Twin studies – Linkage studies Role of heredity • Adoption studies – Individuals diagnosed with an affective disorder who were adopted at an early age – If the disorder has a heritable component one would expect that the adopted individual would have more biological relatives with the same disorder, rather that being like the adopted family • Better evidence comes from twin studies – Compare the concordance rate for monozygotic (100% shared genes) to dizygotic (50% shared genes). • Dizygotic is sometimes also referred to as fraternal Role of heredity • • • Overall (any mood disorder) concordance rate is 65% for identical and about 20% for fraternal. Note that severe depression has a higher heritability effect than less severe depression. Also note that the heritability effect for Bipolar disorder is very large. – 80% vs. 16% • Keep in mind that even fraternal twins are showing heritability effects – General population depression = about 5-6% goes up to 20 some % – General population bipolar = about 1% goes up to 16% Role of heredity • Linkage studies look for similarities in gene location on chromosomes in families that have a history of a disorder • No single dominant gene for affective disorder is known Role of stress • There is a lot of evidence that anxiety and depression are closely related • People diagnosed with depression are often experiencing anxiety • It has also been shown that intense environmental stress and anxiety often precede episodes of depression – Especially early in the disorder • Altered patterns of stress hormones are frequently found in depressed patients Stress • Identical life stressors can be perceived very differently by individuals – Some cope well – Others succumb more easily • It is likely that genetics plays a role in how we respond physically and behaviorally to daily traumas and stress • Neuroscientists have focused on the hypothalamic-pituitary-adrenal (HPA) axis as an important area of the nervous system involved in stress response and etiology of depression HPA axis • When we are stressed the hypothalamus releases CRF (corticotropin releasing factor). – This is in response to NTs such as NE, ACh, and GABA • CRF causes the anterior pituitary gland to release ACTH (adrenocorticotropic hormone) into the blood stream • ACTH causes the adrenal glands (atop the kidneys) to increase the release of cortisol as well as other glucocorticoids – These substances all play a role in the stress response • Sympathetic reaction. • Normally increasing cortisol levels feedback to the brain and the HPA to shut down. 16.3 The HPA axis HPA • One consistent finding in depressed individuals is abnormal secretion of cortisol. – Many depressed patients have elevated cortisol levels – This is the result of greater-than-normal release of ACTH HPA • Depressed patients often have enlarged pituitary and adrenal glands – However, this enlargement is likely due to the increased activity that is asked of the glands, rather than the original abnormality – The hypersecretion is likely due to abnormal regulation of CRF by the hypothalamus • Studies have shown higher-than-normal CRF levels in the CSF (cerebrospinal fluid). – Also increased numbers of CRF-producing cells have been found in the hypothalamus • Postmortem • It has also been shown that antidepressant drugs and electroconvulsive therapy reduce CRF levels in depressed patients Circadian secretion of cortisol • Another consistent finding in depressed patients is an abnormal circadian rhythm of cortisol secretion • Notice the higher than normal levels, but also flatter release function for depressed patients • May reflect a general abnormality in the biological clock – Disrupted sleep and temperature patterns are also common Dextramethasone challenge • Depressed individuals also tend to fail to dextramethasone challenge. – Dextramethasone is a synthetic glucocorticoid – Should act as a negativefeedback stimulus • Suppress hypothalamic release of CRF • Suppress pituitary release of ACTH – Which should decrease cortisol levels • Depressed patients that don’t respond to dextramethasone challenge – more likely to relapse Consequences of altered glucocorticoid levels • Normal release of glucocorticoids is useful in preparing an organism for stress • When the levels are persistently elevated several systems begin to show pathological changes – Damage to immune system – Disrupts organ function – neuronal atrophy in hippocampus • Leading to cognitive impairment – imbalances in the serotonin system • Correlated with anxiety – hormonal changes • Associated with depression Altered biological rhythms • Not just cortisol • Altered sleep rhythms are very common in depression • Normal sleep cycle has 4 stages of nonREM sleep – lasting about 70-100 minutes • Followed by 10-15 minutes of REM sleep • You cycle through these stages 4 or 5 times per night • Depressed individuals have distinct abnormalities in their sleep rhythm • 1) long period before sleep onset • 2) significant decrease in time spent in slow-wave sleep • 3) onset of REM sleep occurs much earlier after onset of sleep finally begins • Can sometime occur immediately after falling asleep • 4) REM sleep is significantly increased during the first third of sleep. • 5) normally REM periods tend to increase as the night progresses, but depressed individuals do not show this pattern • 6) When ocular movement is measured depressed individuals show more frequent and vigorous eye movements. • Which suggests more intense dreaming. 16.5 Altered sleep architecture in depression (Part 1) 16.5 Altered sleep architecture in depression (Part 2) • These alterations in sleep patterns are similar to what happens when someone required to alter their sleep pattern by 12 hours • Sometimes circadian rhythms seem desynchronized – Sleep awake cycle – Temp cycle – Hormone cycle • Has led to novel treatment – Sleep deprivation therapy. Box 16.2 Sleep Deprivation Therapy (Part 1) Box 16.2 Sleep Deprivation Therapy (Part 2) • Animal models of depression • No perfect model – Animals don’t have feelings of worthlessness and guilt • Animals models can mimic certain aspects of depression – – – – Reduction in motor activity Changes in neuroendocrine response Cognitive changes Changes in eating and sleeping • Reserpine induced sedation – Reserpine blocks VMAT (vesicular monoamine transporter) – Causes DA and NE levels to drop to very low levels • Remember the reserpine rabbits (ch. 5). – Causes extreme sedation • Clinically viable antidepressants antagonize the effects of reserpine – so it is effective for testing monoamine based medications – Not useful for novel approaches that don’t involve the monoamine system • Behavioral despair or forced swim test • Rats become immobile after learning they cannot escape – Immobility is thought to reflect a lowered mood • Resigned to fate • Similar to learned helplessness – Depressed humans often express they feel hopeless and that nothing they do has an effect • Antidepressants reduce the amount of time spent freezing Maternal separation • Induce stress at an early age by separating young rats from their mothers for brief periods of time during the first few weeks of life • This model has shown that early stress can alter corticotropin releasing factor function – May predispose individuals to clinical depression later in life • Known as the stress-diathesis model of depression – Stress (early stress experiences) – Diathesis (genetic predisposition) Stress-diathesis model • They propose that the genetic character of depression is expressed by – lowered monoamine levels in the brain – increased reactivity of the HPA axis to stress • These factors create a lowered threshold for depression • Negative early life experiences may lower the threshold even further • Nemeroff et al. showed that maternal separation rats (during first 3 weeks of life) showed elevated stress responses later in life – – – – Elevated ACTH and cortisol levels Increased CRF in the brain Increased CRF gene expression Serotonin reuptake blockers reversed these effects • Not yet understood how 5-HT reuptake blockade modifies CRF activity Therapies for affective disorders • There are several drug classes that are effective antidepressants • All treatment methods require chronic administration. – Significant change can occur in 1-3 weeks, but maximum effectiveness may not be achieved for 4-6 weeks – Suggests that the clinical effect must depend on compensatory changes that take time to develop MAO-Is • Monoamine oxidase inhibitors – MAO-Is – Oldest antidepressants • Iproniazid used in 1950s to treat tuberculosis – It was noted that it had significant mood elevating effects • Can have severe and dangerous side effects – With appropriate dietary restrictions MAO-Is can be safe • Tend to work well with patients that don’t respond to other treatments and don’t want ECT • Also effective for anxiety and eating disorders (bulimia and anorexia nervosa). • Common MAO-Is – Phenelzine (Nardil) – tranylcypromine (Parnate) – Isocarboxazid (Marplan) Mechanism of action for MAO-Is • Monoamine oxidase is an enzyme that breaks down monamines (NE, DA, and 5-HT) • Inhibition of MAO increases the amount of monamines for release into the synapse • It is likely receptor density changes, or changes in second messenger function that leads to relief – The NT changes would occur almost immediately – However complete effects can take weeks to develop Side effects of MAO-Is • • • • Hypertension Insomnia Overeating MAO-Is inhibit MAO in the liver – MAO is responsible for deaminating tyramine • Tyramine is a by-product of fermentation in many foods • If these foods aren’t avoided than higher-than-normal NE levels can occur – Leading to dramatic increases in blood pressure – Headache, nausea, sweating, vomiting – Possible stroke – MAO-Is also inhibit other liver enzymes (cytochrome P-450) • Thus the effects of alcohol and other drugs can be intensified and prolonged. Tricyclic antidepressants • Named because the drugs all have a characteristic three-ring structure • Imipramine is the prototypical tricyclic antidepressant – Originally developed as an antipsychotic it was not very effective, but found to have mood elevating effects Tricyclic antidepressants: mechanism of action • Act by binding to the presynaptic transporter proteins. – Inhibit reuptake – Prolongs the duration of the NTs in the synapse – Eventually cause pre- and postsynaptic changes • Many tricyclics inhibit the reuptake of NE and 5-HT – Some are more effective at inhibiting one or the other • Doesn’t seem to influence the drugs effectiveness • Does determine side effects Tricyclic antidepressants: side effects • Most TCAs also block choline, histamine, and α-adrenergic receptors – Which influences side effects • Histamine receptor blockade can cause sedation and fatigue • Cholinergic receptor blockade can cause drymouth, constipation, urinary retention, dizziness, confusion, blurred vision, and impaired memory • α-adrenergic receptor blockade along with increased synaptic NE can lead to hypotension, tachycardia, and arrhythmia – Particularly problematic for elderly patients with cardiac disorders • Low therapeutic index – 10 times the normal dose can cause fatalities – Particularly problematic given that these drugs are being supplied to patients that are potentially suicidal Second-generation antidepressants • These drugs are an attempt to provide faster onset of action with fewer side effects. • They were designed to more selective in their action. – Avoiding anticholinergic and cardiovascular effects of previous drugs • Turns out that none of the drugs are more effective nor do they have a faster onset • The biggest difference is the nature of their side effects Selective serotonin reuptake inhibitors (SSRIs) • Drugs in this class include – Fluoxetine (Prozac) – Sertraline (Zoloft) – Paroxetine (Paxil) • They are useful to treat depression but have also been used to treat anxiety disorders, obesity, and alcoholism • The SSRIs are safer than other antidepressants • The SSRIs are more selective than TCAs in enhancing serotonin function. – Block 5-HT transporter more than noradrenergic transporter • Takes several weeks to see full effects Side effects of SSRIs • Do not affect NE, ACh, or histamine • Thus SSRIs do not produce sedation, cardiovascular toxicity, or anticholinergic side effects • However there are side effects related to the increased serotonin activity – – – – – – – – Anxiety Restlessness Movement disorders Muscle rigidity Nausea Headache Insomnia Sexual dysfunction (occurs in 40-70% of patients) • A major reason that patients terminate treatment – Especially young males Side effects of SSRIs • SSRIs are generally safer than than TCAs and MAOIs • Can have life-threatening effects when combined with other serotonergic agonists, or drugs that interfere with the metabolism of SSRIs – Referred to as serotonin syndrome • • • • • Severe agitation Disorientation and confusion Ataxia Muscle spasms Exaggerated autonomic activity – – – – – – Fever Shivering Chills Diarrhea Hypertension Increased heart rate SSRIs and dependence • Also can cause physical dependence – About 60% of patients experience withdrawal when treatment is terminated – Can last for several weeks • • • • • • • • • • • Dizziness Ataxia Nausea Vomiting Diarrhea Fatigue Chills sensory disturbances Insomnia Vivid dreams Anxiety Irritability Third generation antidepressants • The newer versions of antidepressants have returned to affecting both the NE and 5-HT system – Mirtzapine (remeron) • Causes increased release of NE and 5-HT at the synapse • There are also SNRIs (serotonin norepinephrine reuptake inhibitors) – Duloxetine (cymbalta) – Venlafaxine (Effexor) • Third generation antidepressants resemble tricyclics but with fewer side effects Electroconvulsive therapy • Hungarian psychiatrist (early 1900s) – spontaneous seizures = improved mood • Psychiatrists began inducing seizures as a treatment for depression – Administer insulin • In 1938 electroconvulsive therapy (ECT) was introduced – Still used today – Generally for patients that don’t respond to drugs • ECT effectiveness is 80-90% – Higher than conventional treatments – Low incidence of side effects • Public tends to consider it archaic which limits its use • Must be administered several times a week for several weeks to be effective ECT mechanism of action • Enhances the function of several neurotransmitter systems – NE, 5-HT, DA, and GABA • Repeated treatments lead to down-regulation of β2- and α2adrenergic receptors • Has a low incidence of side effects – Makes it very appropriate for those with cardiovascular disorders, elderly, medically ill, and pregnant women • Most significant side effect is confusion and memory loss. • Can cause anterograde amnesia for several days to weeks after treatment • Also can cause retrograde amnesia for events preceding treatment – Squire – t.v. programs that only ran for one year. – Can lose memory for time during ECT and several months prior to treatment Transcranial magnetic stimulation • TMS is a new brain stimulation technique – Place a magnet on the scalp – Causes a localized current in the brain • There is evidence that this treatment can be effective – – – – Noninvasive Painless No convulsions Anesthesia not necessary Drugs to treat bipolar disorder • Lithium carbonate is the most effective treatment • Has no effect on mood or behavior of normal individuals • One to two weeks of lithium eliminates or reduces symptoms in 60-80% of manic episodes. – Does not cause depression or produce sedation • Not as effective at terminating episodes of depression – So it is often administered with antidepressants • Very good at reducing future episodes of mania and depression – Those that continue with lithium maintenance • Less than 2 weeks in hospital per year – Without lithium • 8-13 weeks in hospital per year – See next figure 16.10 Lithium’s effectiveness for bipolar disorder (Part 1) • Most patients require lifetime treatment with a mood stabilizer (lithium) • Stopping use causes symptoms to return • Still many stop – Don’t like side effects • Impaired memory and confusion • Fail to experience normal mood swings • Object to the loss of the manic phase – Todd Mechanism of action of mood stabilizers • Lithium enhances 5-HT actions – Elevates tryptophan, 5-HT, and 5-HIAA (major metabolite) • The increase in serotonin eventually alters synaptic function • Reduces catecholamine activity by enhancing reuptake and reducing release • Despite these direct effects scientists suspect the major action of lithium is on second messenger function • Its ability to alter second messenger function regardless of the NT system may be what allows it to limit extreme swings of mood in either direction Side effects of lithium • Lithium is not metabolized – Excreted by kidney – The rate of excretion is dependent on sodium levels – If the patient is sodium deficient lithium can build up • Side effects at therapeutic levels are mild – – – – – Thirst and increased urination Impaired concentration and memory Fatigue Tremor Weight gain Side effects of lithium • The therapeutic index is low – Blood levels must be monitored – If levels get too high • • • • • • Cramps Vomiting Diarrhea Kidney dysfunction Tremor Confusion – Very high levels can lead to seizures, coma, and death Other therapies for bipolar disorder • New drugs – Carbamazepine (tegretol) – Valproate (depakene) – Topiramate (topamax) – Tiagabine (gabitrol) • Have different toxicity profile from lithium • Similarly effective 16.10 Lithium’s effectiveness for bipolar disorder (Part 2) Monoamine hypothesis • Neurochemical basis of mood disorders • The earliest theory was the monoamine hypothesis – Depression is the result of low monoamine levels – Mania is the result of high monoamine levels • Originated with the observation that reserpine (high blood pressure med) induced depression as a side effect in many patients – We know that reserpine blocks VMAT • Causing depletion of monoamines – Led to the idea that reduced levels of monoamines was responsible for depression • More support came when the mechanism of action for TCAs and MAO-Is was considered – increase the activity of NE and/or 5-HT – Drugs in both classes reverse reserpine-induced reduction in motor activity. 16.11 Effects of reserpine, the MAO-I iproniazid, and the TCA imipramine on rat locomotor activity Monoamine hypothesis • It was shown that depressed patients had reduced levels of NE and 5-HT metabolites (MHPG and 5-HIAA) • It was shown that the manic-like activity produced by amphetamines and cocaine was associated with increased catecholamine release – With prolonged use depletion of these NTs occurred leading to depression, lethargy, and drug craving • If you put all of these pieces of evidence together, it provides support for the monoamine hypothesis. Monoamine hypothesis • However, the monoamine hypothesis is now considered to be too simplistic. – The most important problem with the theory is that it fails to account for the time lag in effectiveness of antidepressant treatments – It is also unclear which NTs are most important, and how they specifically contribute to the disorder. • We suspect NE and 5-HT, but these systems are very complicated and appear to be capable of interacting with each other. • Nevertheless, the monoamine hypothesis has been extremely influential. Driving modern research on mood disorders for decades. Serotonin dysfunction • Face validity – Serotonin has influence on sensitivity to pain, emotionality, and response to reward and punishment. – Also sleep, eating, and thermoregulation • Rats with depleted stores of 5-HT – Irritable and aggressive – Overly sensitive to pain – Altered eating patterns Serotonin dysfunction • 1) turnover – Measure principle metabolite • 5-HIAA – High 5-HIAA are assumed to reflect increased function of serotonin • Lower = lower – Low 5-HIAA found postmortem in depressed individuals and suicide victims – Low 5-HIAA found in CSF of depressed individuals • Blood and urine levels have not led to conclusive results Serotonin dysfunction • 2) precurser levels – Tryptophan • Frequently low in depressed patients • When formerly depressed patients are rapidly depleted of tryptophan depressed symptoms returned to many of the patients • 3) receptor binding – Postmortem analysis showed increased density of postsynaptic 5-HT2 receptors in unmedicated individuals. • Could be compensatory change due to low serotonergic activity – Animal studies show chronic antidepressants lead to down regulation of 5-HT2 receptors – Table 16.4 shows that almost all treatments lead to down regulation of 5-HT2 • ECT is the only exception Serotonin dysfunction • 4) PET scans – Depressed patients show increased activity in medial orbitofrontal cortex and amygdala • Areas that are known to be involved in emotion – Activity in amygdala is correlated with severity of depression • Returns to normal after antidepressant drug treatment – Activity in orbitofrontal cortex may reflect effort to control unpleasant thoughts and emotions Serotonin effects in animals • Acute versus chronic effects of antidepressants • Acute – Reuptake blocked • 5-HT lingers in synapse – Autoreceptors activated • Decreased release • Two effects cancel each other out Serotonin effects in animals • Chronic effects – Tolerance (down regulation) of autoreceptors occurs • Now there is an increase in 5-HT release – Reuptake blockade remains • 5-HT lingers • Now both actions lead to an increase in 5-HT activity Serotonin effects in animals • This difference between acute and chronic effects of antidepressants in animals may explain the lag in antidepressant effectiveness. • It has also been shown that the electrophysiological response to serotonin agonists is increased by long-term antidepressant treatment – This effect can take 15 days to fully develop • Also follows the time course of antidepressant effectiveness – See table 16.4 again – This finding supports the notion that treatment has led to receptor changes that have increased the sensitivity of the serotonergic system • It is not fully understand how down regulation of serotonin receptors can lead to increased responsiveness to 5-HT agonists – Perhaps it has to do with differences in changes to presynaptic and post synaptic receptors we discussed above • Tolerance in presynaptic autoreceptors? • Sensitization in postsynaptic receptors? Norepinephrine dysfunction • Face validity of NE – Adrenergic system is involved in • • • • Endocrine effects Reward Attention and arousal Stress response • Animal studies – electrical stimulation of locus coeruleus produces • Vigilance • Anxiety • Inhibition of exploration – Electrical recording in locus coeruleus shows • Increased activity during threatening situations • Decreased activity during sleep, grooming, and feeding – Antidepressant drugs • decrease firing rate of locus coerulus • reduce NE metabolites Norepinephrine dysfunction • Human studies are not conclusive • MHPG (major NE metabolite) – Higher, lower, no change – Generally found to be higher in patients undergoing treatment • Suggests an increase in NE turnover due to antidepressant use • Untreated unipolar and bipolar patients do not show differences in adrenergic receptor binding • Chronic treatment causes down regulation of both β-receptors and α2-autoreceptors. – Unfortunately these effects are opposite to one another • Decrease autoreceptors = increase activity • Decrease postsynaptic receptors = decrease activity • It would seem that the down regulation of autoreceptors may eventually win out. – Like we discussed with serotonergic system – Leading to increased noradrenergic turnover • Down-regulation of β-receptors is a very consistent finding across treatments for depression – TCAs, MAO-Is, SSRIs, SNRIs, ECT, Lithium – Takes 7-21 days NE and 5-HT modulate one another • Most consistent finding of antidepressants are down-regulation of β-receptors and 5-HT2 receptors and an enhanced physiological response to 5-HT • Sulser (1989) proposed a “serotoninnorepinephrine” hypothesis of depression • Comparing the noradrenergic and serotonergic systems shows considerable structural and functional overlap. – See Figure 16.14 Serotonin-norepinephrine hypothesis • Destroying 5-HT terminals prevents down regulation of β-receptors due to chronic antidepressant treatment • 5-HT agonists can indirectly stimulate the noradrenergic system – Causing β-receptor down-regulation • Increased noradrenergic activity can increase activity in the raphe nuclei Neurobiological models of depression • Glucocorticoid hypothesis – Focuses on the abnormalities that are seen in stress hormones for depressed patients • The hippocampus has receptors that when activated by high levels of glucocorticoids help to inhibit CRF release from the hypothalamus • When prolonged or intense stress occurs these hippocampal neurons are damaged and stop responding – This causes the negative feedback system to fail – Increasing cortisol levels then lead to further hippocampal damage – Could lead to the cognitive symptoms of depression • Antidepressant drugs reverse this damage and increase neurogenesis in the hippocampus Glucocorticoid hypothesis • Intracerebroventricular administration of CRF elicits stress-responses in animals – Enhanced cortisol levels – Sympathetic activity • Clinical tests of CRF antagonists are in the works – R121919 • Preliminary findings – Decreases anxiety and depression scores – Minimal side effects Neurotrophic hypothesis • Focuses on the mechanism of hippocampal neuron loss that occurs following stress • Stress causes deficits in neurotrophic factors – Such as BDNF (brain-derived neurotrophic factor). – Needed during neural development – Also regulate changes in adult neurons • This theory posits that decreases in neurotrophic factors leads to atrophy of neurons – And that antidepressants may protect cells by preventing this decrease • Been shown that – 1) chronic stress reduces BDNF in hippocampus of rats – 2) chronic antidepressant treatment increased BDNF in both animals and humans • Not acute – 3) antidepressants prevent stress-induced reductions in BDNF • There is no way to directly inject BDNF into humans as a treatment • BDNF is dependent on cAMP second messenger system – Appears that with chronic treatment the down regulation of βand 5-HT receptors lead to an increase in cAMP activity • It may be possible to increase BDNF production by enhancing the cAMP cascade directly. – Perhaps by inhibiting phosphodiesterase • An enzyme that normally degrades cAMP – Perhaps by activating CREB • A transcription factor that induces the production of cAMP 16.16 Up-regulation of second-messenger pathway by chronic antidepressant treatment