Psychiatry

There are a number of psychiatric disturbances that accompany neurologic illnesses (e.g., Alzheimer disease, Parkinson disease, stroke, multiple sclerosis, and epilepsy) and neurological manifestations of primary psychiatric disorders (e.g., schizophrenia, depression, mania, anxiety, substance abuse, and obsessive-compulsive disorder [OCD]). The study of the psychiatric manifestations of neurologic diseases and investigation of the neurobiological basis of psychiatric illnesses has produced a remarkable convergence of data regarding the anatomic substrates of behavioral disorders. Hence, this compendium would not be complete without a survey of the major “primary” psychiatric disorders that neurologists are likely to encounter often during the course of their practice.

Some examples of the convergence between neurology and psychiatry are shown here:

Poststroke depression develops in one-third of all stroke survivors and has a negative impact on recovery, rehabilitation, and quality of life. Although more commonly associated with involvement of the dorsolateral prefrontal cortex and the caudate nuclei, the localization value of depression is poor.
Psychosis has been associated with a variety of neurologic diseases that affect the temporal lobes, and studies of the brains of schizophrenic patients have revealed consistent temporal lobe abnormalities.
Neurologic diseases associated with OCD nearly all involve subcortical structures of prefrontal-subcortical circuits, and PET studies of idiopathic OCD implicate this same circuitry. The ventral capsule/ventral striatum and subthalamic nucleus have become targets of deep brain stimulation in severe OCD.
Psychiatric symptoms in neurologic diseases can guide psychiatric disorders (e.g., dopaminergic therapy-induced psychosis in Parkinson disease supports the theory of dopaminergic hyperactivity in schizophrenia).
Neurological symptoms in psychiatry diseases can guide neurological disorders (e.g., response of OCD to serotonergic agents has supported use of same agents to treat OCD in neurologic disorders).

Behavioral neurology is the discipline within neurology most closely allied with psychiatry since it aims at explaining the neurobiological basis of “negative symptoms” (deficit syndromes), including aphasia, amnesia, agnosia, apraxia, and neglect. Psychiatry aims at delving into the “positive symptoms,” which include hallucinations, delusions, depression, mania, anxiety, and OCD. Neuropsychiatry is the discipline that integrates the neuroanatomy and cognitive neuropsychology of both “negative” and “positive” symptoms and is growingly becoming an important field within neurology. Neuropsychiatry is based on neuroanatomy and neurophysiology and attempts to understand the mechanisms of behavior, whereas psychiatry explains the motivations of behaviors using methods from the fields of psychology, sociology, and anthropology. Neuropsychiatry applies a neurobiological approach to behavior; psychiatry places behavior in a social-cultural context. Human behavior is the common denominator for these disciplines and the critical target of neurologists.

Depression

Depression consists of a pervasive depressed mood or anhedonia, which causes significant social and occupational dysfunction. The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria require five or more of the following symptoms during the same 2-week period, with at least one of the symptoms being either depressed mood or loss of interest or pleasure in activities of daily life (not clearly attributable to another medical condition).

Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g., appears tearful).
Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day.
Significant weight loss when not dieting or weight gain (e.g., a change of >5% of body weight in a month), or decrease or increase in appetite nearly every day.
Insomnia or hypersomnia nearly every day.
Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).
Fatigue or loss of energy nearly every day.
Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).
Diminished ability to think or concentrate, or indecisiveness, nearly every day.
Recurrent suicidal ideation with or without a specific plan to commit suicide.

The lifetime prevalence is between 5% and 9% in females and 2% to 4% in males. About 50% of those who have had a major depressive episode will have a recurrence. Comorbid disorders include alcoholism (60% of alcoholics develop depression), eating disorders (60%), and panic disorder (80%).

Depression may cause (1) shortened latency of REM sleep; (2) suppression of endogenous cortisol secretion after a dexamethasone suppression test (injection of 1 mg IM of dexamethasone; caveat: dementia and weight loss may cause nonsuppression); and (3) lack of elevation of TSH to thyrotropin-releasing hormone.

The DSM-5 lists eight specific disorders recognized under depressive disorder:

Disruptive mood dysregulation disorder
Major depressive disorder (including major depressive episode)
Persistent depressive disorder (dysthymia)
Premenstrual dysphoric disorder
Substance/medication induced depressive disorder
Depressive disorder due to another medical condition
Other specific depressive disorder
Unspecified depressive disorder

In addition, DSM-5 added two specifiers: with anxious distress, and with mixed features.

Antidepressant Drugs

“Real-world” effectiveness of antidepressants by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial supported a start with citalopram, followed, if no response, by sertraline, venlafaxine, or bupropion, or the addition of another medication or cognitive behavioral therapy. Escitalopram, sertraline, and extended-release venlafaxine yield similar responses at 8 weeks. For moderate-to-severe depression, first-line medications include SSRIs, SNRIs, bupropion, and mirtazapine.

Selective Serotonin (5-HT) Reuptake Inhibitors (SSRIs)

Common side effects include sexual dysfunction, insomnia, agitation, anxiety, headache, and anorexia. Effective in (and, in the case of fluvoxamine, approved for) OCD and panic disorder
Fluoxetine (Prozac)		10-20 mg → 80 mg/d [20]	Longest T½ (9 d). Risk of SIADH. 95% protein bound
Paroxetine (Paxil)		20 mg → 60 mg/d [20, 30]	Dizziness, diarrhea, mild dry mouth, constipation
Sertraline (Zoloft)		50 mg → 200 mg/d [50, 100]	Mild dry mouth. Diarrhea is more common
Fluvoxamine (Luvox)		50 mg → 150 mg bid [25, 50, 100]	Only SSRI approved for kids. Avoid theophylline and warfarin
Citalopram (Celexa)		20 mg → 40 mg/d [20]	Effective also for premenstrual syndrome
Escitalopram (Lexapro)		10 mg → 20 mg/d [10, 20]	Excellent tolerance
Vilazodone (Viibryd)		10 mg → 40 mg/d [10, 20, 40]	Excellent tolerance
Vortioxetine (Trintellix)		10 mg → 20 mg/d [5, 10, 20]	Excellent tolerance
5-HT₂, 5-HT₃ antagonists	Nefazodone (Serzone)	50 mg bid → 300 mg bid [100, 150, 200, 250]	Orthostatic hypotension, somnolence, dry mouth, no risk of sexual dysfunction
	Trazodone (Desyrel)	50 mg → 400 mg/d/bid [50, 100, 150, 300]	Orthostatic hypotension, priapism (rare), sedation

Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)—Non-Tricyclics

Venlafaxine (Effexor)	25 mg tid → 225 mg/d [25, 37.5, 50, 75, 100]	HTN, nausea, insomnia, anxiety, dry mouth, also approved for anxiety disorder
Desvenlafaxine (Pristiq)	50 mg/d	HTN, nausea, somnolence, off-label use for anxiety disorders
Duloxetine (Cymbalta)	30 mg → 60 mg/d [30, 60]	Also beneficial for peripheral neuropathy, may increase energy
Sertraline is the safest SSRI when there is coadministration with tricyclic antidepressants, neuroleptics, and type I antiarrhythmic agents such as quinidine because it has the smallest effect on the P450 2D6 liver microsomal enzyme. Both paroxetine and sertraline also have minimal effects on P450 3A34, responsible for clearing the largest number of nonpsychiatric drugs as well as several benzodiazepines. Citalopram did not improve functional recovery in nondepressed ischemic stroke patients. Escitalopram did not reduce moderate or severe depressive symptoms in acute stroke patients. Fluoxetine did not improve functional outcome after acute stroke.

SNRIs—Tricyclics (TCA)—Tertiary amines (primarily serotonin)

Anticholinergic effects and α-blocking effect (sedation, orthostatic hypotension). Contraindicated in glaucoma, urinary retention, and cardiac disorders (long QTc). Sexual dysfunction may occur.
Amitriptyline (Elavil)	25 mg → 300 mg qhs [10, 25, 50, 75, 100, 150]	High sedation and anticholinergic activity
Clomipramine (Anafranil)	25 mg → 250 mg qhs [25, 50, 75]	High seizure risk, sedation, Effective for OCD
Doxepin (Sinequan)	25 mg → 300 mg qhs [10, 25, 50, 75, 100, 150]	Sedating
Imipramine (Tofranil)	25 mg → 300 mg qhs [10, 25, 50, 75, 100, 150]	Sedating. Demethylated to Desipramine. Panic disorder
TCA levels are increased by fluoxetine, neuroleptics, H₂-blockers, estrogens, valproate, and methylphenidate and decreased by barbiturates, CBZ, PHT (P-450 inducers), and cigarette smoking. Pharmacologic augmenters of antidepressants include lithium, triiodothyronine (T₃), stimulants, neuroleptics, and L-tryptophan. Nonpharmacologic interventions include sleep phase advancement, high-intensity (>2,500 lux) light, ECT, and high-frequency repetitive transcranial magnetic stimulation (rTMS) over the DLPFC. DBS of the ventral anterior limb of the internal capsule can be considered for treatment-resistant cases.

SNRIs—Tricyclics—Secondary Amines (Primarily Norepinephrine)

Anticholinergic and α-blocking effect (sedation, orthostatic hypotension), less severe. It may lower seizure threshold. Arrhythmogenic by leading to AV delay and long QTc.
Desipramine (Norpramin)	25 mg → 300 mg qhs [10, 25, 50, 75, 100, 150]	Stimulant effect: am dose prevents insomnia. Panic disorder
Nortriptyline (Pamelor)	25 mg → 150 mg/tid-qid [10, 25, 50, 75]	Sedating. Effective for poststroke depression, panic disorder
Protriptyline (Vivactil)	15 mg → 60 mg/tid-qid [5, 10]	Effective for sleep apnea
Amoxapine (Asendin) (tetracyclic)	25 mg bid → 300 mg/d [25, 50, 100, 150]	Tardive dyskinesia, NMS, galactorrhea. No CV effects
Nortriptyline is the tricyclic of choice given its mild sedating properties (useful in agitated patients to promote sleep), lower propensity to cause orthostatic hypotension, fewer anticholinergic side effects, and availability of easily interpretable blood levels (therapeutic level is 50-150 ng/dL).

Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)

Contraindicated when there is history of seizures, bulimia, and anorexia but good choice (along with nefazodone) if there are sexual side effects from other agents. Seizures threshold is not substantially lowered with the newer SR or XL formulations. Bupropion is a mild stimulant and is preferred over SSRIs in depressed patients with bipolar illness and adults with ADHD. Its dopaminergic and noradrenergic effect have prompted its use to increase energy and drive, as with the psychostimulant modafinil and the dopamine agonist pramipexole.
Bupropion (Wellbutrin)	100 mg bid → 150 mg tid [75, 100, SR-100, SR-150]	Agitation, hypertension, insomnia, tremor, constipation

Norepinephrine Antagonist and Serotonin Antagonist (NASA)

It inhibits serotonin reuptake and blocks 5-HT₂ and 5-HT₃ receptors. The risk of agranulocytosis is about 0.1%. Mirtazapine, along with paroxetine and trazodone, may be helpful in insomnia, though trazodone (see above) may not help mood and may cause priapism.

Mirtazapine (Remeron)

15 mg → 45 mg qhs [13, 30]

Risk of agranulocytosis. Sedation, weight gain

Besides nefazodone, mirtazapine, and bupropion avoid sexual dysfunction and the latter may boost sexual performance at doses equivalent to 150mg bid (SR formulation). Mirtazapine’s weight-gain side effect is considered an advantage in cases where weight loss is a problem; bupropion, on the other hand, can induce further weight loss.

Agomelatine is a novel melatonergic agonist and a 5-HT2c antagonist. The melatonergic function appears to improve sleep patterns, whereas the serotonergic antagonism results in the release of norepinephrine and dopamine. Agomelatine has no discontinuation syndrome, exhibits infrequent sexual dysfunction, and is weight neutral.

Monoamine Oxidase Inhibitors (MAOI)

Potential risks are hypotension, insomnia, and sexual dysfunction (anorgasmia, ejaculatory incompetence). Concomitant use of sympathomimetics (epinephrine, norepinephrine, and pseudoephedrine) and the intake of tyramine-rich foods may cause a hypertensive crisis. Other complicating drugs are meperidine or dextromethorphan (delirium), SSRIs (serotonin syndrome; see elsewhere in this book). Peripheral neuropathy results from vitamin B6 malabsorption. Weight gain follows carbohydrate craving. Finally, a reversible lupus-like reaction and hyperprolactinemia have been reported.
Phenelzine (Nardil)	15 mg tid → 90 mg/d [15]	Must be on tyramine-free diet for 2 wk after stopping. Risk of hypertensive crisis and serotonin syndrome. 2 wk washout between MAOI and SSRIs and TCAs
Tranylcypromine (Parnate)	10 mg am → 60 mg/d [10]
Isocarboxazid (Marplan)	10 mg bid → 60 mg/d [10]

Bipolar Disorder

Bipolar spectrum encompasses episodes of mania alternating or mixed with episodes of depression. Mania is a persistently elevated, expansive, or irritable mood that may be accompanied by decreased need for sleep, talkativeness, flight of ideas, distractibility, increase in goal-directed activity or psychomotor agitation, and excessive involvement in highly pleasurable and potentially risky activities. Males and females are equally affected and 15% of first-degree relatives have affective disorders. Alcohol and drug abuse are more prominent than in unipolar patients. The recurrence after a single manic episode is 90%. The concordance rate among monozygotic twins is 70% to 80%. Rapid cycling (four or more episodes a year) occurs in 10% of patients, mostly women and patients on TCA. Childhood-onset psychotic depression is more likely to become acutely bipolar at the onset of puberty, especially if there is TCA-induced hypomania, hypersomnic depression, and bipolar family history. Cyclothymic disorder applies to those whose mood never meet criteria for depression or mania but occur frequently for at least 2 years with a symptom-free interval never longer than 2 months at a time.

Bipolar disorder II (“bipolar disorder NOS”) refers to those whose episodes of hypomania and major depression do not meet criteria for bipolar disorder. Comorbidities include borderline personality disorder, eating disorders, and substance abuse.

Lithium is the drug of choice for bipolar disorder, schizoaffective disorder, prophylaxis against recurrent unipolar depression, and intermittent explosive disorder. The side effects include hypothyroidism (TSH monitoring warranted), diabetes insipidus, weight gain, acne, arrhythmias, psoriasis, leukocytosis, downbeat nystagmus, periodic alternating nystagmus, and tremor. Lithium is to be avoided in the elderly and those with renal insufficiency, dehydration, and suicidal ideation (to prevent overdose).

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