/ \202 uoxetine combination for major depression with psychotic features. J Clin Psychopha rmacol 24: 365 \200\22373), olanzapine/sertraline vs. olanzapine/placebo (Meyers BS, Flint AJ, Rothschild AJ, et al. (2009) A double-blind randomized controlled trial of olanzapine p lus sertraline vs. olanzapine plus placebo for psychotic depression: the study of pharmacot herapy of psychotic depression (STOP-PD). Arch Gen Psychiat 66: 838 \200\22347), and for OF C (olanzapine \200\223 \202 uoxetine) vs. olanzapine or \202 uoxetine alone (Trivedi MH, Thase ME, Osuntokun O, et al. (2009) An integrated analysis of olanzapine/ \202 uoxetine combination in clinical trials of treatment resistant depression. J Clin Psychiatry 70: 387 \200\22396). 3 Wijkstra J, Lijmer J, Balk FJ, et al. (2006) Pharmacological treatment for unipolar psychotic depres- sion: systematic review and meta-analysis. Br J Psychiat 188: 41 0 \200\22315. 07_Semple_Chap07.indd 259 12/10/2012 6:36:10 PM CHAPTER 7 Depressive illness 260 An approach to treatment-resistant depression Commonly de \201 ned as \200\230failure to respond to adequate (dose and dura- tion \200\224i.e. max BNF dose for at least 4 wks) cour ses of 2 antidepressants, or 1 antidepressant and ECT \200\231. The consequences of resista nt depression include reduced quality of life, excessive strain on relationships (which may lead to break-up of families), signi \201 cant personal economic impact, increased physic al comorbidity (e.g. malignancy, cardiovascular disease, even premature death), increased r isk of suicide, therapeutic aliena- tion (making further interventions dif \201 cult due t o dif \201 culties forming a therapeutic alliance), and high use of psychiatric services ( without clear bene \201 t). Differentiating treatment resistance It is important to distinguish actual treatment resist ance from chronicity of symptoms. Apparent treatment failure may also occur due to: incorre ct initial diagnosis (i.e. not depressive disorder in the \201 rst place), inadequate ini tial treatment, poor compliance, incomplete formulation (esp. role of maintaining factors), and issues of comorbidity (both physical and other psychiatric disorders). Risk factors for treatment resistance Concurrent physical illness, drug/alcohol abuse, pers onality disorder, high premorbid neuroticism, long period of illness prior to treatment. Management1 \200 Review diagnostic formulation: unaddressed maintaining factors (e.g. social, physical, psyc hological)? Note: a proportion of individuals with chronic, refractory depression will have unrecognized bipolar disorder. Check patient understanding/compliance: Continue monotherap y at maximum tolerable dose: BNF guidelines (esp. if there has been partial bene \201 t). Consider change in antidepressant: Consider augmentation with a mood stabilizer: Consider a dditional augmentative agents: Box 7.4). Consider combining antidepressants from different classes: caution is advised, due to possible serious adverse reactions (e.g. b p. 960). Con sider use of ECT: psychotic symptoms). Consider possibility of psychosurgery or other advan ced intervention: b pp. 296 \200\2239. is diagnosis correct? Are there any \200 serum levels may help. may mean exceeding \200 \200 try different class of antidepressant. e.g. lithium. e.g. T3, tryptophan (see see b p. 284 (esp. if severe biological features or see 1 Useful guidance and assessment tools for treatment-resistant depression including advice regard- ing criteria for \200\230adequate treatment \200\231 can be found on the Dundee Ad vanced Intervention Service website: M http://www.advancedinterventions.org.uk/library_tool s.htm 07_Semple_Chap07.indd 260 12/10/2012 6:36:10 PM AN APPROACH TO TREATMENT-RESISTANT DEPRESSION 261 Points to note \200 There is little de \201 nitive evidence to support any speci \201 c augmentative regime ( see Box 7.5). Spontaneous remission is possible: \200\230regression to the mean \200\231 s uggests that symptoms will improve; bear in mind that the natural life of depression is 6 \200\22318mths, even when untreated. Psychological and social interventions, particularly w hen psychosocial factors appear paramount, may be important (often overlooked or undisclose d) aspects of management. Box 7.4 Tryptophan (L-Tryptophan, Optimax ) \200 \200 Mode of action: Indications: resistant depression (lasting more than 2yrs). Usual dose: Com mon adverse effects: eosinophilia \200\223myalgia syndrome (rare, monitoring of FBC necessa ry). precursor for serotonin. restricted specialist use as an adjunct for treatment- \200 1g tds, increased to max 6g/day. drowsiness, headache, nausea, dizziness, Box 7.5 STAR*D trial The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial is one of the lar gest independent studies undertaken by the NIMH to examine the effectiveness of a variety o f treatments for non-psychotic major depression. The initial report was published in the Am erican Journal of Psychiatry in Nov. 2006.1 \200 A fairly representative outpatient sampl e ( steps: \200 \200 n = 3671) underwent 4 Level 1 Level 2 cognitive therapy) or combine (bupropion, buspirone, cognitive therapy); Le vel 2a switch to bupropion or venlafaxine XR; Level 3 lithium or T3); Level 4 \200\224 plus mirtazapine). \200\224citalopram; \200\224switch (to bupropion, sertraline, venlafaxine XR, or \200\224if cognitive therapy alone or plus citalopram add or \200\224switch (to nortriptyline or mirtazapine) or augment (with switch (to tranylcypromine) or combine (venlafaxine XR Remission rates were 37%, 31%, 14%, and 13% for each level, with an overall cumulative remi ssion rate of 67%. The trial highlighted patient preference for combinations/ augmentations and provided some evidence to support certain strategies: e.g. lithium or T3 augmentation; combining citalopram plus bupropion, buspirone, or venlafaxine plus mirtazapine. 1 Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006) Acute and longer-term outcomes in depre ssed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiat 1 63: 1905 \200\22317. 07_Semple_Chap07.indd 261 12/10/2012 6:36:10 PM CHAPTER 7 Depressive illness 262 Atypical depressive episode Regarded as a subtype of depressive disorder, rather than a sep arate entity. Atypical features coded in DSM-IV as an \200\230episode speci \201 er \200 \231 (like melancholic, post-partum, catatonic). Listed under \200\230other depressive epi - sodes \200\231 in ICD-10. Clinical features \200 Mood is depressed, but remains reactive (able to enjoy certain experiences but not to \200 \230normal \200\231 levels). Hypersomnia (sleeping more than 10hrs/day, at least 3 days/wk, for at least 3mths). Hyperphagia (excessive eating with weight gain of over 3kg in 3mths). \200\230Leaden paralysis \200\231 (feeling of heaviness in the limbs, present for at leas t 1hr/day, 3 days/wk, for at least 3mths). Over-sensitivity to perceived rejection. Other i nfrequent symptoms may include: initial insomnia rather than early morning wakening (EMW); reversed diurnal mood variation (better in the morning); severe motor retardation; absence of feelings of guilt. \200 \200 1 Epidemiology Onset usually in late teens and early twenties, often (up to 30%) family histo ry of affective disorders. Comorbidity Higher rates of anxiety (esp. panic disorder and soc ial phobia), somatization disorder (see b p. 802), alcohol and drug misuse than in other de pressive disorders. Management \200 Best evidence is for the use of phenelzine (15mg/day increased gradually to 60 \200\22390mg /day in divided doses \200\224continue for 8 \200\22312wks to assess bene \201 t) or anoth er monoamine oxidase inhibitor (MAOI) (see b p. 272 for guidance on prescribing/dietary adv ice). RIMAs theoretically ought to be as effective and safer (but evidence is lacking). Alt ernatives include SSRIs (e.g. \202 uoxetine or sertraline), or possibly a NARI (e.g. rebo xetine). TCAs have traditionally been regarded as less effective. However, some individuals may respond well, and the best evidence is for the use of imipramine. Where there is failu re to respond to an adequate trial of an antidepressant, follow management principles outli ned at b pp. 256 \200\2239 and b p. 260). 1 \200\230Rejection sensitivity \200\231 (to both real and imagined rejection) adds to the dif \201 culty of managing atypical depression, as the patient may have had adverse exper iences with doctors in the past, been labeled as \200\230personality disordered \200\231, and may \201 nd the idea of a therapeutic alliance alien. 07_Semple_Chap07.indd 262 12/10/2012 6:36:10 PM SEASONAL AFFECTIVE DISORDER 263 Seasonal affective disorder (SAD) Somewhat controversial concept, both in terms of diagnosi s (see clini- cal features) and treatment (using light therapy \200\224b p. 298). In DSM-IV seasonal pattern is included in speci \201 ers describing the course of recur- rent depre ssive episodes of both depressive and bipolar disorder. Included under \200\230recurrent d epressive disorder \200\231 in ICD-10. Clinical features There must be a clear seasonal pat tern to recurrent depressive episodes (i.e. they have occurred at the same time of year eac h time and fully remit once the season is over). In the northern hemi- sphere this is said to be usually around January/February ( \200\230winter depres- sion \200\231). Symptoms are generally mild to moderate with low self-esteem, hypersomnia, fatigue, increased appetite (including carbohydrate craving), weight gain, and decreased social and occupational functi oning. Etiology It is unclear whether this constitutes a separate subtype of depressive dis order, or whether it is simply a manifestation of atypical depression (see b p. 262). The s peculated mechanism involving mela- tonin synthesis has not been con \201 rmed in controll ed studies, and some authors suggest that seasonal psychosocial factors may be more importa nt in determining the timing of recurrent depressive episodes (e.g. increased work demands over the Christmas and New Year periods for shop- workers). Epidemiology In the US, prevale nce of SAD is estimated at \210 5%, 4:5 = 1:5. Management \200 therapy (see b p. 298): initially, 2hrs of 2500lux (or equivalent) Light on waking (respons e seen within 5 days and full response in 1 \200\2232 wks). Maintenance therapy should be g iven all winter (30min of 2500lux every 1 \200\2232 days). Patients should avoid exposure t o bright light during night-time. Good prognostic factors \200\224patients with clear hyper somnia, carbohydrate craving, reduced energy in the afternoon. Pharmacological: best eviden ce for bupropion XL (licensed in the USA not UK), SSRIs (sertraline, citalopram, escitalopr am, \202 uoxetine). Alternatives include pre-sunrise propranolol (60mg/ day) to suppress morning melatonin; melatonin/agomelatine at night; or other antidepressants (e.g. mirtazapi ne, reboxetine, duloxetine, moclobemide). 07_Semple_Chap07.indd 263 12/10/2012 6:36:10 PM CHAPTER 7 Depressive illness 264 Dysthymia (ICD-10)/dysthymic disorder (DSM-IV) Previously considered a subtype of personali ty disorder. Essentially, the presence of chronic, low-grade depressive symptoms. These may be long- standing, but careful history-taking reveals a time when the person did feel \200\230well \200\231. It is possible to have superimposed depressive episodes (dou- ble de pression), when care is needed in assessing treatment response, as baseline may be dysthymi c, rather than euthymic. Clinical features \200 \200 \200 \200 \200 \200 \200 \200 Depressed mood (>2yrs). Reduced/increased appetite. Insomnia/hypersomnia. Reduced energy/fa tigue. Low self-esteem. Poor concentration. Dif \201 culties making decisions. Thoughts of hopelessness. Etiology Findings suggest dysthymia is biologically related to depressive disorder, e.g. fa mily history suggesting shared genetics; shortened REM latencies in sleep studies; diurnali ty of symptoms; TRH/TSH challenge test abnormalities; low testosterone and adrenal-gonadal steroid levels; lowered IL-1- ; small genual corpus callosum volume; enlarged amygdala; s- allele polymorphism of 5-HT transporter gene. Epidemiology Prevalence 3 \200\2235%, 4:5 1:2 , usually early onset (<20yrs), but late-onset subtype seen (>50yrs). Course Less severe. M ore chronic than depression. Community studies show low spontaneous remission rate (2 \200 \22320yrs, median 5yrs). Management \200 Pharmacological: SSRIs are probably the treatment of choice with best evidence for citalopr am (40mg/day) and \202 uoxetine (20 \200\22340mg/ day). Alternatives include moclobemide, TCAs (e.g. amitriptyline, desipramine, imipramine), MAOIs, or low dose amisulpiride (25 \200\22350mg/ day). Drug therapy may take several months to show bene \201 t1 and should b e regarded as a long-term treatment. Psychological: in combination with an antidepressant). although evidence is lacking, CBT may be useful (usually Prognosis Variable: spontaneous recovery reported as 13% over 1yr in community samples; out patient studies suggest 10 \200\22320% of treated patients achieve remission within 1yr; 2 5% suffer chronic symptoms. 07_Semple_Chap07.indd 264 12/10/2012 6:36:10 PM DYSTHYMIA/DYSTHYMIC DISORDER 265 1 Silva de Lima M, Moncrieff J, Soares B (2000) Drugs versus placebo for dysthymia. Cochran e Database System Rev 9: CD001130. 07_Semple_Chap07.indd 265 12/10/2012 6:36:10 PM CHAPTER 7 Depressive illness 266 Antidepressants Assumed mode of action All currently available antidepressants appear to ex ert antidepressant action by increasing the availability of monoamines (5-HT, NE, and DA) v ia one or more of the following: \200 \200 Presynaptic inhibition of reuptake of 5-HT, NE, or DA. Antagonist activity at presynaptic i nhibitory 5-HT or NE receptor sites, which enhances neurotransmitter release. Inhibition of monoamine oxidase, reducing neurotransmitter breakdown. Increasing the availability of neu rotransmitter precursors. Although this net increase happens almost immediately following admin- istration, initial r esolution of depressive symptoms generally takes 10 \200\22320 days, implying therapeutic e ffect involves mechanisms possibly related to receptor regulation over time/changes in intr acellular signaling. Selectivity vs. speci \201 city Although the newer antidepressants are more selective than the TCAs and MAOIs in their pharmacological effects, this should not be confused with them being more speci \201 c for any particular type of depressive symptoms. All antidepressan ts have unwanted and often unpleasant side-effects. A balance needs to be struck between ef \201 cacy in treating psychiatric symp- toms and the possibility of iatrogenic problems. Patients may not be able to tolerate the anticholinergic side-effects of TCAs, or will be u nable to achieve a therapeutic level because of side-effects. Similarly, nausea or GI upset may limit the usefulness of SSRIs in some individuals. Sometimes side-effects may be usefu l (e.g. sedation for patients with insomnia) or combinations of antidepressants may be more ef \201 cacious than one alone (or may offset side-effects) (e.g. mirtazapine + SSRIs/SNR Is for sexual side- effects; SSRI + trazodone combination for those troubled by insomnia, b ut who have responded well to the antidepressant effects of the SSRI). Cautionary notes Particular caution is necessary in prescribing for certain patient groups (see b pp. 968 \200\22379) such as those with renal or hepatic impairment, cardiac problems , epilepsy; pregnant or breast-feeding women; the eld- erly; children; and those on other m edications which may interact with antidepressants. There are also well-recognized problems such as weight gain (b p. 930), hyponatraemia (b p. 966), sexual dysfunction (b p. 938), a nd discontinuation syndromes (b p. 964). Combining/switching antidepressants (see Table 7.3) An adequate \200\230washout \200\231 p eriod is required when switching to or from the MAOIs, whereas it is usual to cross-taper b etween other antidepressants (i.e. gradually reducing the dose of one, whilst slowly increa sing the dose of the other). During this process, or when combining antidepressants, side-e ffects may be enhanced (due to pharmacokinetic effects) and it is possible to induce the se rotonin syndrome (see b p. 960). 07_Semple_Chap07.indd 266 12/10/2012 6:36:10 PM ANTIDEPRESSANTS 267 The following pages outline the main groups of antidepressants. This information should be used as a guide and the clinician is always advised to consult manufacturers \200\231 data sheets, or more detailed formularies, for less common problems or speci \201 c details of administration. 07_Semple_Chap07.indd 267 12/10/2012 6:36:11 PM 0 7 _ S e m p l e _ C h a 2 6 8 p 0 7 . i n d d Table 7.3 Swapping or stopping antidepressants C H A P T E R 2 6 8 e n m o r p y c l y n a r T TO i e d m e b o l c o M m a r p o l a t i c s E e n i t a l e m o g A e n m a x o v u F / e n p a z a t r i M e n x a f a l n e V m a r p o l a t i C e n i t e x o b e R s e n i z a r d y H i e n i t e x o u D e n o d o z a r T e n i t e x o r a P 7 D e p r e s s i v e n e i t e x o u F n o p o r p u B i e n n i r e s n a i M i i i i l a r t r e S s A C T l FROM l l TCAs NRP 1 wk 1 wk 1 wk Care Care Great care Great care Great care Care Care SS NRP NRP NRP NRP NRP NRP i l l n e s s 2 wks 2 wks 1 wk NRP 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks Care Hydrazines 1 \200\2232 wks 2 wks 2 wks NRP DR 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 2 wks 1 wk NRP Tranylcy- promine 2 wks 2 wks NRP DR 2 wks Moclobemide OccP NRP NRP NRP 2 wks NRP NRP NRP NRP SS NRP NRP NRP NRP NRP NRP Citalopram/ Escitalopram Care 1 wk 1 wk 1 wk SS SS SS SS SS Care SS NRP Care NRP NRP NRP NRP Fluoxetine Great care 5 wks 5 wks 3 wks SS SS SS SS Care SS NRP Care NRP NRP NRP NRP Fluvoxamine Great care 4 \200\2235 1 \200\2232 wks 3 days SS SS SS SS Care SS Care NRP Care NRP NRP NRP Care days 1 2 / 1 0 / 2 0 1 2 6 : 3 6 : 1 1 P M 0 7 _ S e m p l e _ C h a p 0 7 . i n d d Paroxetine Great care 2 wks 2 wks 5 days SS SS SS SS Care SS NRP Care NRP NRP NRP NRP 2 6 9 Sertraline Care 1 \200\2232 wks 1 \200\2232 wks 7 \200\22313 days SS SS SS SS Care SS NRP Care NRP NRP NRP NRP Venlafaxine NRP 1 wk 1 wk NRP Care Care Care Care Care SS NRP Care NRP NRP NRP NRP Duloxetine SS 5 days 5 days SS SS Care SS SS SS SS SS NRP SS NRP NRP SS NRP Mianserin NRP 2 wks 2 wks NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP Trazodone OccP 2 wks 2 wks NRP Care Care Care Care Care Care SS NRP NRP NRP NRP NRP Mirtazapine NRP 1 wk 1 wk NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP Reboxetine NRP 1 wk 1 wk NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP Bupropion Care 1 wk 1 wk NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP NRP Agomelatine NRP NRP NRP NRP NRP NRP Care NRP NRP NRP NRP NRP NRP NRP NRP NRP Over 4 wks Over 4 wks Over 4 wks Over 4 wks Over 4 wks NRP Slowly over at least 4 wks Over 4 wks Slowly over at least 4 wks Over 4 wks Slowly over at least 4 wks Just stopping Over 4 wks Over 4 wks Over 4 wks Over 4 wks Over 4 wks Reduce to 20mg then stop A N T D E P R E S S A N T S I Key: NRP, no reported problems; SS, risk of serotonin syndrome; OccP, occasional problems; DR, dietary restrictions should continue 1 2 / 1 0 2 6 9 / 2 0 1 2 6 : 3 6 : 1 1 P M CHAPTER 7 Depressive illness 270 Tricyclic antidepressants (TCAs) \200 \200 See Table 7.4. Common mode of action and effects/side-effects: \200 Serotonin/noradrenaline (and dopamine) reuptake inhibition antidepressant effects. dry mout h, blurred vision, Anticholinergic (antimuscarinic \200\224M1) \200\224 constipation, urina ry retention, drowsiness, confusion/memory problems (particularly in the elderly), palpitat ions/tachycardia. Adrenergic antagonism ( (occasionally syncope), tachycardia, sexual dysfu nction. 5-HT Antihistaminergic (H1) \200\224 \200\224 A1) \200\224drowsiness, postural hypotension \200 Advantages: of patient groups); possibly more effective in severe depression; low co st. Disadvantages SSRIs; all TCAs may slow cardiac conduction and lower seizure threshold. Contraindications: disease, pregnancy and lactation (see b pp. 968 \200\22379). Cautions en docrine disorders (hyperthyroidism, adrenal tumors, diabetes); urinary retention/prostatic hypertrophy; constipation; glaucoma; epilepsy; psychotic disorders; patients with thoughts of suicide; elderly (use lower doses). Signi \201 cant interactions sheets): alcohol, anti coagulants, anticonvulsants, antihypertensives, antipsychotics, barbiturates, BDZs (rare), cimetidine, digoxin, MAOIs (rare), methylphenidate, morphine, SSRIs, smoking. Monitoring: U &Es, FBC, and weight during long-term therapy. 2 antagonism \200\224anxiolytic, reduced sexual dysfunction, sedation. drowsiness, weight g ain. well-established ef \201 cacy and large literature (in all varieties : toxicity in overdose; may be less well tolerated than acute MI, heart block, arrhythmias, IHD, severe liver (also see b p. 266): cardiovascular, liver, renal disease; (variable for different agents \200\224always check data it is good practice to monitor cardiac and liver function, 07_Semple_Chap07.indd 270 12/10/2012 6:36:11 PM 0 7 _ S e m p l e _ C h a p 0 7 Table 7.4 Tricyclic antidepressants (TCAs) . i n d d Drug Half-life (hr) Formulations Usual Usual maintenance dose Max daily dose Notes Indications 2 starting dose 7 1 100 \200\223150mg 150mg Metabolized to nortriptyline Depression, nocturnal enuresis, chronic pain, migraine, insomnia 75mg/day (divided or just at night) 10mg/day Amitriptyline 8 \200\22324 T 10/25/50mg C 25/50mg S25 or 50mg/5mL C 10/25/50mg SR 75mg Inj 12.5mg/mL C/T 25mg Clomipramine (Anafranil ) 17 \200\22328 30 \200\223150mg/day (divided or just at night) 75 \200\223150mg/day 75 \200\223150mg/day 2 25mg 250mg Most SSRI-like of the TCAs. Can be given IV/IM Depression, OCD & phobic disorders, adjunctive treatment of catalepsy (in narcolepsy) Depre ssion (with anxiety) Dosulepin (Prothiaden ) Doxepin (Sinepin ) 14 \200\22340 (hospital) 300mg 8 \200\22324 C 10/25/50/75mg 75mg/day Up to 300mg/ day (divided if <100mg/d) Depression (esp. if sedation needed) T R C Y C L C Imipramine 4 \200\22318 T 10/25mg S25mg/5mL T 70mg S 70mg/5mL 25mg up to tds 50 \200\223100mg/day 200mg Metabolized to desipramine May be safer in over-dose. Least proconvulsant. Metabolized to d esipramine Manufacturer recommends plasma monitoring in doses <100mg/d ( \200\230therapeuti c window \200\231 50 \200\223150ng/mL) May be very sedating Depression, nocturnal enuresis I Lofepramine (Gamanil ) 1.6 \200\2235 70mg/day 70 \200\223210mg/day 210mg Depression I A N T D E P R E S S A N T S Nortriptyline (Allegron ) 18 \200\22396 T 10/25mg 25mg tds 75 \200\223100mg 150mg Depression, nocturnal enuresis I Trimipramine (Surmontil ) 7 \200\22323 T 10/25mg C 50mg 75mg/day 150 \200\223300mg/day 300mg Depression (with anxiety) Key: T = tablets; C = capsules; S = oral suspension/solution; SR = modi \201 ed release ca psules; Inj = injectable form 1 2 / 1 0 2 7 1 / 2 0 1 2 6 : 3 6 : 1 2 P M CHAPTER 7 Depressive illness 272 Monoamine oxidase inhibitors (MAOIs) and reversible monoamine oxidase inhibitors (RIMAs) \200 Mode of action: \200 MAOIs: and tyramine) and MAO-B (acts on DA, tyramine, phenylethylamine, benzylamine), leadi ng to accumulation of monoamines in synaptic cleft (Table 7.5). RIMAs: \200 Side-effects: \200 irreversible inhibition of MAO-A (acts on NE, DA, 5-HT, act by reversible inhibition of MAO-A (Table 7.5). Risk of hypertensive crisis allowing pressor amines to enter the bloodstream (hence foods h igh in tyramine and certain medications should be avoided). Sources of dietary tyramine: ch eese), meat extracts and yeast extracts (including Bovril , Marmite , Oxo , and other fe rmented soya bean extracts), alcohol \200\224including low-alcohol drinks (especially chian ti and forti \201 ed wines and beers), non-fresh \201 sh, non-fresh poultry, offal, avoc ado, banana skins, broad-bean pods, caviar, herring (pickled or smoked). indirect sympathom imetics (amfetamine, Medications: fen \202 uramine, ephedrine, phenylephrine, phenylpropan olamine), cough mixtures containing sympathomimetics, nasal decongestants with sympathomime tics, levodopa (L-dopa), pethidine, antidepressants (TCAs, SSRIs/SNRIs, mirtazapine, buprop ion, St John \200\231s wort [Box 7.6]). These effects may be less with RIMAs. However, larg e amounts of tyramine-rich food should be avoided. Other side-effects: insomnia, anxiety, a ppetite suppression, weight gain, postural hypotension, ankle oedema, sexual dysfunction, p ossible dependency. due to inhibition of intestinal MAO, cheese (except cottage and cream antimuscarinic actions, hepatotoxicity, usually used as second-line therapy for treatment-resistant Indications: depression (partic ularly atypical symptoms)/anxiety disorders (with or without panic attacks). Cautions: cont rolled hypertension, hyperthyroidism, porphyria, phaeochromocytoma. Advantages: anxiety dis orders. cardiovascular disease, hepatic failure, poorly well-established ef \201 cacy in a broad range of affective and 07_Semple_Chap07.indd 272 12/10/2012 6:36:12 PM 0 7 _ S e m p l e _ C h a p 0 7 . i n d d 2 7 3 Table 7.5 MAOIs and RIMAs Drug Class Half-life (hr) Formulations Usual starting Usual maintenance dose Max daily dose Notes dose 10 \200\22340mg/day 60mg/day Hydrazine derivative \200\224less stimulating Isocarboxazid MAOI 36 T 10mg 30mg/day (divided or single daily dose) Moclobemide (Manerix ) RIMA 1 \200\2232 T 150mg 150mg bd 150 \200\223600mg/day 600mg/day May be used for social phobia. Possible hyponatraemia. \200\230Cheese reaction \200\231 le ast likely Phenelzine (Nardil ) MAOI 1.5 T 15mg 15mg tds 15mg every other day to 15mg qds 60mg/day (hospital 90mg/ day) Hydrazine derivative \200\224less stimulating Tranylcypromine MAOI 2.5 T 10mg 10mg bd 10mg/day 30mg/day (or greater if supervised) Most stimulant of MAOIs (amfetamine-related). Do not give after 3p.m. Increased risk of sig ni \201 cant interactions M A O I S A N D Key: T = tablets R M A S I 1 2 / 1 0 2 7 3 / 2 0 1 2 6 : 3 6 : 1 2 P M CHAPTER 7 Depressive illness 274 Disadvantages: RIMAs). Other signi \201 cant drug interactions check data sheets): antidia betics, anti-epileptics, antihypertensives, antipsychotics, barbiturates, BDZs, B-blockers, buspirone, cimetidine, dopaminergics (selegiline), dextromethorphan, mazindol, pethidine, morphine, 5-HT1 agonists (rizatriptan, sumatriptan), tetrabenazine. dietary restrictions and drug interactions (less so with (variable for MAOIs vs. RIMAs \200\224always 07_Semple_Chap07.indd 274 12/10/2012 6:36:12 PM This page intentionally left blank CHAPTER 7 Depressive illness 276 Selective serotonin reuptake inhibitors (SSRIs) \200 Common mode of action and effects/side-effects: inhibition (leads to i5-HT in synaptic clef t; see Table 7.6). \200 serotonin reuptake 5-HT bulimic effects. 5-HT dysfunction. 5-HT \200 Advantages: cardiotoxic; fewer antichol inergic side-effects; low toxicity in overdose. Disadvantages: restlessness, and insomnia; may be less effective for severe depressive episodes; problems on discontinuation (see b p. 964). Contraindications: (also see b p. 266): variable and signi \201 cant inhibitory Cau tions effects on hepatic P450 (particularly CYP2D6) enzymes. Hence, take care when co-presc ribing with drugs that undergo extensive liver metabolism and have a narrow therapeutic ran ge. Signi \201 cant interactions data sheets): alcohol, anticoagulants, anticonvulsants, a ntipsychotics, BDZs, B-blockers, bupropion, buspirone, cimetidine, cyproheptadine, hypoglyc aemics, lithium, methadone, MAOIs, morphine, smoking, TCAs, theophylline, warfarin. 1A agonism \200\224antidepressant, anxiolytic, anti-obsessive, anti- 2 agonism \200\224agitation, akathisia, anxiety/panic, insomnia, sexual 3 agonism \200\224nausea, GI upset, diarrhea, headache. ease of dosing; may be better tolerated than TCAs \200\224less commonly cause nausea and GI upset, headache, \200 manic episode, concomitant use of MAOIs. (variable for different agents \200\224always check Box 7.6 St. John \200\231s wort (SJW, Hypericum perforatum) Considered a \201 rst-line antidepressant in many European countries (and recently becomi ng popular in the US); not yet in the UK. May be effec- tive for mild \200\223moderate depr essive symptoms.1 \200 Mode of action: (and/or NARI/MAOI). Usual dose: Notable interactions: anticoagulants (esp. warfarin), antidepressants (risk of serotonin syndrome \200\224b p. 960), anti-epileptics, antivirals, barbiturates, ciclosporin, digoxin, 5-HT1 agonists (rizatriptan, sumatriptan), oral contraceptives, theophylline. recent research suggests it may act as a weak SSRI \200 300mg tds (with food to prevent GI upset). 1 Linde K, Berner MM, Kriston L. (2008) St John \200\231s wort for major depression. Cochra ne Database System Rev 4: CD000448. 07_Semple_Chap07.indd 276 12/10/2012 6:36:12 PM 0 7 _ S e m p l e _ C h a p 0 7 . i n Table 7.6 Selective serotonin reuptake inhibitors (SSRIs) d d 2 Drug Half-life (hr) Formulations Usual starting dose Usual maintenance dose Max daily dose Notes Indications 7 7 Depression, panic disorder (with or without agoraphobia) 20 \200\22360mg od 60mg Least likely to interact with other drugs. Less likely to reduce seizure threshold (caution ) Citalopram (Cipramil ) 33 T 10/20/40mg S 40mg/mL 20mg od (10mg for panic, increase slowly) S E L E C T Escitalopram (Cipralex ) 30 T 5/10/20mg S 10mg/mL 10mg od (5mg for panic, increase slowly) 5 \200\22320mg od 20mg The active enantiomer of citalopram Depression, panic disorder (with or without agoraphobia), social anxiety I V E Fluoxetine (Prozac ) 24 \200\223140 C 20/60mg S 20mg/5mL 20mg od 20 \200\22360mg od 60mg Most alerting. May cause weight loss Depression (with or without anxiety symptoms), OCD, bulimia nervosa, PMDD S E R O T O N N R E U P T A K E Fluvoxamine (Faverin ) 13 \200\22322 T 50/100mg 50 \200\223100mg od 100 \200\223300mg (if <150mg, in divided doses) 300mg Moderately sedating Depression, OCD I Paroxetine (Seroxat ) 10 \200\22324 T 20/30mg S 20mg/10mL 20mg od (10mg for panic, increase slowly) 20 \200\22350mg od 50mg Most anticholinergic. Withdrawal syndrome may be more frequent. May be sedating Depression (with or without anxiety), OCD, panic disorder (with or without agoraphobia), so cial phobia, PTSD, GAD I N H B I Sertraline (Lustral ) 25 \200\22336 T 50/100mg 50mg (25mg for PTSD, increase slowly) 50 \200\223200mg od 200mg Moderately alerting. Fewer drug interactions, but caution still necessary Depression (with or without anxiety), OCD, PTSD I T O R S 1 2 Key: T = tablets; C = capsules; S = oral suspension/solution / 1 0 2 7 7 / 2 0 1 2 6 : 3 6 : 1 2 P M CHAPTER 7 Depressive illness 278 Other antidepressants 1 Serotonin/noradrenaline reuptake inhibitors (SNRIs) \200 \200 Mode of action: Common adverse effects: appetite, dry mouth, dizziness, agitation, insomnia , sexual dysfunction, headache, nervousness, sweating, weakness. 5-HT and NE reuptake inhibition. nausea, GI upset, constipation, loss of Venlafaxine (Efexor , Efexor XL plus many other brand names) \200 Half-life: 1 \200 \2232hrs; peak plasma conc. 5hrs (10hrs for metabolite: desmethylvenlafaxine [Pristiqs US license for depression, anxiety, and menopausal symptoms, 2008 \200\224not licensed in UK yet]). Formulations: Indications: Usual dose: if necessary after at least 2wks to max 375mg /day. Severe depression, begin at 150mg/day, increasing by 75mg every few days to max dose 375mg/day. For GAD and social anxiety, 75mg od (increased 2-weekly to max 225mg/day). Advan tages: more rapid onset of action than other antidepressants; available in controlled relea se form allowing od administration. Disadvantages: monitor blood pressure (BP) at doses ove r 200mg; troublesome side- effects; discontinuation effects common. \200 \200 37.5/75mg tabs (MR 75/150mg caps; 75/150/225mg tabs). depression, GAD, social anxiety. depression, 37.5mg bd (or 75mg od of MR form), increased variable pharmacological pro \201 le over dose range; possibly moderate to high doses less well tolerated; need to Duloxetine (Cymbalta , Yentreve ) \200 \200 \200 Half-life: Formulations: Cautions: potential hepatotoxicity (i.e. cases of severe elevation s of liver enzymes or liver injury with a hepatocellular, cholestatic, or mixed pattern hav e been reported); also caution in glaucoma secondary to mydriasis. Indications: incontinenc e. Usual dose: as necessary to max 120mg/day; diabetic neuropathy 60 \200\223120mg/day (div ided doses); stress urinary incontinence 20 \200\22340mg bd. Advantages: May have utility i n treating chronic pain and urinary incontinence. Disadvantages: discontinuation effects co mmon (note: little evidence that doses greater than 60mg/day confer any additional bene \201 t in depression). 8 \200\22317hrs; peak plasma conc. 6hrs. 30/60mg capsules. depression, GAD, diabetic neuropathy, stress urinary depression 60mg od; GAD start with 30mg od, increasing as for venlafaxine, but no controlled release form available. dose-dependent elevations in BP require monitoring; Tetracyclic antidepressants (TeCAs) Mianserin \200 \200 \200 \200 Mode of action: Half-life Formulations: Indications: similar to TCAs, but with less anticholinergic side-effects. 12 \200\22329hrs; peak plasma conc. 1-3hrs. 10/30mg tabs. depression, particularly if sedation required. 07_Semple_Chap07.indd 278 12/10/2012 6:36:13 PM OTHER ANTIDEPRESSANTS 1 279 Common adverse effects: blood dyscrasias more common (esp. elderly \200\224FBC recommended 4-wkly for \201 rst 3mths of treatment, therafter 3 \200\2236-monthly; stop treatment and check FBC if fever, sore throat, stomatitis, or other signs of infection develop), jaundic e, arthritis, arthralgia. Usual dose: single night-time dose, increased gradually as necess ary; usual range 30 \200\22390mg/day. Advantages: cardiotoxicity), sedating (which may be a desirable effect). idiosyncratic adverse effects. Disadvantages: as for TCAs, but less cardiovascular problems, 30 \200\22340mg (elderly 30mg) daily in divided doses or as a better side-effect pro \201 le than some TCAs (e.g. Serotonin antagonist/reuptake inhibitors (SARIs) Trazodone (Molipaxin ) \200 Mode of action: \200 \200 5-HT 5-HT agonism through the active metabolite (m-chlorophenylpiperazine) \200\224antidepr essant effect; 1A/1C/2A antagonism \200\224sedating/anxiolytic, less sexual dysfunction; H \200 Common adverse effects: similar to TCAs (but less anticholinergic and cardiotoxi c); rarely priapism (discontinue immediately: see b p. 942). 3 \200\2237hrs; peak plasma co nc. 0.5 \200\2232hrs. Half-life: 50/100mg caps; 150mg tabs; liquid 50mg/5mL. Formulations: depression (esp. with insomnia), anxiety disorders. Indications: Usual dose: 150mg/day (as divided dose or just at night), increased to 300mg/day (max dose 600mg/day in divided doses \200\224in hospital). For anxiety, start at 75mg/day \200\224max 300mg/day. sedation (may be used in low doses as an adjunct to other Advantages: less sedating antidepressants or to counter sexual dysfunction), safer in epilepsy than TCAs. Disadvantages: may not be tolera ted. 1 antagonism \200\224orthostatic hypotension; 1 antagonism \200\224sedation and weight gain . sedation; orthostatic hypotension; otherwise \200 \200 \200 the higher doses necessary for antidepressant effects 07_Semple_Chap07.indd 279 12/10/2012 6:36:13 PM CHAPTER 7 Depressive illness 280 Other antidepressants 2 Noradrenergic and speci \201 c serotonergic antidepressant (NaSSA) Mirtazepine (Zispin SolTab ) \200 Mode of action: \200 \200 M \200 \200 \200 H \200 Common adverse effects: s edation (greater at lower doses), increased appetite, weight gain. Less common: transaminas e elevation, jaundice, oedema, orthostatic hypotension, tremor, myoclonus, blood dyscrasias (rare agranulocytosis \200\224if a patient develops a sore throat, fever, stomatitis or si gns of infection accompanied by neutropenia, discontinue medication and closely monitor pat ient). Half-life: 20 \200\22340hrs; peak plasma conc. 1 \200\2233hrs. Formulations: 15mg/mL . Indications: Usual dose: (divided dose or just at night). Advantages: upset. Disadvantage s: (may be used to advantage). 2 antagonism \200\224increases 5-HT and NE release (antidepressant) 1 antagonism \200\224or thostatic hypotension 1 antagonism \200\224anticholinergic side-effects 5-HT 5-HT 2A/C antagonism \200\224sedating/anxiolytic, less sexual dysfunction 3 antagonism \200\224r educed nausea/GI upset 1 antagonism \200\224sedation and weight gain \200 15/30/45mg tabs/orodispersible tabs; oral solution \200 depression (with anxiety, agitation, insomnia, weight loss). 15 \200\22330mg nocte, increas ed if necessary to max 45mg/day low toxicity in overdose, less sexual dysfunction and GI weight gain, sedating effects may be lost at higher doses Noradrenaline reuptake inhibitor (NARI) Reboxetine (Edronax ) \200 \200 Mode of action: Common adverse effects: dizziness, tachycardia, sexual dysfunction, dysuria , urinary retention, dry mouth, constipation, hypokalaemia if used long term in the elderly . Half-life: Formulations: Indications: Usual dose: doses (max 12mg/day). Advantages: patie nts with symptoms of fatigue or hypersomnia; may improve social functioning; relatively saf e in overdose. Disadvantages: NE reuptake inhibition. insomnia, sweating, postural hypotension/ \200 \200 \200 13hrs; peak plasma conc. 2hrs. 4mg tabs (scored). depression (particularly with atypical features). 4mg bd, increased after 3 \200\2234 wks t o 10mg/day in divided novel mode of action; alerting effects may be useful for mainly due to adverse effects. 07_Semple_Chap07.indd 280 12/10/2012 6:36:13 PM OTHER ANTIDEPRESSANTS 2 281 Noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion (Zyban ) \200 Mode of action: \200 Common adverse effects: (nausea, vomiting, abdominal pain, constipation), h ypertension (esp. if also using nicotine patches), risk of seizures (0.4%), taste disturban ce. Half-life: plasma conc. 4hrs. Formulations: Indications: depression (with marked psycho motor retardation or hypersomnia), but only licensed in UK for treatment of nicotine depend ence (and possibly withdrawal from other stimulants); may be useful in adult/child ADHD (un licensed). Usual dose: day max single dose 150mg, min 8h between doses (max duration of tre atment for nicotine dependence 7 \200\2239 wks). Advantages: patients with symptoms of fati gue or hypersomnia, may help treat impulse disorders/addictions when used primarily as an a ntidepressant. Disadvantages: (rare, but may be severe). NE and DA reuptake inhibition.