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Antidepressant Drugs

  • Paul Howard
    Affiliations
    Duchess of Kent House (P.H.), Reading, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Vanderbilt University (J.S.), Nashville, Tennessee, USA; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Robert Twycross
    Affiliations
    Duchess of Kent House (P.H.), Reading, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Vanderbilt University (J.S.), Nashville, Tennessee, USA; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • John Shuster
    Affiliations
    Duchess of Kent House (P.H.), Reading, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Vanderbilt University (J.S.), Nashville, Tennessee, USA; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Mary Mihalyo
    Affiliations
    Duchess of Kent House (P.H.), Reading, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Vanderbilt University (J.S.), Nashville, Tennessee, USA; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Andrew Wilcock
    Correspondence
    Address correspondence to: Andrew Wilcock, DM, FRCP, Hayward House Macmillan Specialist Palliative Care Unit, Nottingham University Hospitals NHS Trust, Nottingham NGS 1PB, United Kingdom.
    Affiliations
    Duchess of Kent House (P.H.), Reading, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Vanderbilt University (J.S.), Nashville, Tennessee, USA; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
    Search for articles by this author
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/Key

      5HT1A, 5HT2, 5HT3, etc.
      5-hydroxytryptamine-1A, -2, and -3 receptors, etc.
      α, α1, α2
      Alpha, alpha-1 and -2 receptors
      AChM
      Anticholinergic (muscaric) receptor
      ALS/MND
      Amyotrophic lateral sclerosis/motor neuron disease
      b.i.d.
      Bis in die, twice daily
      CBT
      Cognitive behavioral therapy
      CNS
      Central nervous system
      CYP
      Cytochrome P450
      D2
      Dopamine-2 receptor
      DA
      Dopamine
      DSM
      Diagnostic and Statistical Manual of Mental Disorders
      ECG (EKG)
      Electrocardiogram
      GABA
      Gamma-aminobutyric acid
      GI
      Gastrointestinal
      H1
      Histamine-1 receptor
      IM
      Intramuscular
      IV
      Intravenous
      MAOI
      Monoamine oxidase inhibitor
      MARI
      Monoamine re-uptake inhibitor
      NDRI
      Norepinephrine and dopamine re-uptake inhibitor
      NE
      Norepinephrine (noradrenaline)
      NICE
      National Institute for Health and Clinical Excellence
      NMDA
      N-methyl-D-aspartate
      NNH
      Number needed to harm, i.e., the number of patients needed to be treated in order to harm one patient sufficiently to cause withdrawal from a drug trial
      PO
      Per os, by mouth
      p.r.n.
      Pro re nata, as needed
      q2 h, q6h
      Every 2 hours, 6 hours, etc.
      RA
      Receptor antagonist
      RCT
      Randomized controlled trial
      SC
      Subcutaneous
      SNRI
      Serotonin and norepinephrine re-uptake inhibitor
      SSRI
      Selective serotonin re-uptake inhibitor
      TCA
      Tricyclic antidepressant
      t.i.d.
      Ter in die, three times daily
      Tm
      Time to reach maximum plasma concentration
      Indications: Depression, anxiety and panic disorders, post-traumatic stress disorder, stress incontinence and urgency, †chronic pain, †agitated delirium, †sweating, †hot flashes, †insomnia, †pruritus, †bladder spasm, †pathological laughing and crying, †drooling.

      Pharmacology

      Depression: Antidepressants enhance transmission of one or more monoamines (Fig. 1, Box 1). Some have additional actions which may contribute towards their beneficial and/or undesirable effects (Table 1). Although increased monoamine transmission occurs within hours, the antidepressant effect is slower to appear because this requires normalization of receptor sensitivity and neuroplasticity. Many of the early-onset undesirable effects from antidepressant drugs are a consequence of enhanced monoamine transmission in the presence of receptors that have been upregulated to compensate for a relative monoamine deficit. As receptor sensitivity returns to normal, these undesirable effects generally resolve and beneficial effects begin to emerge.
      Figure thumbnail gr1
      Fig. 1Predominant mechanism of action of antidepressants. aMonoamine oxidase type A breaks down serotonin, norepinephrine (noradrenaline) and dopamine. Type B breaks down dopamine. Antidepressant-MAOIs are either non-selective (e.g., phenelzine) or type A selective (e.g., moclobemide). Antiparkinsonian MAOIs (e.g., selegiline) are Type B selective. bBlockade of pre-synaptic α-adrenergic receptors removes inhibition of serotonin and norepinephrine release. cBlockade of post-synaptic 5HT2A and 5HT2C-receptors removes inhibition of dopamine and norepinephrine release from the post-synaptic neuron.
      Classification of Antidepressants According to Principal Actionsa
      Monoamine re-uptake inhibitors (MARIs)
      Serotonin and norepinephrine (SNRIsb or dual inhibitors)
      Amitriptylinec, venlafaxine, duloxetine
      Serotonin (selective serotonin re-uptake inhibitors, SSRIs)
      Sertraline, citalopram, paroxetine, fluoxetine
      Norepinephrine (NRIs)
      Nortriptylinec, lofepramine, desipraminec, reboxetine
      Norepinephrine and dopamine (NDRIs)
      Bupropion
      Psychostimulant-antidepressantsd
       Dextroamphetamine, methylphenidate, modafinil
      Receptor antagonists
       Trazodone (α1, 5HT2)
       Mirtazapine (central α2, 5HT2, 5HT3)
      Monoamine oxidase inhibitors (MAOIs)e
       Phenelzine, tranylcypromine
      aAbbreviated names broadly reflect those found elsewhere;
      • Stahl S.M.
      Psychosis and schizophrenia.
      confusion is inevitable because S is used for Selective, Specific, and Serotonin.
      bSNRI is sometimes reserved for dual inhibitors without additional receptor binding affinities (e.g., venlafaxine and duloxetine).
      cTCAs differ in their modes of action, and do not comprise a single discrete drug class.
      dReverse dopamine re-uptake transporters.
      eMAOIs are included for completeness; their use by non-psychiatrists is not recommended.
      Table 1Transporter and Receptor Affinities for Selected Antidepressants

      National Institute of Mental Health (NIMH). (2006) NIMH's psychoactive drug screening program. Available from http://pdsp.med.unc.edu. Accessed August 2012.

      • Stahl S.M.
      • Pradko J.F.
      • Haight B.R.
      • et al.
      A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor.
      • Béïque J.C.
      • Lavoie N.
      • de Montigny C.
      • Debonnel G.
      Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters.
      • Hamon M.
      • Bourgoin S.
      Pharmacological profile of antidepressants: a likely basis for their efficacy and side effects?.
      DrugRe-uptake TransportersReceptor Affinities
      5HTNE
      The norepinephrine re-uptake transporter also clears dopamine in the prefrontal cortex where dopamine re-uptake transporters are absent. Reduced dopamine in the prefrontal cortex is related to anhedonia and inattention.
      DA5HT2A5HT2CH1α1α2AChM
      Agomelatine (not USA)
      Agomelatine is also a melatonin (type 1 and 2) receptor agonist. Although animal models raise this as a target of possible interest, the contribution which this makes towards its clinical effects in humans is unclear.
      -+---
      Amitriptyline+++++-++++++++++++++++
      Bupropion-+++-----
      Citalopram+++--------
      Desipramine++++-+-++++-+
      Duloxetine+++++++------
      Fluoxetine+++--++----
      Imipramine++++-+++++++-+/+++
      Varies with different AChM receptor subtypes.
      Lofepramine (not USA)++++--++--/++
      Varies with different AChM receptor subtypes.
      Methylphenidate--++-----
      Mirtazapine---+++++++-+++-
      Nortriptyline++++-+++++++++++-++
      Paroxetine++++------+
      Reboxetine (not USA)-+++-----
      Sertraline+++-+---+--
      Trazodone---+++-+++-
      Venlafaxine++
      Despite in vitro studies suggesting a relatively low affinity for serotonin and norepinephrine re-uptake transporters, in vivo studies suggest venlafaxine is a dual inhibitor. In vitro assays measure the ability of a drug to displace another compound of known affinity; it may be that venlafaxine binds to a different site on monoamine re-uptake transporters and so cannot displace the reference compounds.18
      -------
      Affinity=+++ high, ++ moderate, + low, - negligible or none; blank=no data.
      a The norepinephrine re-uptake transporter also clears dopamine in the prefrontal cortex where dopamine re-uptake transporters are absent. Reduced dopamine in the prefrontal cortex is related to anhedonia and inattention.
      b Agomelatine is also a melatonin (type 1 and 2) receptor agonist. Although animal models raise this as a target of possible interest, the contribution which this makes towards its clinical effects in humans is unclear.
      c Varies with different AChM receptor subtypes.
      d Despite in vitro studies suggesting a relatively low affinity for serotonin and norepinephrine re-uptake transporters, in vivo studies suggest venlafaxine is a dual inhibitor. In vitro assays measure the ability of a drug to displace another compound of known affinity; it may be that venlafaxine binds to a different site on monoamine re-uptake transporters and so cannot displace the reference compounds.
      • Béïque J.C.
      • Lavoie N.
      • de Montigny C.
      • Debonnel G.
      Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters.
      Neuroplasticity is the ability of the CNS to adapt structurally and functionally in response to external stimuli and is mediated by nerve growth factors (e.g., brain derived neurotrophic factor). In depression, neuroplasticity is impaired in the limbic and prefrontal cortex circuits which regulate mood, attention, energy, appetite and sleep. By enhancing monoamine transmission, antidepressants help increase the production of nerve growth factors and restore neuroplasticity.
      • Castren E.
      • Rantamaki T.
      Role of brain-derived neurotrophic factor in the aetiology of depression: implications for pharmacological treatment.
      Depression refractory to one antidepressant can respond following a switch to another antidepressant or to the use of combination treatment which targets different, or multiple, monoamines (see Titrating, switching and combining antidepressants).
      • Belmaker R.H.
      • Agam G.
      Major depressive disorder.
      • Tran P.V.
      • Bymaster F.P.
      • McNamara R.K.
      • Potter W.Z.
      Dual monoamine modulation for improved treatment of major depressive disorder.
      Anxiety and Panic Disorder: Antidepressants and benzodiazepines inhibit the amygdala's so-called fear circuits through 5HT1A and GABAA receptors, respectively.
      • Akimova E.
      • Lanzenberger R.
      • Kasper S.
      The serotonin-1A receptor in anxiety disorders.
      • Maron E.
      • Shlik J.
      Serotonin function in panic disorder: important, but why?.
      The amygdala is a “threat sensor” which integrates sensory information with contextual information (e.g., interpretations, memories). If a fear response is required, the amygdala's effector pathway activates the relevant circuits (respiratory and cardiovascular centers, pituitary-adrenal axis, sympathetic autonomic nervous system, and fear-related areas of the cerebral cortex).
      Pain: The analgesic effects of antidepressants also are due to enhanced monoamine transmission, e.g., in descending pain modulation pathways.
      • Nickel F.T.
      • Seifert F.
      • Lanz S.
      • Maihöfner C.
      Mechanisms of neuropathic pain.
      • McCleane G.
      Antidepressants as analgesics.
      These pathways can induce both analgesia (norepinephrinergic (noradrenergic) and serotoninergic activity) and hyperalgesia (serotoninergic activity).
      • Heinricher M.M.
      • Tavares I.
      • Leith J.L.
      • Lumb B.M.
      Descending control of nociception: specificity, recruitment and plasticity.
      • Dogrul A.
      • Ossipov M.H.
      • Porreca F.
      Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors.
      The latter may explain the inconsistent analgesic effect of SSRIs and why SNRIs appear no more effective then NRIs.
      • Watson C.P.
      • Vernich L.
      • Chipman M.
      • Reed K.
      Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial.
      Sodium-channel blockade and NMDA-glutamate-receptor antagonism also may contribute to the analgesic efficacy of some antidepressants,
      • McCleane G.
      Antidepressants as analgesics.
      including the modest effect of topical doxepin.
      • McCleane G.
      Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.
      • McCleane G.J.
      Topical doxepin hydrochloride reduces neuropathic pain: a randomised, double-blind, placebo-controlled study.
      The beneficial and undesirable effects of antidepressants vary for multiple reasons including differing:
      • mechanisms of action (Fig. 1)
      • monoamines affected (Box 1)
      • effects on other receptors (Table 1)
      • pharmacokinetic profiles (Table 2).
        Table 2Pharmacokinetic Details for Selected Antidepressants
        • Wen B.
        • Ma L.
        • Rodrigues A.D.
        • Zhu M.
        Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine.
        • Jefferson J.W.
        • Pradko J.F.
        • Muir K.T.
        Bupropion for major depressive disorder: pharmacokinetic and formulation considerations.
        • Hiemke C.
        • Härtter S.
        Pharmacokinetics of selective serotonin reuptake inhibitors.
        • Fleishaker J.C.
        Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression.
        • Venkatakrishnan K.
        • Greenblatt D.J.
        • von Moltke L.L.
        • et al.
        Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4.
        • Richelson E.
        Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs.
        • Kaye C.M.
        • Haddock R.E.
        • Langley P.F.
        • et al.
        A review of the metabolism and pharmacokinetics of paroxetine in man.
        • Schulz P.
        • Dick P.
        • Blaschke T.F.
        • Hollister L.
        Discrepancies between pharmacokinetic studies of amitriptyline.
        • Abernethyl D.R.
        • Divoll M.
        • Greenblatt D.J.
        • Harmatz J.S.
        • Shader R.I.
        Absolute bioavailability of imipramine: influence of food.
        DrugBio-availability PO (%)Tmax (h)Plasma Half-life (h)Metabolism
        Agomelatine (not USA)>801–21–2CYP1A2
        Significant first-pass metabolism.
        Amitriptyline45413–36Multiple pathways
        Active metabolite(s); listed in table if can be administered separately.
        (nortriptyline
        Active metabolite(s); listed in table if can be administered separately.
        )
        Bupropion>871.521CYP2B6
        Active metabolite(s); listed in table if can be administered separately.
        Citalopram80
        Tablet product: bioavailability of drops 25% higher.
        336Multiple pathways
        Active metabolite(s); listed in table if can be administered separately.
        Desipramine30–504–67–77CYP 2D6
        Significant first-pass metabolism.
        ,
        Active metabolite(s); listed in table if can be administered separately.
        Duloxetine90612CYP1A2, CYP2D6
        Fluoxetine904–81–4 days 7–15 days
        Active metabolite(s); listed in table if can be administered separately.
        Multiple pathways
        Active metabolite(s); listed in table if can be administered separately.
        Imipramine45321Multiple pathways
        Active metabolite(s); listed in table if can be administered separately.
        (desipramine
        Active metabolite(s); listed in table if can be administered separately.
        )
        Methylphenidate301–32Non-CYP hepatic carboxylesterase
        Significant first-pass metabolism.
        Mirtazapine50220–40CYP1A2, CYP2D6, CYP3A4
        Nortriptyline607–8.515–39CYP2D6
        Significant first-pass metabolism.
        ,
        Active metabolite(s); listed in table if can be administered separately.
        Paroxetine50
        Increases with multiple dosing.
        515–20Multiple pathways
        Reboxetine (not USA)952–412CYP3A4
        Sertraline>446–826CYP3A4
        Trazodone6517CYP2D6, CYP3A4
        Active metabolite(s); listed in table if can be administered separately.
        Venlafaxine13 (45)
        m/r product.
        2.5 (4.5–7.5)
        m/r product.
        5 (11)
        Active metabolite(s); listed in table if can be administered separately.
        CYP2D6, CYP3A4
        Active metabolite(s); listed in table if can be administered separately.
        a Significant first-pass metabolism.
        b Active metabolite(s); listed in table if can be administered separately.
        c Tablet product: bioavailability of drops 25% higher.
        d Increases with multiple dosing.
        e m/r product.
      The clearance of many antidepressants is significantly affected by CYP2D6 metabolizer phenotype, and to a lesser extent by CYP2C19. Further, serotonin re-uptake transporter polymorphisms may influence SSRI efficacy.
      • Porcelli S.
      • Fabbri C.
      • Serretti A.
      Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy.
      However, clinical benefit from genotyping has yet to be demonstrated.
      • Kirchheiner J.
      • Rodriguez-Antona C.
      Cytochrome P450 2D6 genotyping: potential role in improving treatment outcomes in psychiatric disorders.
      St. John's wort (hypericum extract) is as effective as conventional antidepressants in treating mild–moderate depression and causes fewer undesirable effects.
      • Linde K.
      • Berner M.M.
      • Kriston L.
      St. John's wort for major depression.
      However, NICE discourages its use because of:
      • uncertainty about appropriate doses
      • variation in the nature of products
      • potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anti-epileptics).

        National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      Cautions

      In patients with a history of mania, antidepressants may precipitate a recurrent episode, particularly when administered without a mood stabilizer.

      Suicide Risk

      The risk of antidepressant-related suicidal ideation needs to be balanced against the greater risk of non-fatal self harm and completed suicide from untreated depression.
      • Freeman S.A.
      Suicide risk and psychopharmacology: assessment and management of acute and chronic risk factors.
      One in 1,000 patients attempt suicide in the six months after starting antidepressants: one-third are successful.
      • Simon G.E.
      • Savarino J.
      • Operskalski B.
      • Wang P.S.
      Suicide risk during antidepressant treatment.
      In those aged ≤25 years, antidepressants are associated with suicidal ideation and non-fatal self-harm (NNH 143).
      • Stone M.
      • Laughren T.
      • Jones M.L.
      • et al.
      Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration.
      • Bridge J.A.
      • Iyengar S.
      • Salary C.B.
      • et al.
      Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials.
      The risk is greater with SSRIs than TCAs,
      • Martinez C.
      • Rietbrock S.
      • Wise L.
      • et al.
      Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study.
      and is present even when an antidepressant is used for non-depressive illnesses.
      • Bridge J.A.
      • Iyengar S.
      • Salary C.B.
      • et al.
      Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials.
      In adults ≥25 years old, there is a smaller increase in the risk of non-fatal self-harm (NNH ca. 700), no increase in suicide or suicidal thoughts, and no difference between SSRIs and TCAs.
      • Martinez C.
      • Rietbrock S.
      • Wise L.
      • et al.
      Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study.
      • Gunnell D.
      • Saperia J.
      • Ashby D.
      Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review.
      • Fergusson D.
      • Doucette S.
      • Glass K.C.
      • et al.
      Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials.
      Suicidal ideation should be evaluated when treating depression in all age groups. Consider the safety in overdose of both the antidepressant and concomitant medicines. In both the USA and Europe, regulators have emphasized the need for close monitoring of adherence to treatment, treatment response, and emergence of thoughts of self-harm, particularly during the first month after starting an antidepressant, and to encourage patients to report to their doctor any deterioration in mood or behavior.

      Medicines and Healthcare Products Regulatory Agency. (2007) Antidepressants: suicidal behaviour. Drug Safety Update 2007;1(1): 7–8. Available from http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON079102. Accessed August 21, 2012.

      • Reeves R.R.
      • Ladner M.E.
      Antidepressant-induced suicidality: an update.

      Epilepsy

      Antidepressants cause a dose-dependent reduction in seizure threshold. The risk is lowest for SSRIs, higher with TCAs, and highest with clomipramine, bupropion and maprotiline.
      • Harden C.L.
      • Goldstein M.A.
      Mood disorders in patients with epilepsy: epidemiology and management.
      There are fewer data and less experience with mirtazapine and venlafaxine. In patients with epilepsy, antidepressants also may cause seizures by altering anti-epileptic drug levels as a result of a drug–drug interaction. Thus, citalopram is widely favored for use in patients with epilepsy because of the low risk of reduction in seizure threshold and lack of significant interactions with anti-epileptic drugs. Antidepressants also can cause seizures through hyponatremia.
      It is hard to quantify the risk of using low-dose TCAs for neuropathic pain in patients with previous seizures because the risk is dose-related and animal studies even suggest a possible anti-epileptic action at low doses.
      • Dailey J.W.
      • Naritoku D.K.
      Antidepressants and seizures: clinical anecdotes overshadow neuroscience.
      Epilepsy is associated with both mood disorders and psychosis. Symptoms may occur in between (inter-ictal), during (ictal), or in the days or weeks after (post-ictal) seizures. Optimization of anti-epileptic medication should be considered alongside antidepressant treatment, particularly for ictal and post-ictal mood-related symptoms.
      • Blumer D.
      • Montouris G.
      • Davies K.
      The interictal dysphoric disorder: recognition, pathogenesis, and treatment of the major psychiatric disorder of epilepsy.
      Further, anti-epileptic drugs can cause (and treat) mood disorders: seek specialist advice if symptoms develop after their introduction or titration.
      • Harden C.L.
      • Goldstein M.A.
      Mood disorders in patients with epilepsy: epidemiology and management.

      Parkinson's Disease

      SSRIs can worsen extrapyramidal symptoms because serotonin reduces nigrostriatal dopamine release via inhibitory 5HT2 receptors. However, the risk appears small; few RCTs report any worsening.
      • Skapinakis P.
      • Bakola E.
      • Salanti G.
      • et al.
      Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials.
      SSRIs are thus still often used in preference to TCAs which can worsen autonomic dysfunction (α blockade) and cognitive impairment (AChM blockade).
      5HT2 antagonist antidepressants might be expected to avoid serotonin-mediated exacerbations. In small pilot RCTs, Parkinsonian symptoms improved with nefazodone
      • Avila A.
      • Cardona X.
      • Martin-Baranera M.
      • et al.
      Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial.
      but not mirtazapine.

      Zhang LS, Chen ZM, Zhang P. Mirtazapine vs. fluoxetine in treatng Parkinson's disease with depression and anxiety. Medical Journal of Chinese People's Health 2006. DOI: CNKI: SUN:ZMYX.0.2006-2023-2001.

      Antiparkinsonian D2 agonists can themselves improve mood. In RCTs evaluating pramipexole for motor symptoms, mood and motivation also improved.
      • Leentjens A.F.
      • Koester J.
      • Fruh B.
      • et al.
      The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies.
      Further, in an RCT, pramipexole was more effective than sertraline for depression in patients with Parkinson's disease.
      • Barone P.
      • Scarzella L.
      • Marconi R.
      • et al.
      Depression/Parkinson Italian Study Group
      Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study.

      Monoamine Oxidase Inhibitors (MAOIs)

      Included for general information. MAOIs are not recommended in palliative care. They can cause serious adverse events when prescribed concurrently with various other drugs. Seek advice from a psychiatrist if caring for a patient already receiving an MAOI; their previous mental illness is likely to have been difficult to treat and switching or adding other psychotropics is difficult and risky.
      MAOIs are potentially dangerous because of the risk of serious dietary and drug interactions. Hypertensive crises are mainly associated with the consumption of tyramine-containing foods (Table 3). Typically, the patient experiences severe headache, and may suffer an intracranial hemorrhage. Drug interactions occur with sympathomimetics (e.g., ephedrine, pseudoephedrine, dextroamphetamine, nefopam), serotoninergics (see below) and levodopa.
      Table 3Tyramine-Containing Foods Associated With MAOI-Related Syndrome
      AlcoholFava Beans
       Red wine (white wine is safe)Meat (smoked or pickled)
       BeerMeat or yeast extracts
      Broad bean pods

      Cheese (old)
      Pickled herring
      Toxicity has been reported with serotoninergic opioids (e.g., fentanils, meperidine [pethidine], tramodol). However, although pharmaceutical companies marketing morphine and oxycodone also advise against concurrent use, their affinity for the serotonin re-uptake transporter is negligible,
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.
      and toxicity has not been reported.

      Baxter K. Stockley's drug interactions (online edition). London: Pharmaceutical Press, 2011. Available from www.medicinescomplete.com. Accessed August 2012.

      Further, insisting on a two-week washout before treating pain is impracticable.

      Drug Interactions

      MAOIs have numerous clinically significant drug interactions, which may result in hypertensive crises and serotonin toxicity.
      Several pharmacodynamic interactions (e.g., serotonin toxicity, bleeding risk, antimuscarinic effects, QT prolongation with citalopram and escitalopram) can be predicted from the mode of action of antidepressants (see Box 1 and Table 1).
      In addition, potentially serious interactions may result from induction or inhibition of hepatic metabolism. Some antidepressants inhibit cytochrome P450 enzymes:
      • CYP1A2 inhibition by fluvoxamine: e.g., tizanidine levels increased ≤33 times
      • CYP2D6 inhibition by fluoxetine and paroxetine: e.g., TCA levels increased ≤10 times; paroxetine may reduce the efficacy of tamoxifen (a pro-drug).
        • Kelly C.M.
        • Juurlink D.N.
        • Gomes T.
        • et al.
        Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.
      The metabolism of others is affected by P450 inhibitors and inducers:
      • CYP2D6: most TCAs
      • CYP3A4: mirtazapine.

      Serotonin Toxicity (“Serotonin Syndrome”)

      Serotonin toxicity results from the ingestion of drug(s) which increase brain serotonin to levels sufficient to cause severe symptoms necessitating hospital admission and medical intervention (see Box 2 and Box 3).

      Gillman P. Serotonin toxicity, serotonin syndrome: 2006 update, overview and analysis. 2006. Available from www.psychotropical.com. Accessed August 2012.

      It has been characterized as a triad of neuro-excitatory features:
      • autonomic hyperactivity: sweating, fever, mydriasis, tachycardia, hypertension, tachypnea, sialorrhea, diarrhea
      • neuromuscular hyperactivity: tremor, clonus, myoclonus, hyperreflexia, and hypertonia (advanced stage)
      • altered mental status: agitation, hypomania, and delirium (advanced stage).
      Drugs With Clinically Relevant Serotoninergic Potency
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.

      Gillman P. Serotonin toxicity, serotonin syndrome: 2006 update, overview and analysis. 2006. Available from www.psychotropical.com. Accessed August 2012.

      • Gillman P.K.
      A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.
      Antidepressants
      Monoamine oxidase inhibitors (MAOIs) All types
      Selective serotonin re-uptake inhibitors (SSRIs) All
      Serotonin and norepinephrine re-uptake inhibitors (SNRIs)
      Clomipramine and imipramine (but not reported with other TCAs), duloxetine, milnacipran (not UK), venlafaxine
      Psychostimulants (serotonin releasers)
      Dextroamphetamine, MDMA (methylenedioxymethamphetamine, Ecstasy) (but not methylphenidate)
      Other drugs
      H1 antihistamines (serotonin re-uptake inhibitors)
      Chlorpheniramine, brompheniramine (but not other H1 antihistamines)
      Opioids (serotonin re-uptake inhibitors)
      Dextromethorphan, propoxyphene, fentanils, methadone, pentazocine, meperidine (pethidine), tramodol (but not other opioids)
      Miscellaneous
      MAOIs
      Furazolidone, linezolid (antibacterials)
      Methylene blue
      Procarbazine (antineoplastic)
      Selegiline (antiparkinsonian)
      SNRI
      Sibutramine (anorectic)
      Treatment of Serotonin Toxicity
      • Boyer E.W.
      • Shannon M.
      The serotonin syndrome.
      In severe cases (e.g., rigidity, hemodynamic instability, temperature >38.5oC, deteriorating blood gases) seek urgent advice from a critical care specialist: ventilation and paralysis±inotropic support may be required.
      Discontinue causal medication (toxicity generally resolves within 24 h).
      Provide supportive care, e.g., IV fluids, oxygen.
      Symptomatic measures in mild–moderate cases:
      • benzodiazepines for agitation, myoclonus and seizures, e.g., midazolam 5–10 mg SC p.r.n.
      • 5HT2A antagonista, e.g.:
        • chlorpromazine 50–100 mg IM or
        • olanzapine 10 mg IM or
        • cyproheptadine 12 mg PO stat followed by 8 mg q6 h and 2 mg q2 hp.r.n. until symptoms resolve; ts can be crushed and given by enteral feeding tube.
      aPrevents deaths from hyperpyrexia in animals and probably in humans. Generally give IM; the PO route is suitable only for mild toxicity and, in the case of overdose, in patients who have not received oral activated charcoal.
      • Gillman P.K.
      The serotonin syndrome and its treatment.
      • Gillman P.K.
      Serotonin syndrome: history and risk.
      The onset of toxicity is generally rapid and progressive, typically as a second serotoninergic drug reaches effective blood levels (e.g., after one or two doses). Occasionally, recurrent mild symptoms may occur for weeks before the development of severe toxicity. Clonus (inducible, spontaneous or ocular), agitation, sweating, tremor and hyperreflexia are essential features. Spontaneous clonus, in the presence of a serotoninergic drug, is the most reliable indicator of serotonin toxicity.
      • Dunkley E.J.
      • Isbister G.K.
      • Sibbritt D.
      • Dawson A.H.
      • Whyte I.M.
      The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
      Neuromuscular signs are initially greater in the lower limbs, then become more generalized as toxicity increases. Other symptoms include shaking, shivering (and chattering of the teeth), and sometimes trismus. It can be distinguished from neuroleptic (antipsychotic) malignant syndrome by its faster onset and pyramidal rather than extrapyramidal neuromuscular findings.
      Different drugs increase serotonin levels to differing degrees. An overdose of the older irreversible MAOI tranylcypromine alone will produce hyperpyrexia, and even death,
      • Whyte I.
      Monoamine oxidase inhibitors.
      whereas overdoses of reversible MAOIs or SSRIs alone will cause serotoninergic effects but rarely (if ever) life-threatening serotonin toxicity.
      • Isbister G.K.
      • Hackett L.P.
      • Dawson A.H.
      • Whyte I.M.
      • Smith A.J.
      Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.
      • Flanagan R.J.
      Fatal toxicity of drugs used in psychiatry.
      Thus death from serotonin toxicity is generally associated with the combination of two different types of drug which elevate serotonin levels via different mechanisms of action (an MAOI combined with either an SSRI or a serotonin releaser).
      • Isbister G.K.
      • Hackett L.P.
      • Dawson A.H.
      • Whyte I.M.
      • Smith A.J.
      Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.
      Opioids are relatively weak serotonin re-uptake inhibitors and may only cause symptoms in higher doses or susceptible individuals. Fatalities from serotonin toxicity involving opioids have been seen with dextromethorphan, pethidine (meperidine), tramodol, and possibly fentanyl.
      • Gillman P.K.
      Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity.

      Undesirable Effects

      A synopsis is contained in Table 4. Overall, discontinuation with SSRIs is marginally less than with TCAs (NNT 33).
      • Anderson I.M.
      Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability.
      Table 4Relative Frequency and Mechanisms of Undesirable Effects of Antidepressants
      • Bhuvaneswar C.G.
      • Baldessarini R.J.
      • Harsh V.L.
      • Alpert J.E.
      Adverse endocrine and metabolic effects of psychotropic drugs: selective clinical review.
      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      • Jacob S.
      • Spinler S.A.
      Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults.
      Undesirable EffectPutative MechanismRelative FrequencyRelative Frequency
      SNRINRISSRIRA
      AmitriptylineClomipramineDuloxetineImipramineVenlafaxineDesipramineLofepramineNortriptylineCitalopramFluoxetineParoxetineSertralineMirtazapineTrazodone
      GI (nausea, diarrhea)↑Serotonin (acting on 5HT3)+++++++++++++
      CNS (agitation, restlessness, anxiety, insomnia)↑Serotonin (acting on 5HT2)+++++++++++
      Weight gain5HT2 and H1 antagonism+++++++
      SedationH1, AChM and α1-adrenergic antagonism++++++++++
      Postural hypotensionα1-adrenergic antagonism+++++++++++
      Sexual dysfunction↑Serotonin (acting on 5HT2)+++++++++++++++++++
      Dry mouth, constipationAChM antagonism+++++++++
      SIADH↑Serotonin (acting on 5HT2); ↑norepinephrine (acting on α1)++++++++++++++++++
      Key: ++=relatively common or strong; +=may occur or moderately strong; –=absent or rare/weak.
      SNRI=serotonin and norepinephrine re-uptake inhibitor; NRI=norepinephrine re-uptake inhibitor; SSRI=selective serotonin re-uptake inhibitor; RA=receptor antagonist.

      GI Bleeding and Platelet Function

      SSRIs and SNRIs (e.g., amitriptyline, duloxetine, imipramine, venlafaxine) decrease serotonin uptake from the blood by platelets. Because platelets do not synthesize serotonin, the amount of serotonin in platelets is reduced.
      • Ross S.B.
      • Aperia B.
      • Beck-Friis J.
      • et al.
      Inhibition of 5-hydroxytryptamine uptake in human platelets by antidepressant agents in vivo.
      This adversely affects platelet aggregation.
      • Li N.
      • Wallén N.H.
      • Ladjevardi M.
      • Hjemdahl P.
      Effects of serotonin on platelet activation in whole blood.
      After confounding factors have been controlled for, serotonin re-uptake inhibitors triple the risk of GI bleeding.
      • van Walraven C.
      • Mamdani M.M.
      • Wells P.S.
      • Williams J.I.
      Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study.
      • Paton C.
      • Ferrier I.N.
      SSRIs and gastrointestinal bleeding.
      This may be important in already high-risk patients. If an antidepressant is indicated in such patients, safer alternatives would include an NRI (e.g., desipramine [not UK], nortriptyline) or mirtazapine.

      QT Prolongation

      Citalopram and escitalopram exhibit dose-related QT prolongation. Regulators recommend correction of hypokalemia and hypomagnesemia and advise ECG monitoring in those with cardiac disease or receiving other QT prolonging drugs.

      Medicines and Healthcare Products Regulatory Agency. Citalopram and escitalopram: QT interval prolongation - new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings. Drug Safety Update 2011;5(5): A1. Available from http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON137769. Accessed August 21, 2012.

      The dose of citalopram should not exceed 40 mg daily, with the FDA recently recommending an even smaller maximum dose of 20 mg daily in patients >60 years, those with hepatic impairment, CYP 2C19 poor metabolizers, or with concurrent use of a CYP 2C19 inhibitor.

      U.S. Food and Drug Administration. (2012) Celexa (citalopram hydrobromide) - drug safety communication: Revised recommendations, potential risk of abnormal heart rhythms. 2012. Available from http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm297624.htm. Accessed August 21, 2012.

      Other SSRIs appear less affected, at least in overdose.
      • Isbister G.K.
      • Bowe S.J.
      • Dawson A.
      • Whyte I.M.
      Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose.

      Fracture Risk

      The European Medicines Agency highlighted a consistently increased fracture risk with SSRIs and TCAs across a number of observational studies.

      European Medicines Agency. Pharmacovigilance working party March 2010 plenary meeting. 2010. Available from http://www.emea.europa.eu/docs/en_GB/document_library/Report/2010/04/WC500088721.pdf. Accessed August 2012.

      The mechanism is uncertain; data regarding both the risk of falls and bone density are conflicting.

      Use of Antidepressants in Palliative Care

      Note. Generic formulations of a number of antidepressants are available, e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine, which are about one-third of the cost of the brand name formulations.

      Neuropathic Pain

      Amitriptyline and nortriptyline are commonly used for neuropathic pain.

      Palliativedrugs.com. Survey Jan-Feb 2009. 2009. Available from www.palliativedrugs.com. Accessed August 2012.

      Most RCTs have been of amitriptyline, although nortriptyline was better tolerated when compared with amitriptyline.
      • Watson C.P.
      • Vernich L.
      • Chipman M.
      • Reed K.
      Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial.
      Their efficacy and tolerability appear comparable to alternatives (e.g., anti-epileptic drugs and other SNRI and NRI antidepressants),
      • Saarto T.
      • Wiffen P.J.
      Antidepressants for neuropathic pain.
      • Dworkin R.H.
      • O'Connor A.B.
      • Backonja M.
      • et al.
      Pharmacologic management of neuropathic pain: evidence-based recommendations.
      • Finnerup N.B.
      • Otto M.
      • McQuay H.J.
      • Jensen T.S.
      • Sindrup S.H.
      Algorithm for neuropathic pain treatment: an evidence based proposal.
      • Watson C.P.
      • Gilron I.
      • Sawynok J.
      • Lynch M.E.
      Nontricyclic antidepressant analgesics and pain: are serotonin norepinephrine reuptake inhibitors (SNRIs) any better?.
      although few have been directly compared.
      Bupropion, duloxetine, venlafaxine and most other TCAs are also superior to placebo. In head-to-head comparisons, both duloxetine vs. amitriptyline,
      • Kaur H.
      • Hota D.
      • Bhansali A.
      • et al.
      A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial.
      and venlafaxine vs. imipramine
      • Sindrup S.H.
      • Bach F.W.
      • Madsen C.
      • Gram L.F.
      • Jensen T.S.
      Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial.
      were comparable. SSRIs are modestly effective (three of four RCTs),
      • Otto M.
      • Bach F.W.
      • Jensen T.S.
      • Brøsen K.
      • Sindrup S.H.
      Escitalopram in painful polyneuropathy: a randomized, placebo-controlled, cross-over trial.
      • Sindrup S.H.
      • Bjerre U.
      • Dejgaard A.
      • et al.
      The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy.
      • Max M.B.
      • Lynch S.A.
      • Muir J.
      • et al.
      Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.
      • Sindrup S.H.
      • Gram L.F.
      • Brøsen K.
      • Eshøj O.
      • Mogensen E.F.
      The selective serotonin re-uptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms.
      but inferior to imipramine.
      • Sindrup S.H.
      • Gram L.F.
      • Brøsen K.
      • Eshøj O.
      • Mogensen E.F.
      The selective serotonin re-uptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms.
      The benefit reported with mirtazapine
      • Christodoulou C.
      • Douzenis A.
      • Moussas G.
      • Lykouras L.
      Effectiveness of mirtazapine in the treatment of postherpetic neuralgia.
      has not been confirmed in RCTs.
      Alternatives to antidepressants include anti-epileptics
      • Howard P.
      • Twycross R.
      • Shuster J.
      • et al.
      Anti-epileptic drugs.
      and opioids. In head-to-head comparisons, the efficacy of TCAs (amitriptyline or nortriptyline) was similar to gabapentin or pregabalin. Overall, tolerability also was comparable; although one RCT found fewer withdrawals due to adverse effects with TCAs, one found a greater number and one found similar numbers.
      • Chandra K.
      • Shafiq N.
      • Pandhi P.
      • Gupta S.
      • Malhotra S.
      Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial–the GONIP Trial.
      • Morello C.M.
      • Leckband S.G.
      • Stoner C.P.
      • Moorhouse D.F.
      • Sahagian G.A.
      Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain.
      • Bansal D.
      • Bhansali A.
      • Hota D.
      • Chakrabarti A.
      • Dutta P.
      Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial.
      They are also often used together: nortriptyline combined with gabapentin was more effective than either drug alone.
      • Gilron I.
      • Bailey J.M.
      • Tu D.
      • et al.
      Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.
      Nortriptyline was as effective as morphine.
      • Raja S.N.
      • Haythornthwaite J.A.
      • Pappagallo M.
      • et al.
      Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.

      Other Pain Syndromes

      Antidepressants are of benefit for various other pain syndromes including migraine and tension headache (TCAs),
      • Jackson J.L.
      • Shimeall W.
      • Sessums L.
      • et al.
      Tricyclic antidepressants and headaches: systematic review and meta-analysis.
      chronic low back pain (TCAs),
      • Staiger T.O.
      • Gaster B.
      • Sullivan M.D.
      • Deyo R.A.
      Systematic review of antidepressants in the treatment of chronic low back pain.
      fibromyalgia (duloxetine),
      • Lunn M.P.
      • Hughes R.A.
      • Wiffen P.J.
      Duloxetine for treating painful neuropathy or chronic pain.
      and osteo-arthritis (duloxetine).
      • Chappell A.S.
      • Ossanna M.J.
      • Liu-Seifert H.
      • et al.
      Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.

      Depression

      See also Palliativedrugs.com Quick Practice Guide: Depression (p.782).
      Treatment is tailored to the severity of symptoms, their functional impact and patient preference (Fig. 2). First-line drug treatment is generally with sertraline or citalopram. They have fewer drug interactions, lower risk in overdose, and are marginally better tolerated than alternatives.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      Efficacy has been confirmed in palliative populations.
      • Rayner L.
      • Price A.
      • Evans A.
      • et al.
      Antidepressants for the treatment of depression in palliative care: systematic review and meta-analysis.
      Frequent re-evaluation of response, adherence, and alternative and concurrent sources of distress is required throughout.
      Figure thumbnail gr2
      Fig. 2Overview of the management of depression.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      • Rayner L.
      • Price A.
      • Hotopf M.
      • Higginson I.J.
      The development of evidence-based European guidelines on the management of depression in palliative cancer care.
      aSub-threshold symptoms=patients with <5 DSM IV symptoms required for a diagnosis of depression. bCBT=cognitive behavioral therapy. cSee below, managing an inadequate initial response.
      Methylphenidate, with its rapid onset, may be preferable in patients with a very short prognosis, e.g., 2–4 weeks. This is shorter than suggested by consensus guidance
      • Block S.D.
      Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians - American Society of Internal Medicine.
      because of the recognition that conventional antidepressants act faster than previously thought.
      • Tylee A.
      • Walters P.
      Onset of action of antidepressants.
      However, trials of psychostimulants are generally of short duration and with outcome measures of uncertain clinical significance. Thus, conventional antidepressants should be used if the patient has a sufficient prognosis for a response to manifest.
      • Block S.D.
      Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians - American Society of Internal Medicine.
      • Candy M.
      • Jones L.
      • Williams R.
      • Tookman A.
      • King M.
      Psychostimulants for depression.
      • Orr K.
      • Taylor D.
      Psychostimulants in the treatment of depression: a review of the evidence.
      Concurrent use with a conventional antidepressant may hasten the response compared with the latter alone, particularly in relation to fatigue.
      • Orr K.
      • Taylor D.
      Psychostimulants in the treatment of depression: a review of the evidence.
      Modafinil can be used if methylphenidate is poorly tolerated.
      Although an SNRI or NRI may be considered if depression and neuropathic pain co-exist, slower titration is required to avoid higher rates of discontinuation.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      They are therefore often treated separately (e.g., with an SSRI plus either gabapentin or nortriptyline).

      Titrating, Switching and Combining Antidepressants

      If there is no response after four weeks, or only a partial response after 6–8 weeks:
      • increase the dose, particularly if there has been a partial response and minimal undesirable effects or
      • switch antidepressants, particularly if there has been minimal improvement or bothersome undesirable effects or
      • combine with a second antidepressant or adjuvant psychotropic drug, particularly if a previous switch was unhelpful.

        National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      Dose titration is straightforward but, for SSRIs, of uncertain value. A systematic review found dose titration in patients not responding to SSRIs taken for 3–6 weeks no more effective than continuing the dose unaltered.
      • Adli M.
      • Baethge C.
      • Heinz A.
      • Langlitz N.
      • Bauer M.
      Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review.
      Nonetheless, many guidelines highlight individual variation in effective doses and therefore recommend dose titration if the existing drug is well tolerated.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      A dose-response effect is more clearly established with TCAs and venlafaxine.
      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      The efficacy of second-line antidepressants appears comparable regardless of mode of action.
      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      • Rush A.J.
      • Warden D.
      • Wisniewski S.R.
      • et al.
      STAR*D: revising conventional wisdom.
      • Ruhé H.G.
      • Huyser J.
      • Swinkels J.A.
      • Schene A.H.
      Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review.
      Options include an alternative SSRI or mirtazapine. One SSRI can be directly substituted for another without cross-tapering or a washout period.
      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      • Ruhé H.G.
      • Huyser J.
      • Swinkels J.A.
      • Schene A.H.
      Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review.
      Mirtazapine 15 mg can be directly substituted for SSRIs at usual doses (fluoxetine, citalopram or paroxetine 20 mg; sertraline 50 mg).
      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      • Fava G.A.
      • Mangelli L.
      Assessment of subclinical symptoms and psychological well-being in depression.
      Opinion varies on the need to taper higher SSRI doses before switching.
      • Rush A.J.
      • Warden D.
      • Wisniewski S.R.
      • et al.
      STAR*D: revising conventional wisdom.
      • Fava G.A.
      • Mangelli L.
      Assessment of subclinical symptoms and psychological well-being in depression.
      Switching SSRIs is most effective when the first SSRI is poorly tolerated but benefit also is seen in non-responders,
      • Ruhé H.G.
      • Huyser J.
      • Swinkels J.A.
      • Schene A.H.
      Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review.
      perhaps because of differing additional actions (see Table 5). The effect of mirtazapine on additional monoamines is theoretically advantageous; its onset may be faster.
      • Watanabe N.
      • Omori I.M.
      • Nakagawa A.
      • et al.
      Mirtazapine versus other antidepressive agents for depression.
      Venlafaxine has a marginally higher response rate (NNT=10) compared with switching to a second SSRI
      • Ruhé H.G.
      • Huyser J.
      • Swinkels J.A.
      • Schene A.H.
      Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review.
      but is less well tolerated. Switching to or from TCAs and MAOIs requires additional care because of the potential for clinically significant pharmacokinetic or pharmacodynamic drug interactions, respectively (see above).
      • Taylor D.
      • Paton C.
      • Kerwin R.
      The Maundsley prescribing guidelines.
      Table 5Differences Between SSRIs
      • Hashimoto K.
      Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship.
      • Rao N.
      The clinical pharmacokinetics of escitalopram.
      • Carrasco J.L.
      • Sandner C.
      Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overview.
      • Haddad P.M.
      Antidepressant discontinuation syndromes: clinical relevance, prevention and management.
      • Preskorn S.H.
      Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism.
      DrugAdditional ActionsHepatic Enzyme InhibitionDiscontinuation Reaction Risk
      Approximates to half-life (see Table 1)
      CYP 1A2CYP 2C9CYP 2C19CYP 2D6CYP 3A4
      CitalopramH1 antagonist (R- enantiomer)+Low
      EscitalopramNone+Low
      Fluoxetine5HT2C antagonist
      These actions theoretically contribute to their antidepressant effects but the affinity, and overall contribution of these additional actions is much less than the predominant serotonin re-uptake inhibition
      ++++++++Minimal
      FluvoxamineSigma-1 agonist
      The action of sigma-1 receptors is poorly defined, but sigma-1 receptor agonists may have antidepressant, pro-seizure, euphoric and/or dysphoric effects.
      ++++++++Moderate
      ParoxetineNorepinephrine re-uptake inhibitor
      These actions theoretically contribute to their antidepressant effects but the affinity, and overall contribution of these additional actions is much less than the predominant serotonin re-uptake inhibition
      +++High
      SertralineDopamine re-uptake inhibitor
      These actions theoretically contribute to their antidepressant effects but the affinity, and overall contribution of these additional actions is much less than the predominant serotonin re-uptake inhibition
      +Low
      Key: +=weak inhibition; ++=moderate inhibition; +++=marked inhibition
      a Approximates to half-life (see Table 1)
      b These actions theoretically contribute to their antidepressant effects but the affinity, and overall contribution of these additional actions is much less than the predominant serotonin re-uptake inhibition
      c The action of sigma-1 receptors is poorly defined, but sigma-1 receptor agonists may have antidepressant, pro-seizure, euphoric and/or dysphoric effects.
      A partial response to an antidepressant can be increased (“augmented”) by adding a second psychotropic drug. This avoids potential loss of the initial improvement but is generally less well tolerated than monotherapy.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      Options include:
      • an antipsychotic (e.g., aripiprazole, quetiapine or olanzapine added to an SSRI)
      • mirtazapine (added to an SSRI or venlafaxine)
      • a range of options used only by psychiatrists (e.g., lithium, tri-iodothyronine).
      NICE suggests primary care clinicians seek advice before adding a second drug.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      Palliative care specialists using some of the above for other indications should be aware of their potential benefit when concurrent depression has only partially responded to an antidepressant.
      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      • Shelton R.C.
      • Osuntokun O.
      • Heinloth A.N.
      • Corya S.A.
      Therapeutic options for treatment-resistant depression.

      Duration of Treatment

      Consider stopping treatment six months after full remission in those without risk factors for relapse. Risk factors include previous depression and the severity, duration, degree of treatment resistance, and the presence of residual symptoms. Treatment is tapered slowly (see below). Treat those with risk factors for longer: one year if full remission but one risk factor; and ≥2 years if ≥2 risk factors.

      National Institute for Health and Clinical Excellence (NICE). Clinical guidleline 90 and 91. Depression. 2009. Available from www.nice.org.uk. Accessed August 2012.

      • Anderson I.M.
      • Ferrier I.N.
      • Baldwin R.C.
      • et al.
      Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
      In palliative care, the latter is likely to mean lifelong/indefinitely.

      Anxiety and Panic Disorders

      The efficacy of cognitive behavioral and drug therapy is comparable.
      • Bandelow B.
      • Seidler-Brandler U.
      • Becker A.
      • Wedekind D.
      • Rüther E.
      Meta-analysis of randomized controlled comparisons of psychopharmacological and psychological treatments for anxiety disorders.
      Drug treatment is tailored to the likely duration of use:
      • benzodiazepine, if prognosis is days to weeks
      • SSRI (+/- a benzodiazepine initially), if prognosis is months.
      Although supporting evidence (and licensing) for SSRIs varies for different anxiety disorders,
      • Baldwin D.S.
      • Anderson I.M.
      • Nutt D.J.
      • et al.
      British Association for Psychopharmacology
      Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology.
      a class effect is plausible. Citalopram and sertraline are licensed for panic disorder, well tolerated, have fewer drug interactions, and are generally more familiar to prescribers. All SSRIs can initially exacerbate anxiety: start low and consider a concurrent benzodiazepine for the first few weeks.
      If response is inadequate, combine with cognitive behavioral therapy (evidence best for panic disorder)
      • Bandelow B.
      • Seidler-Brandler U.
      • Becker A.
      • Wedekind D.
      • Rüther E.
      Meta-analysis of randomized controlled comparisons of psychopharmacological and psychological treatments for anxiety disorders.
      or switch to an alternative SSRI or SNRI.
      • Baldwin D.S.
      • Anderson I.M.
      • Nutt D.J.
      • et al.
      British Association for Psychopharmacology
      Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology.

      National Institute for Health and Clinical Excellence (NICE). Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults: management in primary, secondary and community care. Clinical Guideline 113. 2011. Available from www.nice.org.uk. Accessed August 2012.

      In general psychiatry, switching is not advocated within three months because benefit can take longer to manifest than in depression.
      • Baldwin D.S.
      • Anderson I.M.
      • Nutt D.J.
      • et al.
      British Association for Psychopharmacology
      Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology.

      National Institute for Health and Clinical Excellence (NICE). Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults: management in primary, secondary and community care. Clinical Guideline 113. 2011. Available from www.nice.org.uk. Accessed August 2012.

      However, in patients with a short prognosis, consider adding a benzodiazepine to obtain more rapid benefit. Pregabalin also acts quickly but is reserved for patients not responding to antidepressants; supporting trials are fewer, mainly confined to generalized anxiety disorder and response rates appear lower than for SSRIs and benzodiazepines.
      • Baldwin D.S.
      • Anderson I.M.
      • Nutt D.J.
      • et al.
      British Association for Psychopharmacology
      Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology.
      • Baldwin D.
      • Woods R.
      • Lawson R.
      • Taylor D.
      Efficacy of drug treatments for generalised anxiety disorder: systemic review and meta-analysis.

      Agitated Delirium

      The benefit reported with trazodone
      • Okamoto Y.
      • Matsuoka Y.
      • Sasaki T.
      • et al.
      Trazodone in the treatment of delirium.
      remains unconfirmed in clinical trials. Treatment of underlying causes, non-drug management (e.g., orientation strategies, correction of sensory deprivation) and prevention of complications are central to delirium management. Antipsychotics are generally used first-line when medication is needed.
      • Howard P.
      • Twycross R.
      • Shuster J.
      • Mihalyo M.
      • Wilcock A.
      Antipsychotics.

      Agitation and Challenging Behaviors in Dementia

      Evidence for antidepressants is even more limited than for antipsychotics, and certainly insufficient to justify routine use.
      • Jeste D.V.
      • Blazer D.
      • Casey D.
      • et al.
      ACNP white paper: update on use of antipsychotic drugs in elderly persons with dementia.
      • Sink K.M.
      • Holden K.F.
      • Yaffe K.
      Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence.
      Larger studies have not replicated the earlier benefit reported for trazodone.
      • Jeste D.V.
      • Blazer D.
      • Casey D.
      • et al.
      ACNP white paper: update on use of antipsychotic drugs in elderly persons with dementia.

      Sweating

      Like other antimuscarinics, amitriptyline is used for paraneoplastic sweating unresponsive to NSAIDs.
      • Twycross R.
      • Wilcock A.
      • Toller C.S.
      Skin care.
      However, like all monoamine reuptake inhibitors, it can also cause sweating.
      • Marcy T.R.
      • Britton M.L.
      Antidepressant-induced sweating.

      Hot Flashes

      Venlafaxine and SSRIs are of benefit in hot flashes associated with the menopause, hormone therapy and androgen ablation therapy for prostate cancer.
      • Rada G.
      • Capurro D.
      • Pantoja T.
      • et al.
      Non-hormonal interventions for hot flashes in women with a history of breast cancer.
      • Quella S.K.
      • Loprinzi C.L.
      • Sloan J.
      • et al.
      Pilot evaluation of venlafaxine for the treatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer.

      Insomnia

      When insomnia co-exists with other indications, sedating antidepressants (e.g., TCAs, mirtazapine, trazodone) are often selected. Doxepin 3–6 mg at bedtime PO improves both sleep latency and fragmentation in primary insomnia. Benefit is sustained for ≥12 weeks without rebound insomnia after discontinuation.
      • Weber J.
      • Siddiqui M.A.
      • Wagstaff A.J.
      • McCormack P.L.
      Low-dose doxepin: in the treatment of insomnia.
      Trazodone is commonly used although evidence is limited.
      • Mendelson W.B.
      A review of the evidence for the efficacy and safety of trazodone in insomnia.

      Pruritus

      Two small RCTs suggest benefit within a few days from sertraline (cholestatic pruritus)
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • et al.
      Sertraline as a first-line treatment for cholestatic pruritus.
      and paroxetine (pruritus of mixed cause in cancer patients).
      • Zylicz Z.
      • Krajnik M.
      • Sorge A.A.
      • Costantini M.
      Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial.
      Benefit also is reported in pruritus associated with polycythemia vera.
      • Tefferi A.
      • Fonseca R.
      Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus.
      Mirtazapine is reported to improve pruritus of mixed cause in advanced disease.
      Like other H1 antagonists, doxepin can be used for histamine-mediated pruritus and/or for night sedation.

      Bladder Spasm, Stress Incontinence and Urgency

      Antimuscarinic antidepressants (e.g., amitriptyline) reduce detrusor contractions associated with urgency, although licensed alternatives have additional direct effects on the detrusor muscle.
      • Twycross R.
      • Wilcock A.
      • Toller C.S.
      Urinary symptoms.
      Duloxetine has a limited role in stress incontinence.

      National Institute for Health and Clinical Excellence (NICE). (2006) Urinary incontinence: the management of urinary incontinence in women. Clinical Guideline 40. 2006. Available from www. http://guidance.nice.org.uk/CG40. Accessed August 2012.

      Pathological Laughter and Crying

      Frequent brief uncontrollable laughter and/or crying, incongruent with external events, can complicate numerous neurological disorders, including Parkinson's disease, cerebral tumors, multiple sclerosis, strokes, ALS/MND, and dementia. It can be socially disabling. Functional imaging suggests dysregulation of serotoninergic and other monoaminergic pathways. The differential diagnosis includes:
      • seizures: generally complex partial seizures and thus an alteration of consciousness during/after episodes
      • depression or other mood disorders: mood alteration is persistent whereas the emotion that may accompany pathological laughter and crying is short-lived.
      Validated assessment tools are available to aid diagnosis.
      • Robinson R.G.
      • Parikh R.M.
      • Lipsey J.R.
      • Starkstein S.E.
      • Price T.R.
      Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study.
      First-line treatment is with citalopram or sertraline; doses can be lower than those required for depression. Benefit is often seen within days. Second-line options include amitriptyline, imipramine, nortriptyline and levodopa.
      • Wortzel H.S.
      • Oster T.J.
      • Anderson C.A.
      • Arciniegas D.B.
      Pathological laughing and crying: epidemiology, pathophysiology and treatment.

      Drooling and Sialorrhea

      Like other antimuscarinics, amitriptyline reduces salivation.
      • Twycross R.
      • Wilcock A.
      • Toller C.S.
      Alimentary symptoms.

      Stopping Antidepressants

      Abrupt cessation of antidepressant therapy (particularly an MAOI) after regular administration for >8 weeks may result in a discontinuation reaction (withdrawal syndrome).
      • Haddad P.M.
      Antidepressant discontinuation syndromes: clinical relevance, prevention and management.
      Discontinuation reactions depend on the class of antidepressant, and are more common with drugs with shorter half-lives (Box 4). Thus, with SSRIs, they are most common with paroxetine and least common with fluoxetine.
      Antidepressant Discontinuation Reactions
      • Haddad P.M.
      Antidepressant discontinuation syndromes: clinical relevance, prevention and management.
      SSRIs and venlafaxine: “FINISH
      • Berber M.J.
      FINISH: remembering the discontinuation syndrome. Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, and Hyperarousal (anxiety/agitation).
      Flu-like symptoms (fatigue, lethargy, myalgia, chills)
      Insomnia (including vivid dreams)
      Nausea
      Imbalance (ataxia, vertigo, dizziness)
      Sensory disturbances (paraesthesia, sensations of electric shock)
      Hyperarousal (restlessness, anxiety, agitation)
      TCAs
      Flu-like symptoms (fatigue, lethargy, myalgia, chills)
      Insomnia (including vivid dreams)
      GI disorders (nausea, diarrhea)
      Mood disorders (depression or mania)
      Movement disorders (rare: akathisia, parkinsonism)
      Trazodone
      Flu-like symptoms (fatigue, lethargy, myalgia, chills)
      GI disorders (nausea, diarrhea)
      Restlessness
      Tremor
      Headache
      Mirtazapine
      Nausea
      Dizziness
      Hyperarousal (anxiety, agitation)
      Headache
      MAOIs
      Insomnia
      Movement disorders (ataxia, athetosis, catatonia, myoclonus)
      Mood disorders (lability, depression, agitation, aggression)
      Paranoia
      Hallucinations
      Seizures
      Altered speech (pressured, slow)
      Discontinuation reactions differ from a depressive relapse or a panic disorder. They generally start abruptly within a few days of stopping the antidepressant (or reducing its dose). In contrast, a depressive relapse is uncommon in the first week after stopping an antidepressant, and symptoms tend to build up gradually and persist. Discontinuation reactions generally resolve within 24 h of re-instating antidepressant therapy, whereas the response is slower with a depressive relapse.
      Ideally, antidepressants taken for >8 weeks should be progressively reduced over four weeks. If a mild discontinuation reaction is suspected, re-assurance alone may be adequate. If distressing, restart the antidepressant and reduce more gradually.
      Some patients experience discontinuation symptoms even during tapering. When this happens, increase the dose and, before continuing with tapering, consider:
      • using a liquid formulation and reducing the dose in smaller steps or
      • switching from venlafaxine or a short half-life SSRI to fluoxetine.
        • Haddad P.M.
        Antidepressant discontinuation syndromes: clinical relevance, prevention and management.

      Palliativedrugs.com Quick Practice Guide: Depression

      Sadness and tears, even if associated with transient suicidal thoughts, do not justify the diagnosis of depression or the prescription of an antidepressant. Often they are part of an adjustment reaction, and improve with time. Other patients are demoralized rather than medically depressed and respond to symptom management and psychosocial support.

        Evaluation

      • 1.
        Screening: about 5–10% of patients with advanced cancer develop a major depression. Cases will be missed unless specific enquiry is made of all patients:
        • “What has your mood been like lately?…. Are you depressed?”
        • “Have you had serious depression before? Are things like that now?”
      • 2.
        Assessment interview: if depression is suspected, explore the patient's mood more fully by encouraging the patient to talk further with appropriate prompts. Symptoms suggesting clinical depression include:
        • sustained low mood (i.e., most of every day for several weeks) core symptoms
        • sustained loss of pleasure/interest in life (anhedonia)
        • diurnal variation (worse in mornings and better in evenings)
        • waking significantly earlier than usual (e.g., 1–2 h) and feeling “awful”
        • feelings of hopelessness/worthlessness
        • excessive guilt
        • withdrawal from family and friends
        • persistent suicidal thoughts and/or suicidal acts
        • requests for euthanasia.
      • 3.
        Differential diagnosis: the symptoms of depression and cancer, and of depression and sadness overlap. If in doubt whether the patient is suffering from depression, an adjustment reaction or sadness, review after 1–2 weeks of general support and improved symptom management. If still undecided, seek advice from a psychologist/psychiatrist.
      • 4.
        Medical causes of depression: depression may be the consequence of:
        • a medical condition, e.g., hypercalcemia, cerebral metastases
        • a reaction to severe uncontrolled physical symptoms
        • drugs, e.g., antineoplastics, benzodiazepines, antipsychotics, corticosteroids, antihypertensives.

        Management

      • 5.
        Correct the correctable: treat medical causes, particularly severe pain and other distressing symptoms.
      • 6.
        Non-drug treatment:
        • explanation and assurance that symptoms can be treated
        • depressed patients often benefit from the ambience of a Palliative Care Day Center
        • specific psychological treatments (via a clinical psychologist, etc.)
        • other psychosocial professionals, e.g., chaplain and creative therapists, have a therapeutic role, but avoid overwhelming the patient with simultaneous multiple referrals.
      • 7.
        Drug treatment:
        • if the patient is expected to live for >4 weeks, prescribe a conventional antidepressant; if <4 weeks, consider a psychostimulant
        • the starting and continuing doses of antidepressants are generally lower in debilitated patients than in the physically fit
        • all antidepressants can cause withdrawal symptoms if stopped abruptly; generally withdraw gradually over 4 weeks
        • at usual doses, one SSRI can be directly substituted for another without cross-tapering or a washout period. Mirtazapine 15 mg can be directly substituted for SSRIs (fluoxetine, citalopram or paroxetine 20 mg; sertraline 50 mg)
        • taper higher SSRI doses before switching
        • switching to or from TCAs and MAOIs requires additional care – seek advice or see reference texts105
      PCF preferred antidepressants
      First-line
      Psychostimulant, e.g., methylphenidate
      Particularly if prognosis <2–4 weeks:
      • start with 2.5–5 mg b.i.d. (on waking/breakfast time and noon/lunchtime)
      • if necessary, increase by daily increments of 2.5 mg b.i.d. to 20 mg b.i.d.
      • occasionally higher doses are necessary, e.g., 30 mg b.i.d. or 20 mgt.i.d.
      • SSRI, e.g., sertraline or citalopram
      • Particularly if prognosis >2–4 weeks, and if associated anxiety:
      • no antimuscarinic effects, but may cause an initial increase in anxiety
      • if necessary prescribe diazepam at bedtime
      • start with sertraline 50 mg or citalopram 10 mg once daily, increasing the latter to 20 mg after 1 week
      • if no improvement after 4 weeks, or only a partial improvement after 6–8 weeks, either:
        • increase dose by sertraline 50 mg or citalopram 10 mg or
        • switch to a second-line antidepressant
      • maximum daily dose sertraline 200 mg or citalopram 40 mg (20 mg in patients >60 years, those with hepatic impairment, CYP 2C19 poor metabolizers, or concurrent use of a CYP 2C19 inhibitor)
      • low likelihood of a withdrawal (discontinuation) syndrome.
      Second-line
      Alternative SSRI, e.g,. sertraline or citalopram
      Dose as above
      Mirtazapine
      Acts on receptors; it is not a MARI. A good choice for patients with anxiety/agitation:
      • start with 15 mg at bedtime
      • if little or no improvement after 2 weeks, increase to 30 mg at bedtime
      • concurrent H1-receptor antagonism leads to sedation but this decreases at the higher dose because of noradrenergic effects.
      • fewer undesirable effects than TCAs.
      • If no response after 4 weeks, consider third-line options.
      • Third-line options
      • seek advice from a psychiatrist
      • dose escalation
      • switch antidepressant
      • combine an SSRI with mirtazapine, olanzapine or quetiapine.

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