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Gillman’s AD algorithm
by Dr Ken Gillman | Last updated Jan 18, 2020 | Published on Jan 5, 2017 | Anti-
Depressants, General Intro
Gillman’s Antidepressant algorithm

Summary
This commentary presents my antidepressant treatment algorithm
which incorporates concepts from Bayesian reasoning and ‘critical
path analysis’; that makes it a ‘multi-lane’ clinical pathway. It
emphasises procedures which most algorithms neglect. The appendix
discusses problems concerning assumptions about the pharmacology
and methodology relating to the derivation of treatment algorithms,
:
especially the mis-leading conclusions produced by ‘stepped’ trials
and meta-analysis. The term ‘algorithm’ is now used widely to
describe the process of systematic assessment and treatment and
there are now hundreds of references to this in PubMed.
First, my basic ‘fast-lane’ algorithm for more severe cases of
biological/melancholic depression (no AD-free periods required for
any step).
Step 1. Sertraline (or citalopram/escitalopram) or Nortriptyline: 6

weeks.
Step 2. Sertraline (or citalopram/escitalopram) combined with

Nortriptyline 6 weeks.
Step 3). Tranylcypromine.
Cases presenting to a specialist will already be ready for step 2. This

is elaborated below.
Background: theory and considerations

I receive many enquiries about minimally effective AD treatment*
from unfortunate people who have been on various similar
antidepressants for a long time with little regard for what is sensible
and reasonable, and little regard for their ongoing partially-treated
illness and their suffering and deteriorating life circumstances (like
four successive SSRIs, over one or two years — pointless, waste of
time (1)). It is of great concern that a proportion of doctors do not
think critically and logically about advancing people to more
effective treatments in an expeditious manner.
*NB. Opinion in this commentary refers to AD treatment for

:
serious ‘biological’ depression, different criteria may apply to
anxiety and mild forms of depression.
This commentary does not consider non-pharmacological

interventions which are effective and may be the preferred 1st option
for many people, especially those with less severe and persistent
symptoms.
Thinking critically and logically about the expeditious progress of

treatment benefits from incorporating the precepts of ‘critical path
analysis’, which most algorithms do not encompass. A measure of
knowledge and resolve are required to achieve that because there is a
strong natural reluctance to change a treatment, even if it is only
partially effective.
Doctors need to be aware of how the psychology of ‘risk aversion’

and ‘negativity bias’, influence their advice and decisions.
Guidelines and algorithms also have a downside: they promote

intellectual laziness; they deal in generalities not individuals; they
obfuscate the fact that treatment decisions about individuals are the
sole responsibility of the treating doctor; they can stifle innovation
and originality and foster a self-fulfilling conformity. Doctors must
have a meaningful dialogue with patients about their individual
choices.
The forgotten principle of evidence-based medicine

The road to hell is paved with good intentions (Proverb)
It is important to emphasise and adhere to EBM tenets: these require:
“integrating … the best available external clinical evidence from

systematic research…[with] the proficiency and judgment that
individual clinicians acquire through clinical experience and clinical
:
practice… [without which] even excellent external evidence may be
inapplicable to or inappropriate for an individual patient.” (29).
Even excellent external evidence may be inapplicable to, or

inappropriate for, an individual patient.
Despite this injunction, the importance of patient experience and

preferences, and clinical expertise, are commonly under-emphasized
in the care delivered to individuals, and in the synthesizing of
evidence for inclusion in clinical practice guidelines (30, 31).
I have written a long criticism of such things elsewhere.
The explanatory justification doctors give for failure of, ‘I

followed the guidelines’, is inadequate (morally, intellectually
and legally).
The eminent and respected Professor John Ioannidis has recently

made an excoriating comment about EBM/guidelines and suchlike
publications:
“Despite valiant efforts to make them more evidence-based,

guidelines, recommendations and exercise of policy power
unfortunately remain among the least evidence-based activities,
impregnable strongholds of expert-based insolence and eminence-
based innumeracy {Ioannidis, 2019 #21905}.”
‘Impregnable strongholds of expert-based insolence and

eminence-based innumeracy’.
For those not familiar with the etiquette of scientific writing and
restrained expression, that is an extraordinary statement made in an
unprecedented style by someone of exceptional reputation and
standing*; and one which my readers will not be surprised to hear, I
completely agree with.
:
*Professor John Ioannidis, full list of appointments:
Stanford Prevention Research Center, Departments of Medicine,

Department of Health Research and Policy, Department of
Biomedical Data Science, Stanford, University School of Medicine,
Stanford, California; Department of Statistics, Stanford University
School of Humanities and Sciences, Stanford, California; Meta‐
Research Innovation Center at Stanford (METRICS), Stanford
University, Stanford, California
The citation stats Professor Ioannidis has clocked up are mind-

boggling: H-index 190, total citations >250,000
https://scholar.google.com.au/citations?
hl=en&user=JiiMY_wAAAAJ
Algorithms
Anyone who has read much about depression will have heard of
treatment algorithms, things like the widely-discussed [STAR*D
research]. Algorithms can be useful even if they are, perforce, mainly
based on consensus and ‘expert opinion’, because of lack of firm
evidence to choose between many of the alternatives.
It must always be remembered that no matter how authoritative such

algorithms and guidelines may be perceived as being, that they are
not better than the judgement of an experienced scientific clinician.
There are significant variations in pronouncements on the same
topics by different sets of guidelines (2-4): in my considered opinion
this reflects, among other things, the misleading and pseudo-
scientific nature of meta-analysis (see below).
It is insufficiently recognised that guidelines constrain the flexibility

of clinical practice and produce a self-fulfilling sameness in
:
treatment approaches (3, 5). For instance, this applies to the use of
MAOIs: they are only suggested as a ‘last-ditch’ measure, they are
hardly ever used, therefore there is virtually no research about them,
therefore there is no evidence to support their use.
Not an intelligent way of furthering clinical research.
There is another distinctly negative aspect to guidelines and

algorithms: regulators and policy makers may use them to censor and
control doctors, and the use of medicines. This is clearly already
happening and is exemplified by doctors who refuse to prescribe
MAOIs, when they are not ‘in the guidelines’, because the poor little
dears are ‘afraid’ — do they understand how a depressed patient
feels?
I repeat, it must be remembered that EBM tenets require; “integrating

… the best available external clinical evidence from systematic
research…[with] the proficiency and judgment that individual
clinicians acquire through clinical experience and clinical practice…
[without which] even excellent external evidence may be
inapplicable to or inappropriate for an individual patient.” (29).
The usefulness of algorithms can go beyond deciding which drug to

use, and thereby profit from the precepts of critical path analysis (see
below).
In this commentary, I am not going to go into detail concerning the

justification for the choices I present, because my reasoning and the
evidence is in the general literature, and my scientific papers, and
elsewhere on this website.
Complexities and background

It is a complex area, so background explanation is required,
:
especially for people who have not read extensively around the
subject, nor read what I have written previously.
First, I am referring exclusively to the treatment of people who have

drug responsive illnesses and who exhibit the key central changes of
anergia and anhedonia, persistently and consistently, over a period
of a month or more, and to a degree of severity which has
impaired their social, leisure and work function to a
consequential extent.
Such an assessment is best made by an experienced psychiatrist:

doctors are giving drugs to many people who do not need them (6),
this tendency is contributed to by pressures from society’s
expectations and the economics of healthcare, and you have guessed
it, drug company advertising. A connected and toxic trio of factors.
There is a compelling logical argument for stratifying the speed of

progression through the alternatives in the algorithm (it is ‘multi-
path’) depending on the degree of severity of symptoms,
and particularly the degree of functional impairment. When that
is sufficiently severe to endanger relationships, work and people’s
financial security, there is less justification for continuing minimally
effective courses of drugs and engaging ‘fine-tuning’ strategies
which may be less likely to produce substantial improvement.
This is how and where the focus on functional impairment, and the
rapidity and adequacy of improvement, relate to the ‘critical path
analysis’ dimension of the algorithm {Habert, 2016 #21763;Lam,
2016 #21765}.
Whilst most doctors would agree that urgent ECT is strongly

indicated for a severely suicidal patient who has stopped eating, there
seems to be a less clear appreciation of the general need to take
account of the medium-term destructive influence of the illness in
:
less serious cases. That is why an algorithm benefits from
incorporating a multi-lane pathway with decisions based on the
extent and speed of response balanced against the risk of harms from
treatment and deterioration of the illness.
A strong indicator of ‘biological’ depression is real improvement in

core symptomatology (7-9) within 2-3 weeks of starting an
antidepressant. A less decisive response, over a longer time, is not
good evidence of a cause-effect relationship between taking the
drug and improvement, especially when that improvement is in
‘non-core’ and less illness-specific symptoms. Failure to recognise
the key time relationship between drug administration and
improvement (or adverse effects) is a failing of much depression
research.
If a drug response is going to occur, that will usually be evident to an

experienced observer within 2-3 weeks of attaining a therapeutic
dose. It is impossible to mention assessment of improvement without
noting an ‘elephant in the room’: the problem of the sensitivity and
validity of rating-scales generally, and the much mis-used, but
ubiquitous, ‘Hamilton’ rating scale (10, 11), on which most drugs
trials rely (11-14). It is an inadequate instrument that should have
been superseded long-ago (12, 15-17). It was not well-designed to be
sensitive to change in severity of symptoms, particularly the key
‘core’ symptoms, à la Parker and colleagues (8, 9, 18).
Results from drug trials using the DSM diagnosis of MDD are prone
to include too great a percentage of cases that are unlikely to be
‘biological’ depression — see, for instance: (9, 18-22). Also, bias
from sponsorship (a huge proportion of trials are drug company
sponsored) and cases recruited in primary care*** both muddy the
waters even more — to the point of opacity — yet such trials are all
grist-to-the-uncritical-mill of meta-analysis and the formation of
:
guidelines and algorithms.
In summary: we know we are including inappropriate cases in

trials and we know we are assessing change with a poor and
outdated instrument.
That is not smart.
*** It is inconceivable that such cases are predominantly ‘biological’

depression. That explains why mainly sedative drugs like
mirtazapine appear effective: Even a small proportion ‘non-
biological’ cases contaminating the sample will invalidate most
conclusions.
Meta-analysis
If there is space for another ‘elephant in the room’ it is meta-analysis.
This procedure is the 21st century successor to Phrenology and
Psychoanalysis.
Meta-analysis is a capricious and deceitful siren.
Some time ago I coined the expression ‘Penrose stairs with drugs’
see: http://www.psychotropical.com/anti-psychotics and Heres et al.
(23). They showed ‘olanzapine beats risperidone, risperidone beats
quetiapine, and quetiapine beats olanzapine’ and the same illogical
circle (of A>B>C>A) can be replicated with almost all the AD drugs.
It is clear to anyone of a scientific mind that many trials are poor
quality data and that over-interpretation is omnipresent (24).
As I stated in ‘Atypical Anti-Psychotics and Humpty Dumpty’, it is

important to keep repeating that no meta-analysis can be better than
the original data upon which it depends (25, 26). That is the old
computation saying “GIGO”, “garbage in, garbage out”. What would
Charles Babbage have thought? well, we know, because he told us.
:
‘On two occasions I have been asked, —”Pray, Mr. Babbage, if you
put into the machine wrong figures, will the right answers come
out?” … I am not able rightly to apprehend the kind of confusion of
ideas that could provoke such a question.’
Babbage, Passages from the Life of a Philosopher.
Since it has been my view for a long time that clinical trials (many of
which are ‘pseudo-scientific’) have unjustifiably overshadowed good
clinical science and clinical experience, I am much heartened to see,
in researches for this commentary, that researchers are supporting a
re-balancing of that question. The following references are eloquent
testimony to the up-welling of the view about the unreliability of
meta-analysis, and the appropriateness of putting more weight on
scientifically conducted clinical practice (4, 25, 27-32). Several very
savvy authors are represented in these references (Altman,
Ioannidis), which are well worth checking out.
I will retain a healthy respect for my own judgement based on

clinical science and sound Bayesian logic.
Critical path analysis

Critical path analysis is a method for formalising the structure and
timing of a task and focussing more clearly on the assessment of
progress, and the means of quantifying that, and the timing of key
decisions affecting the process. It has not been utilised much in
medicine (33).
To incorporate precepts from critical path analysis a treatment plan it

needs to focus on:
A pre-defined definition of the desired outcome

:
Objective assessments of the baseline state (not self-rating scales)
including symptoms, signs and functional activity assessment
covering work, social and leisure domains.
An assessment of the degree of risk of adverse outcomes engendered

by the illness (e.g. loss of job etc.), and by any treatment.
Objective assessments of the intermediate stages of severity of the

illness (at defined treatment changes).
Predefined time periods for achieving objectives at any treatment

stage.
Both doctor and patient may consider, at each visit:
For how long has the drug been administered?
For how long has the present dose been the same? (Appendix Note 1)
What degree of improvement has so far occurred from baseline or

worst state?
What degree of risk of severe or prolonged impairment of work

social and leisure activities is there in the current situation (i.e. loss
of job, relationship separation, etc.)?
Is that improvement, and the degree of reduction of the risks,

sufficient to justify continuation of this treatment (or this dose)?
How expeditiously should we progress on the ‘critical path’?
An important aspect insufficiently prominent in some algorithms

(and treatment plans) is a clear sense of purpose and urgency about
achieving full remission and avoiding potentially irreversible life
changes (i.e. before peoples’ lives fall apart).
:
There is a too easy and uncritical acceptance of partial improvement
and of continuing in that state with unchanging treatment (Appendix
note 2).
A particular impediment to the expeditious progress of effective

treatments concerns widespread misunderstandings among doctors
about which antidepressant drugs are safe in combination and
whether there is a necessity for washout periods when changing from
one drug to another (most aspects of such interactions are covered in
the relevant sections on this website).
Another element of many of these algorithms is deficient discussion

of combination treatments and statements about drugs which are
possibly less effective. These are matters that an experienced and
knowledgeable clinical psycho-pharmacologist is well positioned to
advise on.
Difficulties with algorithms are an inevitable consequence of

schemes devised by committees, whose members often have an
insufficient depth of knowledge about pharmacology (see below).
Some academics will be miffed by that comment (cf. Prof Ioannidis

comments); but it is true, witness the extensive mis-understandings
about MAOIs and ST that still endure. Many academics should be
ashamed by their poor level of pharmacological knowledge.
This algorithm is a ‘multi-lane’ choice*. The traffic-lane analogy
helps people conceptualise what approach to treatment suits them
best, depending on their attitude to life and risk** (do you usually
drive in the fast lane or the slow lane?). Clearly, if functional
impairment is producing substantial risk of (potentially irreversible)
changes in family, work or financial status (as it so often does) then
:
the a faster-lane pathway will be preferred over a slow-lane.
** I often used to say, ‘Slow and steady wins the race, or, nothing
ventured nothing gained’, your choice.
Step 1
Sertraline (or citalopram/escitalopram)‡ or Nortriptyline*. In a great
majority of cases an SSRI, or SNRI, will already have been utilised
in primary care.
See: ‘When to consider avoiding SRIs as first choice’ in:

http://www.psychotropical.com/anti-depressants/tcas
And, re Sertraline as 1st choice SSRI, rather than (citalopram or

escitalopram) (34, 35) and: http://www.psychotropical.com/sertraline
‡It is unlikely to be useful to exceed the recommended dose with any

SSRI, with the possible exception of Sertraline, its weak DA re-
uptake potency may confer an advantage at doses around 200 mg or
more. Sertraline also has the useful advantage of linear pharmaco-
kinetics even at high dose levels (36, 37).
*NTP is the pharmacological ‘gold-standard’ TCA (38),
Step 2
An SNRI strategy. This may utilise a single drug, e.g. venlafaxine, as
has been fashionable for some years now, or a combination.
Gillman’s algorithm strongly favours two separate drugs (for reasons
explained), as in step 2a).
Step 2a
Sertraline (or citalopram/escitalopram) and nortriptyline
(NTP)*/reboxetine or 2b) clomipramine (CMI)** (SNRI strategy).
:
Or (des)venlafaxine*** or duloxetine etc.
*Sert 50 mg + NTP 50 mg may be sufficient but full doses of Sert

200 mg and NTP 150 mg may be used providing due caution is
exercised about NTP levels (in view of mild 2D6 inhibition of NTP
metabolism by high levels of Sert). Therapeutic drug monitoring (39,
40) of NTP levels is increasingly desirable if Sert in increased
beyond 200 mg daily.
**See note on CMI: http://www.psychotropical.com/clomipramine-

potent-snri-anti-depressant
***Venlafaxine has several disadvantages (relatively more toxic,

especially in the elderly (41)) and I remain unconvinced that it is a)
any better, or b) is a fully effective SNRI, and the evidence for its
superiority is poor, for evidence and refs see:
http://www.psychotropical.com/venlafaxine
Step 2b
An SNRI strategy with addition of lithium and tryptophan. This may
be preferred if factors relating to situation, illness, side-effect
considerations, patient preference etc. militate against proceeding to
step 3 with an MAOI.
Step 3a)
From Step 2a) cease sertraline, continue nortriptyline*; after one
week start tranylcypromine** (TCP); or b) cease CMI, then after
washout 1–2 weeks start TCP***
*For detailed discussion of why it is perfectly safe to combine

tranylcypromine with nortriptyline see section on this website re
MAOIs and my published papers. MAOI/TCA interaction mis-
understandings are the prime exemplar of the poor pharmacological
:
knowledge of psychiatrists.
** The need for 1–2 week washout is a powerful reason for using
SERT+ NTP, rather than Ven or CMI as the ‘SNRI’ strategy.
*** Or, in some cases phenelzine
Step 3b
To either to 2a or 2b) Use preferred augmenting strategy. There is not
strong evidence favouring a particular choice, as yet. Add Li† + L-
tryptophan, quetiapine, olanzapine, aripiprazole or T3 (lamotrigine
may have a place here, especially if BPD is known or suspected).
†I think there is a strong case for ceasing Li augmentation within 4

weeks if there is no clear response. Logically a similar approach
applies to aripiprazole and other augmenting strategies.
Step 3c
Selegiline patch, potentially with the same augmenting agents as
TCP. If the high cost of this is not a consideration it may be quite
effective in high doses, but then its advantage vis a vis tyramine is
diminished, and it is almost certainly not as effective as TCP (see
below).
Step 4a
ECT, then after course finished immediately re-introduce the most
effective previous drug strategy, + Li if not previously used.
Step 4b.1)
Augment the TCP with:
Li‡ +/- L-T +/- NTP*, or bupropion (lamotrigine may have a place
here, esp. if BPD known or suspected)
:
*either just continue NTP from step 2a) or cease it after stabilisation
on TCP and only re-introduce it if needed.
Step 4b.2)
Or, TCP + methylphenidate (or methylphenidate alone, [see separate
note]).
Notes on Gillman’s algorithm

At no stage is an AD free washout needed in my algorithm.
However, if one chooses venlafaxine or CMI in step 2b) one then has
a gap to cover (e.g. by dove-tailing doxepin* or NTP).
*Doxepin is an H1 sedative, not an AD (see (38).
My preference after step 2a) was to go straight to TCP, rather than

expend time on strategies that my experience indicated were less
likely to lead to decisive results, i.e. with various augmentation
options, e.g. lithium (see below). If TCP (or phenelzine) was not
satisfactory then augmentation can be undertaken at that stage, or
after ECT.
A critical path analysis from my experience suggests that the pay-off

with augmentation* may not be worth the delay in reaching
remission: this a where a careful assessment of the potentially
irreversible aspects of functional impairment (work, marriage,
finances) usefully guides the speed of progress through the
algorithm. Hence the reduced emphasis on Bupropion (42, 43),
which is widely preferred (in USA) especially in BPD. It also
highlights that augmentation is often continued, despite the
problems with medium-term SEs, long after it has been seen to
fail.
*The term augmentation can be held to mean the addition of a drug

:
not usually regarded as an AD in its’ own right, as opposed to
combination which usually refers to addition of a drug that is
regarded as an AD in its own right.
In step 2a) sertraline + nortriptyline is preferred (especially because

it facilitates smoother transition to TCP, but also because it enables
separate adjustment of SRI and NRI components (which cancel out
each-others’ SEs to a useful extent, e.g. 5-HT is GI pro-kinetic which
opposes the anti-kinetic effect of TCAs & NRIs).
It has been correctly noted that various combinations risk substantial

increases in the SE burden for patients (44), and possible
pharmacokinetic interactions. However, as observed elsewhere, it is
not valid to generalise about heterogeneous classes of drugs (like
TCAs and ‘atypical anti-psychotics’, see other notes about
[neuroscience-based pharmacology]). Mixing many of the old TCAs
with some SSRIs is not a good idea at all, but nortriptyline (and
sertraline) is quite different. It is a question of knowing your
pharmacology, and most aspects relating to this are discussed
elsewhere on this website (e.g. see menu heading ‘Interactions’, and
in my published papers (38, 45-54).
There has been an ebb and flow of opinion about combinations over
the last three decades. Unfortunately, much of the opinion expressed
about combinations has been unduly influenced by doctors whose
knowledge of pharmacology is inadequate (e.g. see Charpeaud
below*).
I find it hard to suppress a wry smile when I see the latest opinion
about combinations, which champions a combination of an SSRI
with reboxetine (55). I have written about this elsewhere (56), but in
brief I started using combinations of sertraline with both nortriptyline
and reboxetine back in the 1990s. Most patients seemed to prefer for
:
the former, because they found reboxetine made them feel hyped-up
and agitated (similarly to an amphetamine effect), whereas
nortriptyline did not. See also:
http://www.psychotropical.com/anti-depressants/snris
Step 3b) When using ones preferred augmenting strategy, the critical
path requirement is that an objective assessment of pre- and post-
augmentation clinical state is recorded and that a pre-defined degree
of improvement is attained in a pre-defined time-period, or that the
augmentation is ceased.
Californian rocket-fuel
I am aware of the popularity of the ‘Californian rocket-fuel’
combination (Venlafaxine + Mirtazapine) which some might choose
to use in step 2b), however my experience of the superiority of
sertraline + nortriptyline never encouraged me to try that
combination very often, especially because of my scepticism about
the claimed properties of both of those drugs and the greater toxicity
of venlafaxine. It is also important to appreciate the extent of the
deception concerning the bogus pharmacological data about
Mirtazapine, see:
http://www.psychotropical.com/mirtazapine-a-paradigm-of-
mediocre-science
*Charpeaud reported from France (57) that ‘augmenting SSRI/SNRIs

with mirtazapine/mianserin has become the most recommended
strategy of antidepressant combinations. Augmenting SSRI with
tricyclic drugs is now a less recommended strategy of antidepressant
combinations given the increased risk for the occurrence of
pharmacokinetic drug–drug inter-actions and adverse effects’.
This is yet another example of ‘lumping’ (i.e. failing to recognise that

:
the TCAs are a markedly heterogeneous group) and ignorance of
pharmacology and interactions.
I meam requiem doleat.
Lithium augmentation
The history of lithium augmentation goes back further than most
people seem to remember. Its use requires caution and care and a
discussion of relevant considerations is in most good standard texts.
We were using it extensively in London in the 1970s and I must have
been involved in treatment of hundreds of patients using this
technique by the time I had been in Australia for several years in the
mid-1980s. Once I was in private practice, I found myself using it
less and less frequently, partly because decisive improvement was
less common and partly because it was a relatively costly and
troublesome procedure (58). The trend, over more than three
decades, is of a weakening of the evidence for benefit (59), but
Nelson’s & Bauer’s reviews’ (based on low numbers) are more
positive (60, 61), for those sweet innocents who still retain faith in
meta-analysis.
It is possible that a significant contributing factor to my observation

of the poor effect of Li augmentation, was the fact that I was using
clomipramine in a great majority of patients, rather than one of the
other tricyclics. It may be that lithium is working partly, or mainly,
through a ‘serotonergic’ mechanism. In that case adding it to a non-
serotonergic TCA like amitriptyline might produce a more marked
improvement than adding it to clomipramine or tranylcypromine. It
is interesting that the evidence for augmenting of SSRIs is also
modest (62).
‘Atypical’ antipsychotics
:
Evidence has led many to favour augmentation strategies with so-
called ‘atypical’ antipsychotics, which are now in most guidelines for
partial and non-responders, at the same stage of the algorithm as
switching or combination strategies (63, 64).
Atypical antipsychotics* are heterogeneous as a group, like the

TCAs, so it is meaningless to lump them together. I have no 1st-hand
experience of the degree of benefit from any of them. I suggest there
are good reasons for using them with caution** and for regarding
this to be a questionable idea for several reasons, not the least of
which is that neuroleptics reduce DA, when much evidence indicates
that increasing DA is what is needed in depression.*** Perhaps low
doses of weak DA antagonists, like quetiapine, increase DA through
preferential blockade of pre-synaptic receptors? There is a paucity of
data and a great deal of uncertainty about both mechanism and
benefit.
There is the seriously under-recognised problem that once

antipsychotics have been started, they tend not to be ceased, even
when a lack of benefit is clear. Patients may thereby be exposed
to major side effect problems for no reason. That is a serious
error.
Questions like: which one? what dose? and for how long? need to be
answered, and promptly, because of these significant SEs, especially
in the medium to longer term, not to mention the enormous expense.
*most so-called ‘atypical antipsychotics’ (e.g. risperidone) have

tenuous claim to that ill-defined epithet.
**A suggestion of a causal link to increased mortality in older

patients (65-72).
***For discussion about this point see here

:
I do not want to seem too much like a picky scientific purist here, but
it is very important to understand that the drugs in question, these so-
called atypical antipsychotics, cannot be meaningfully grouped
together and many of them are probably not significantly different to
the older neuroleptics like CPZ and thioridazine, despite the
vociferously made claims for them. For instance, risperidone is a
pure D2 antagonists, and a very potent one at that, which is related to
the old classic antipsychotic haloperidol. On the other hand,
quetiapine is closely related to the prototypical tricyclic sedative
promazine, and like promazine is a potent antihistamine with very
weak D2 antagonism. I could go on …
https://www.drugbank.ca/structures/DB01224/image.svg
and, needless-to-say, good old chlorpromazine (73, 74). And, one

could say vis a vis promazine> chlorpromazine> quetiapine, ‘the
wheel is come full circle’ (Edmund, King Lear):
Quite how it is possible to produce a convincing, or even a vaguely

plausible, theoretical explanation of how all these different drugs
could possibly be effective augmenting agents escapes me.
Bayesian reasoning indicates that the weak evidence of efficacy is

very likely to be wrong (30, 75, 76).
Is anyone else getting a sense of Déjà Vu? Remember thioridazine in

depression? e.g. see review of Robertson & Trimble (77).
The theory is weak, the evidence is weak, but the money is good,
hugely good. Even Zuckerberg’s eyes would water. $$$, tens of
:
billions, indeed, probably hundreds of billions by now. I do not think
we need Einstein’s help on this one.
‘A triumph of hope over experience’. Johnson: Boswell’s Life of

Samuel Johnson, 1791
Further considerations about

algorithms
The issue of ‘knowing the pharmacology’ is where some of the
experts producing these algorithms have a little catching-up to do.
There are some unfortunate errors.
Prominent among the various ‘guidelines’ or ‘algorithms’ are:

American Psychiatric Association, British Association for
Psychopharmacology (78), Canadian Network for Mood and Anxiety
Treatments (79), National Institute for Health and Clinical
Excellence (80, 81), Texas Medication Algorithm Project (82), and
World Federation of Societies of Biological Psychiatry (83).
One example of a serious mistake is the suggestion that it is OK to

combine imipramine with MAOIs, and moclobemide with SSRIs
(84) — that has a risk of inducing fatal serotonin toxicity. Yet others
lump all the TCAs together as if they are inter-changeable; then there
is recommending the worst of all the SSRIs, fluvoxamine, as a 1st
line drug: if fluvoxamine (or, indeed, fluoxetine) was submitted for
registration by the FDA now it would be unlikely to be approved, and
for good reason (46). Such criticisms can hardly be over-emphasised,
since this concerns expert panels of specialists. Nevertheless, I can
assure readers that if some of the above advice was followed and it
led, as it could do, so easily, to serious adverse outcomes for patients,
then the doctor involved would find themselves on the losing side in
an expensive malpractice suit.
:
I have seen the legal argument advanced that such errors make the
producers of the guidelines vicariously liable.
Lastly, recommending moclobemide as a 1st or 2nd line AD is

absurd; moclobemide has little useful AD effect. For a drug that has
the most benign side-effect profile ever (one would therefore expect
it to be very popular), its use has shrunk, almost into oblivion. This is
a prime example of a mis-placed faith in meta-analysis.
The ‘CANMAT’ document (79); ‘3.6. How Do second-generation

antidepressants compare in efficacy?’ among other things, reports
‘mirtazapine*** is more effective than SSRIs and venlafaxine’ — we
are back in ‘Penrose stairs’ territory here. As with moclobemide,
anyone who finds mirtazapine to be an effective AD is not treating
biological depression and research that claims it is more effective
than SSRIs and venlafaxine is not credible. This is an example of
where ones clinical experience and judgement must over-ride the
artefacts generated by pseudo-scientific trials and the statistical
legerdemain of meta-analysis — see these refs on this key issue (3,
5).
***Calling mirtazapine a ‘2ndG’ drug is a bit of a stretch — it was

‘invented’ 50 years ago! ‘2ndG’ is a marketing term and has no basis
in pharmacology.
Committees do produce some strange ideas and conclusions, and

intellectual excellence less-frequently prevails in the results.
There has long been great confusion among psychiatrists concerning

what is, and is not, safe to combine. Speaking with my
pharmacologist’s hat on, I regard with despondency some of the
suggestions and recommendations that have been made, and with
dismay at the poor standard of knowledge exhibited in supposedly
informed academic work (glaring examples of this are scattered
:
throughout my commentaries).
From the many possible examples of poor knowledge I will cite,

from the recent literature, something that coincides with my
experience (e.g. (53)) of the commonly expressed errors and
misconceptions (57, 85, 86). The commonest combination used, as
indicated by clinical practice surveys, has been a combination of
fluoxetine with amitriptyline (in-a-word —stupid, because of
multiple CYP450 interactions and inducing potential toxicity). The
contents of this commentary, and the information on my website,
highlight the fact that this is one of the more ill-advised combinations
that you could dream up.
It is axiomatic that any doctor prescribing a drug must have a sound

basic knowledge of its mechanism of action and ill-effects. Such a
level of knowledge would make it plain that this was a high-risk
combination, and if significant ill-effects eventuated, the doctor
would have a poor defence in law in the case of a negligence action
brought against them.
Many of the suggestions and recommendations that are widely made

and accepted are simply ill-advised or plain wrong (see my other
commentaries and my published papers that address these issues in
detail). As an expert in this field I have practised and published
concerning various drug combinations over many years. Indeed, that
is why I am an internationally recognised expert in serotonin toxicity,
that is the ultimate drug interaction with antidepressant drugs that
psychiatrists still misunderstand, decades after they could/should
have mastered it (as exemplified by the incorrect information in some
current guidelines). It is about the only way that psychiatrists can kill
somebody within 12 hours by giving the wrong drugs e.g. Otte et al.
(87). And yet, still, they try.
:
I have frequent enquiries via the web site concerning ill-advised, and
even dangerous, combinations that specialists have contemplated, or
tried to initiate. Fortunately, some patients have educated themselves
better than their doctors (especially those who have learned from this
website and my papers).
Other combinations
Here are one or two other ‘adventurous’ combinations that have no
obvious (major) problems and at least some plausible theoretical
merit — a little caution re 2D6 interactions may be required, e.g. see
here:
Venlafaxine + bupropion (sig. 2D6 inhibitor, and both drugs are

slightly seizure promoting).
MAOI + Mirtazapine (instead of NTP) + bupropion
Selegiline* + bupropion + NTP
Moclobemide** + nortriptyline + bupropion (but not Moc + SSRI)
* Selegiline (trans-D patch), difficult to put in a cost-conscious

algorithm. It is a weak AD and very expensive. Does not boost DA as
much as TCP. For many people, does not justify the time-delay and
expense as a pre-TCP treatment: again, ‘critical-path’ considerations
aid with such decisions.
**I’m not a fan of this drug, it is a drug with such weak effects that it
is of little practical use as monotherapy. However, it clearly does do
something because it aggravates the toxicity of overdoses of SSRIs
(see section on ST). There is therefore some small theoretical merit
in the notion that it might be worth using it in combination, but not
with SRIs, because even in therapeutic doses it can lead to toxicity.
:
Concluding remarks
Guidelines and algorithms have good features, especially, as Bauer et
al. highlight, in reducing unnecessary ‘scattershot therapies’ and the
untimely (too soon and too late) switching of treatment measures
(88). No guide suggests using three, four, or even five SSRIs
sequentially: yet if I had a dollar for every poor patient I have heard
of, who has been subjected to that pointless parade of pills, I would
be a wealthy man.
Algorithms give insufficient weight to systematic evaluation of the

clinical severity after each treatment trial, as Bschor et al.
recommend (89), especially the assessment of deleterious effects of
functional changes: that is where the ‘critical path’ precepts kick in
and indicate faster progression to the next step.
There is generally an under-emphasis on the treatment of residual

symptoms (90), and that is the ‘other-side-of-the-coin’ of the fact that
doctors often settle for incomplete response in clinical practice: i.e.
they fail to set and pursue the goal of achieving complete remission.
Comments and pronouncements in relation incorrect

prohibitions concerning combining or swapping from one drug
to another are frequently incorrect and due to pharmacological
illiteracy: they lead to delays in the progression through the
treatment algorithm.
MAOIs are much under-used: I have written a deal about that over
the years: my recent editorial (2017), review and diet monograph,
sum up key information and references (52-54).
It is hard to avoid the conclusion that the training of psychiatrists in

therapeutic psychopharmacology still leaves much to be desired. A
report-card might read ‘poor standard, consistently near the bottom
:
of the class, must try harder’.
Appendix
Note 1
‘What is the duration of treatment and current dosage?’ Anyone who
cannot answer that quickly is unlikely to be able to make a logical
decision about the optimal next step.
My first entry in my medical notes, after the date of the appointment,

would always be ‘T 2/12, D 3/52; the shorthand for the total time on
drug and the time on the present dose (2/12 = two months, 3/52 =
three weeks). If you have not got that information in the forefront of
your mind every time you see a patient, you are not going to make
logical treatment decisions in a timely manner.
The key assessment is whether there is a definite improvement in

energy and motivation on the one hand, and ability to get pleasure,
enjoyment and satisfaction on the other. That is complemented by a
critical assessment of the level of functioning in work, social and
leisure activities.
Note 2
There is a too-easy and uncritical acceptance of partial improvement
and of continuing in that state with unchanging treatment.
Doctors’ weak and acquiescent acceptance of partial improvement

sets the scene for their all-to-frequent avoidant behaviour. By this I
mean giving doctors an easy excuse not to progress to treatments that
they are less competent and confident to manage. These, they
persuade themselves, are higher risk and ‘after all there is a useful
degree of improvement, so perhaps I should just settle for that’, ‘do
no harm’ they seem to say to themselves. This is doctors treating
themselves, not the patient.
:
Such thoughts and attitudes are a distortion of the mis-understood
aphorism of ‘Primum non nocere’ (first, do no harm). Contrary to
popular opinion, that has nothing to do with the ‘Hippocratic oath’
and has a tenuous claim to validity as a moral precept (91).
I make no apology for proffering the view that a proportion of

doctors simply do not have ‘therapeutic balls’. In a publication, a
little while ago, I described the attitudes to the use of MAOIs
exhibited by many doctors as ‘pusillanimous’ (92), and I have never
resiled from that view (54).
Note 3: trial methodologies

A comment about the methodologies used in trials, like STAR*D, it
is relevant. It is inevitable and undeniable that any patient sample
generated for such trials will contain individuals who were
incorrectly diagnosed and/or are never going to respond to
medication. Therefore, sequential steps will contain a larger and
larger proportion of such patients, compared to sample in previous
steps. That will make the treatments used in the subsequent steps
seem, artefactually, to be effective in a smaller % of the sample.
There is a more detailed analysis of this point [here].
Next, a useful methodology for clarifying the effectiveness vs side

effects of treatment is a trial of dosage reduction. I did this quite
often in clinical practice as a method of ascertaining the most
appropriate balance between beneficial effects and side-effects —
this would confer a double benefit: if they got worse they could then
continue the previous dose in the knowledge that whatever level of
side-effects they had was the price they had to pay for wellness,
unless they wanted to try a different drug. That constitutes a drug,
no-drug, drug, trial which, if a clear drug response occurs on both
occasions, is moderately convincing evidence that it is a drug effect
:
and not a ‘placebo’ effect.
One powerful methodology is to use a sample of patients who have

already responded decisively to antidepressant treatment, especially
ECT. That generates a good sample of ‘biological’ depressive
illnesses. Relapse is quite frequent, soon after ceasing a course of
ECT (~ 50%), for a recent review see (93). The ability of different
drug treatments to prevent, or reverse, that relapse is an instructive
index of their effectiveness.
We must also remember lithium’s proven benefits: Prudic et al. (97)

‘monotherapy with NT was distinctly inferior in relapse prevention
compared to combination NT-Li’; for recent review see review
Rasmussen (98).
A cross-over trial is like a discontinuation trial and, as explained

above, if you swap from amitriptyline to clomipramine quite a lot of
people get a better improvement. If you do the opposite, most of
them get worse.
Many supposed differences or advantages to do with AD drugs are

small, or of uncertain meaning or usefulness; however, when various
signposts all point in the same direction it may pay to heed them:
also, Bayesian logic re-enforces the power of some conclusions,
especially, that CMI is more effective than other TCAs, and that the
newer SNRIs (venlafaxine etc.) may be less effective than CMI (and
also than the NTP + Sert combination).
I strongly advocate an approach which weighs evidence using

Bayesian reasoning. I will give an example of that. There is quite a
lot of evidence that drugs that boost either serotonin, or
noradrenaline, have some effect as ‘antidepressants’. Various trials
(and a lot of clinical experience) done with the older TCAs suggested
the superiority of clomipramine over other TCAs (99-101).
:
Clomipramine is the only one of the TCAs which significantly boosts
both serotonin and noradrenaline (38). If you swap people from
amitriptyline to clomipramine quite a lot of them get a better
improvement. If you do the opposite, most of them get worse. It adds
up, one does not have to be a rocket scientist when the signposts are
pointing in the same direction.
On the other hand, consider a drug like trazodone which does not
boost either serotonin or noradrenaline. Although, as with
moclobemide, it is possible to find ‘meta-analyses’ suggesting it is an
effective AD — it is in the guidelines (102, 103), but I do not know
any psycho-pharmacologists who think it is good for serious
depression. Bayesian reasoning tells us that we would want much
stronger evidence that trazodone, or moclobemide, or vitamin A, was
effective, because it simply does not do what we think needs to be
done to improve depression. Logic dictates that we assign a lower
level of confidence to the possibility it is an AD.
Thank you, Thomas Bayes.
Note 4
I remember how often patients coming for a second opinion, or
relating the results of some previous treatment, would say how much
better they felt. After a few questions, it would be perfectly clear that
they were not in fact functioning any better: e.g. they had not got
back to work, their social and relationship functioning was no
different than previously, and they had not increased participation in
the usual hobbies and pastimes and pleasures of their previous life-
style.
In response to the reply of ‘how much better they felt’ I would

sometimes say ‘It doesn’t matter how you feel’. After allowing time
to register being surprised by that comment, from a supposedly
:
caring psychiatrist, I would go on to explain that this subjective
impression of how they felt (frequently loaded by situationally driven
subjective symptoms such as anxiety) was less important than
whether they had tangible improvement in the drive, motivation and
energy to do activities that they had ceased doing — but had
previously done whilst well — and were also getting a proper degree
of fun, pleasure, satisfaction, enjoyment, fulfilment etc. from reading,
listening to music, socialising, hobbies and pastimes, all the usual
culprits (i.e. anergia and anhedonia).
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" #
PsychoTropical Research | Dr Ken Gillman
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DEPRESSIVE ILLNESS MENU !

Depressants, General Intro

Gillman’s Antidepressant algorithm

Step 1. Sertraline (or citalopram/escitalopram) or Nortriptyline: 6

Step 2. Sertraline (or citalopram/escitalopram) combined with

Step 3). Tranylcypromine.

Cases presenting to a specialist will already be ready for step 2. This

Background: theory and considerations

*NB. Opinion in this commentary refers to AD treatment for

This commentary does not consider non-pharmacological

Thinking critically and logically about the expeditious progress of

Doctors need to be aware of how the psychology of ‘risk aversion’

Guidelines and algorithms also have a downside: they promote

The forgotten principle of evidence-based medicine

It is important to emphasise and adhere to EBM tenets: these require:

“integrating … the best available external clinical evidence from

Even excellent external evidence may be inapplicable to, or

Despite this injunction, the importance of patient experience and

I have written a long criticism of such things elsewhere.

The explanatory justification doctors give for failure of, ‘I

The eminent and respected Professor John Ioannidis has recently

“Despite valiant efforts to make them more evidence-based,

‘Impregnable strongholds of expert-based insolence and

Stanford Prevention Research Center, Departments of Medicine,

The citation stats Professor Ioannidis has clocked up are mind-

It must always be remembered that no matter how authoritative such

It is insufficiently recognised that guidelines constrain the flexibility

Not an intelligent way of furthering clinical research.

There is another distinctly negative aspect to guidelines and

I repeat, it must be remembered that EBM tenets require; “integrating

The usefulness of algorithms can go beyond deciding which drug to

In this commentary, I am not going to go into detail concerning the

Complexities and background

First, I am referring exclusively to the treatment of people who have

Such an assessment is best made by an experienced psychiatrist:

There is a compelling logical argument for stratifying the speed of

Whilst most doctors would agree that urgent ECT is strongly

A strong indicator of ‘biological’ depression is real improvement in

If a drug response is going to occur, that will usually be evident to an

In summary: we know we are including inappropriate cases in

That is not smart.

*** It is inconceivable that such cases are predominantly ‘biological’

Meta-analysis is a capricious and deceitful siren.

As I stated in ‘Atypical Anti-Psychotics and Humpty Dumpty’, it is

Babbage, Passages from the Life of a Philosopher.

I will retain a healthy respect for my own judgement based on

Critical path analysis

To incorporate precepts from critical path analysis a treatment plan it

A pre-defined definition of the desired outcome

An assessment of the degree of risk of adverse outcomes engendered

Objective assessments of the intermediate stages of severity of the

Predefined time periods for achieving objectives at any treatment

Both doctor and patient may consider, at each visit:

For how long has the drug been administered?

What degree of improvement has so far occurred from baseline or

What degree of risk of severe or prolonged impairment of work

Is that improvement, and the degree of reduction of the risks,

How expeditiously should we progress on the ‘critical path’?

An important aspect insufficiently prominent in some algorithms

A particular impediment to the expeditious progress of effective

Another element of many of these algorithms is deficient discussion